AidsInfo Drugs RSS Feed<![CDATA[Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate]]>Atripla is a fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF). Each Atripla tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. [#]

Sustiva is the brand name for efavirenz, a non-nucleoside reverse transcriptase inhibitor. Emtriva is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Viread is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Viread and Emtriva are the components of Truvada.  [#] 

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Atripla is a fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF). Each Atripla tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. [#]

Sustiva is the brand name for efavirenz, a non-nucleoside reverse transcriptase inhibitor. Emtriva is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Viread is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Viread and Emtriva are the components of Truvada.  [#] 

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[#]]]>[#]]]>Film-coated tablet containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg. [#]

The recommended adult dose of Atripla is one tablet once daily on an empty stomach, alone or in combination with other antiretroviral medications. Dosing at bedtime may improve the tolerability of nervous system symptoms. [#]

Atripla is not recommended for use in patients less than 18 years of age. [#]

Atripla should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance less than 50 mL/min). [#]
 

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One Atripla tablet is bioequivalent to one efavirenz tablet (600 mg), one emtricitabine capsule (200 mg), and one tenofovir DF tablet (300 mg) after single-dose administration to fasting healthy volunteers.  In combination studies evaluating the antiviral activity of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed. [#]

Efavirenz is an NNRTI. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination. Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and terminates the chain after incorporation into DNA. [#]

In HIV-infected patients, time-to-peak plasma concentrations (Tmax) of efavirenz were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state peak plasma concentration (Cmax) was 12.9 ± 3.7 μM (mean ± SD), plasma trough concentration (Cmin) was 5.6 ± 3.2 μM, and the area under the plasma concentration-time curve (AUC) was 184 ± 73 μM•hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. In vitro studies suggest cytochrome P450 (CYP) 3A4 and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52 to 76 hours after single doses and of 40 to 55 hours after multiple doses. Following administration of 14C-labeled efavirenz, 14% to 34% of the dose was recovered in the urine (mostly as metabolites) and 16% to 61% was recovered in feces (mostly as parent drug). [#]

Following oral administration, emtricitabine is rapidly absorbed, with the Cmax occurring at 1 to 2 hours post-dose. Following multiple-dose, oral administration of emtricitabine to 20 HIV-infected patients, the steady-state mean Cmax was 1.8 ± 0.7  μg/mL, and the mean AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg (hr)/mL. The mean steady state Cmin at 24 hours post-dose was 0.09 μg/mL.The mean absolute bioavailability of emtricitabine was 93%. In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of concentration over the range of 0.02 to 200 μg/mL. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose, the half-life is approximately 10 hours. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine, and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. [#] 

Following oral administration of a single, 300-mg dose of tenofovir DF to fasting patients, the mean Cmax (achieved in approximately 1 hour) was 296 ± 90  ng/mL, and the mean AUC was 2,287 ± 685  ng(h)/mL. The oral bioavailability of tenofovir from tenofovir DF in fasting patients is approximately 25%. In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01 to 25 μg/mL. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life is approximately 17 hours. Approximately 70% to 80% of an IV dose of tenofovir is recovered unchanged in the urine. [#]

Atripla has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures. [#]

The pharmacokinetics of efavirenz has not been studied in subjects with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance of less than 50 mL/min, Cmax and AUC0-∞ of emtricitabine and tenofovir were increased. [#]

Atripla is in FDA Pregnancy Category D. There are no adequate and well-controlled studies of Atripla in pregnant women. Pregnancy should be avoided in women receiving Atripla. Barrier contraception should always be used in combination with other methods of contraception. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Atripla is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of Atripla. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Atripla should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant online at http://www.APRegistry.com or by calling 1-800-258-4263. [#]

As of July 2009, the Antiretroviral Pregnancy Registry has received prospective reports of 661 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (606 pregnancies). Birth defects occurred in 14 of 501 live births (first-trimester exposure) and 2 of 55 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz. [#]

HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the M184V/I and K65R amino acid substitutions in the viral reverse transcriptase. [#]

In a clinical study of treatment- naïve subjects (Study 934) resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuations. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 analyzed subjects in the emtricitabine + tenofovir DF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/19 analyzed subject isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. [#]

In a clinical study of treatment- naïve subjects, isolates from 8/47 (17%) analyzed subjects receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed greater than 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution. [#]

Cross-resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions. [#]

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Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs including tenofovir DF, a component of Atripla, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Atripla should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). [#]

It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. Atripla is not approved for the treatment of chronic HBV infection, and the safety and efficacy of Atripla have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of Atripla. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Atripla. If appropriate, initiation of anti-hepatitis B therapy may be warranted. [#]

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 subjects treated with regimens containing efavirenz for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated subjects. One percent of efavirenz-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits. [#]

Fifty-three percent (531/1008) of subjects receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing efavirenz and from 3% to 5% in subjects treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms. [#]

Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated subjects were generally similar to those in the indinavir-containing control arm. Patients receiving Atripla should be alerted to the potential for additive central nervous system effects when Atripla is used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. [#]

Emtricitabine and tenofovir are principally eliminated by the kidney; however, efavirenz is not. Since Atripla is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance less than 50 mL/min should not receive Atripla. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Atripla. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera. Atripla should be avoided with concurrent or recent use of a nephrotoxic agent. [#]

In controlled clinical trials, 26% (266/1008) of subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of subjects treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in subjects treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). Atripla can be reinitiated in patients interrupting therapy because of rash. Atripla should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Experience with efavirenz in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash. [#]

Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Atripla needs to be weighed against the unknown risks of significant liver toxicity. [#]

Bone mineral density (BMD) monitoring should be considered for HIV-1 infected subjects who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. In a 144-week study of treatment-naïve subjects receiving tenofovir DF, decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir DF group and 6 subjects in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. (For additional information, consult the tenofovir DF prescribing information). Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir DF. [#]

Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.
Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels. [#]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Atripla. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. [#]

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

In Study 934, an open-label active-controlled study in which 511 antiretroviral-naïve subjects received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254), the most common adverse reactions (incidence ≥ 10%, any severity) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous studies of the individual components. [#]

In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive Atripla or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of Atripla when each was administered in combination with other antiretroviral agents. [#]

In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents:

  • Efavirenz: The most significant adverse reactions observed in subjects treated with efavirenz are nervous system symptoms, psychiatric symptoms, and rash.

             Selected adverse reactions of moderate-severe intensity observed in greater than/or equal to 2% 
             of efavirenz-treated subjects in two controlled clinical trials included pain, impaired concentration,
             abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.

             Pancreatitis has also been reported, although a causal relationship with efavirenz has not been
             established. Asymptomatic increases in serum amylase levels were observed in a significantly higher
             number of subjects treated with efavirenz 600 mg than in control subjects.

  • Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).

    Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. [#]
     
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Atripla should be taken on an empty stomach. However, Atripla has not been evaluated in the presence of food. Administration of efavirenz with a high-fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures. [#]

Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A. In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. [#]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). [#]

Drugs that are contraindicated or not recommended for use with Atripla:

  • Voriconazole: Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered.
     
  • Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine): Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
     
  • Midazolam, triazolam: Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
     
  • Bepridil: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
     
  • Cisapride: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias
    .
  • Pimozide: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
     
  • St. John’s wort (Hypericum perforatum): May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). [#]

Related drugs not for coadministration with Atripla include Emtriva (emtricitabine), Viread (tenofovir DF), Truvada (emtricitabine/tenofovir DF), and Sustiva (efavirenz), which contain the same active components as Atripla. Due to similarities between emtricitabine and lamivudine, Atripla should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). [#]

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Atripla with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. [#]

Atripla should be avoided with concurrent or recent use of a nephrotoxic agent. [#]

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics Cedia DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. For more information, please consult the Sustiva prescribing information. [#]

Established and other potentially significant drug interactions are as follows:

  • Atazanavir: Coadministration of atazanavir with Atripla is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with Atripla.
     
  • Fosamprenavir calcium: Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and Atripla with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when Atripla is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when Atripla is administered with fosamprenavir plus ritonavir twice daily.
     
  • Indinavir: The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
     
  • Lopinavir/ritonavir: A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients should be monitored for tenofovir-associated adverse reactions. Atripla should be discontinued in patients who develop tenofovir-associated adverse reactions.
     
  • Ritonavir: When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Atripla is used in combination with ritonavir.
     
  • Saquinavir: Should not be used as sole protease inhibitor in combination with Atripla.
     
  •  Maraviroc: Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with Atripla.
     
  •  Didanosine: Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with Atripla. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of Atripla and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily. For additional information, please consult the Videx/Videx EC (didanosine) prescribing information.
     
  • Warfarin: Plasma concentrations and effects potentially increased or decreased by efavirenz.
     
  • Carbamazepine: There are insufficient data to make a dose recommendation for Atripla. Alternative anticonvulsant treatment should be used.
     
  •  Phenytoin, Phenobarbital: Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
     
  •  Sertraline: Increases in sertraline dose should be guided by clinical response.
     
  •  Itraconazole: Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
     
  •  Ketoconazole: Drug interaction studies with Atripla and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
     
  • Posaconazole: Avoid concomitant use unless the benefit outweighs the risks.
     
  • Clarithromycin: Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of Atripla is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Atripla.
     
  •  Rifabutin: Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
     
  • Rifampin: Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of Atripla and rifampin have not been established.
     
  • Diltiazem: Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of Atripla is necessary when administered with diltiazem.Other calcium channel blockers (e.g., felodipine, nicardipine, nifedipine, verapamil): No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
     
  • HMG-CoA reductase inhibitors (atorvastatin, pravastatin, simvastatin): Plasma concentrations of atorvastatin, pravastatin,and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
     
  • Ethinyl estradiol/Norgestimate (oral): A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
     
  • Etonogestrel (implant): A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
     
  • Immunosuppressants (cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A): Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with Atripla.
     
  • Methadone: Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. [#]

 

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Atripla is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of Atripla. [#]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). Drugs that are contraindicated or not recommended for use with Atripla:

  • Voriconazole: Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because Atripla is a fixed-dose combination product, the dose of efavirenz cannot be altered.
     
  • Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine): Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
     
  • Midazolam, triazolam: Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
     
  • Bepridil: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
     
  • Cisapride: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
     
  • Pimozide: Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
     
  • St. John’s wort (Hypericum perforatum): May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). [#]
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[#] Emtricitabine: (2R-cis)-4-Amino-5-fluoro- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] -2(1H)-pyrimidinone [#] Tenofovir DF: Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1) [#] ]]>[#] Emtricitabine: 143491-57-0 [#] Tenofovir DF: 147127-20-6 [#] ]]>[#]

Emtricitabine: White to off-white crystalline powder. [#]

Tenofovir DF: White to off-white crystalline powder. [#]

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[#]]]>
Atripla Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60.
Gazzard BG. Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients. Expert Opin Pharmacother. 2006 Apr;7(6):793-802. Review.
Goicoechea M, Best B. Efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all? Expert Opin Pharmacother. 2007 Feb;8(3):371-82.]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Emtricitabine / Rilpivirine / Tenofovir disoproxil fumarate]]>Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) was approved by the U.S. Food and Drug Administration (FDA) on August 10, 2011. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naïve adults.

This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects comparing rilpivirine to efavirenz.

The following points should be considered when initiating therapy with Complera:

  • More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
  • The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
  • More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.

Complera is not recommended for patients less than 18 years of age.

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Complera is available as film-coated tablets. Each tablet contains 200 mg of emtricitabine (FTC),
27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine) and 300 mg of tenofovir disoproxil fumarate (tenofovir DF or TDF, equivalent to 245 mg of tenofovir disoproxil).

Dosage and administration

Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal.

Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).

Pediatric Use: Complera is not recommended for patients less than 18 years of age because not all the individual components of the Complera have safety, efficacy and dosing recommendations available for all pediatric age groups.

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Mechanism of Action

Complera is a fixed-dose combination of antiviral drugs emtricitabine, rilpivirine and tenofovir disoproxil fumarate.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Rilpivirine: Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Tenofovir Disoproxil Fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Pharmacodynamics

Effects on Electrocardiogram
The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 4.8 (8.2) milliseconds (i.e., below the threshold of clinical concern). When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of rilpivirine.

Pharmacokinetics

Complera: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), rilpivirine, emtricitabine and tenofovir exposures were bioequivalent when comparing Complera to Emtriva capsules (200 mg) plus Edurant tablets (25 mg) plus Viread tablets (300 mg) following single-dose administration to healthy subjects (N=34). Single-dose administration of Complera tablet to healthy subjects under fasted conditions provided approximately 25% higher exposure of rilpivirine compared to administration of Emtriva capsules (200 mg) plus Edurant tablets (25 mg) plus Viread tablets (300 mg), while exposures of emtricitabine and tenofovir were comparable (N=15).

Emtricitabine: Following oral administration, emtricitabine is absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of Emtriva to 20 HIV-1 infected subjects, the mean steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 μg per mL and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr per mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg per mL. The mean absolute bioavailability of Emtriva capsules was 93%. Less than 4% of emtricitabine binds to human plasma proteins in vitro over the range of 0.02 to 200 μg per mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine, approximately 14% in the feces and 13% is recovered as metabolites in the urine. The metabolites of emtricitabine include 3′-sulfoxide diastereomers (approximately 9% of the dose) and the glucuronic acid conjugate (approximately 4% of the dose). Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with creatinine clearance >80 mL per minute of 213 ± 89 mL per minute (mean ± SD). The plasma emtricitabine half-life is approximately 10 hours.

Rilpivirine: The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naive HIV-1 infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects. After oral administration, the Cmax of rilpivirine is achieved within 4–5 hours. The absolute bioavailability of rilpivirine is unknown. Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism by the cytochrome CYP3A system. The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14Crilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (less than 1% of dose) were detected in urine.

Tenofovir Disoproxil Fumarate: Following oral administration of a single 300 mg dose of Viread to HIV-1 infected subjects in the fasted state, Cmax was achieved in one hour. Cmax and AUC values were 0.30 ± 0.09 μg per mL and 2.29 ± 0.69 μg•hr per mL, respectively. The oral bioavailability of tenofovir from Viread in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro over the range of 0.01 to 25 μg per mL. Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with creatinine clearance >80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Effects of Food on Oral Absorption
Take Complera with a meal. A food effect trial was not conducted for Complera. Therefore, the specific effect of food with Complera tablets on rilpivirine, emtricitabine and tenofovir exposure has not been established. The recommendation to administer Complera with a meal is based on the increased exposure that was observed when rilpivirine tablets were administered under fed conditions.

Special Populations
Pediatric Patients
Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in adolescent subjects (12 to less than 18 years of age). The pharmacokinetics of rilpivirine in pediatric subjects have not been established.

Patients with Renal Impairment
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax, and AUC of emtricitabine and tenofovir were increased. Rilpivirine: Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction.

Patients with Hepatic Impairment
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Rilpivirine: Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of Viread have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

Hepatitis B and/or Hepatitis C Virus Coinfection
Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in hepatitis B and/or C virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to rilpivirine.

Antiviral Activity

Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate: The triple combination of emtricitabine, rilpivirine, and tenofovir was not antagonistic in cell culture.

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 μM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine, and rilpivirine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.

Rilpivirine: Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM. Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510 to 10830 nM). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 to 1.01 nM and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM. The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 coreceptor antagonist maraviroc or the integrase strand transfer inhibitor raltegravir.

Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 μM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from1.6 μM–5.5 μM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.

Resistance

In Cell Culture
Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir. Rilpivirine: Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.

In Treatment-Naïve HIV-1-infected Subjects
In a pooled resistance analysis for subjects receiving rilpivirine in combination with emtricitabine/tenofovir DF in clinical trials C209 and C215, the emergence of resistance among subjects was greater in the rilpivirine arm compared to the efavirenz arm. In the combined studies, 44% (34/77) of the virologic failures in the rilpivirine arms had genotypic and phenotypic resistance to rilpivirine compared to 23% (10/43) of the virologic failures in the efavirenz arms who had genotypic and phenotypic resistance to efavirenz. Moreover, phenotypic and/or genotypic resistance to emtricitabine and tenofovir emerged in 51% (39/77) and 9% (7/77) of the virologic failures, respectively, in the rilpivirine arms compared to 16% (7/43) and 9% (4/43) in the efavirenz arms. Emerging NNRTI substitutions in the rilpivirine virologic failures included V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6–621. The E138K substitution emerged most frequently on rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V emerged more frequently in rilpivirine virologic failures compared to efavirenz virologic failures.

Cross Resistance

Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate:
In Cell Culture
No significant cross-resistance has been demonstrated between rilpivirine-resistant HIV-1 variants and emtricitabine or tenofovir, or between emtricitabine- or tenofovirresistant variants and rilpivirine.

Rilpivirine:
Site-Directed NNRTI Mutant Virus
Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.

In Treatment-Naïve HIV-1-infected Subjects
Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, H221Y, F227C, M230I or M230L. Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the pooled analysis for subjects receiving rilpivirine in combination with emtricitabine/tenofovir DF in clinical trials C209 and C215, 34 virologic failure subjects had evidence of rilpivirine resistance. Of these subjects, 91% (N=31) were resistant to etravirine and efavirenz, and 65% (N=22) were resistant to nevirapine. In the efavirenz arm, none of the 10 efavirenz-resistant virologic failures were resistant to etravirine at failure. Subjects experiencing virologic failure on rilpivirine developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz.

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the substitutions associated with NNRTI resistance K103N or rilpivirine-associated substitutions were susceptible to emtricitabine.

Tenofovir Disoproxil Fumarate: The K65R substitution selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Viread. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response. HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or rilpivirine-associated substitutions were susceptible to tenofovir.

Pregnancy
Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) is in FDA pregnancy category B. Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120-times higher than human exposures at the recommended daily dose. Rilpivirine: Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Complera should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Complera, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com.

Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that tenofovir is secreted in milk. Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether emtricitabine, rilpivirine, or tenofovir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Complera.

For complete information, see full prescribing information for Complera.

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Warnings: Lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B.

Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of Complera, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Complera should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV
It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy. Complera is not approved for the treatment of chronic HBV infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of Complera. In some patients infected with HBV and treated with Emtriva, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Complera. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Complera. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera. Complera should be avoided with concurrent or recent use of a nephrotoxic agent. Emtricitabine and tenofovir are principally eliminated by the kidney; however, rilpivirine is not. Since Complera is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance below 50 mL per minute should not receive Complera.

Drug Interactions
Caution should be given to prescribing Complera with drugs that may reduce the exposure of rilpivirine. In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N=1368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N=686) or efavirenz (N=682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Complera, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Decreases in Bone Mineral Density
Bone mineral density (BMD) monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Tenofovir Disoproxil Fumarate: In a 144 week study of HIV-1 infected treatment-naive adult subjects treated with tenofovir DF (Study 903), decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir DF group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir DF group and 6 subjects in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the Viread prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Complera. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) are insomnia and headache. Treatment-emergent adverse drug reactions of at least moderate intensity (≥ Grade 2) that occurred in less than 2% of subjects treated with rilpivirine plus any of the allowed background regimen (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous and glomerulonephritis mesangioproliferative.

The most common adverse drug reactions occurred in at least 10% of treatment-naive subjects in a phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another antiretroviral agent are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In addition, adverse drug reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

]]>
Take Complera with a meal. A food effect trial was not conducted for Complera. Therefore, the specific effect of food with Complera tablets on rilpivirine, emtricitabine and tenofovir exposure has not been established. The recommendation to administer Complera with a meal is based on the increased exposure that was observed when rilpivirine tablets were administered under fed conditions.

Complera should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:

  • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
  • the antimycobacterials rifabutin, rifampin, rifapentine
  • proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
  • the glucocorticoid systemic dexamethasone (more than a single dose)
  • St. John’s wort (Hypericum perforatum)

Complera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir DF (Emtriva, Edurant, VIread, Truvada, Atripla), with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil (Hepsera).

Complera is a complete regimen for the treatment of HIV-1 infection; therefore, Complera should not be administered with other antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. Please refer to the Edurant, Viread and Emtriva prescribing information as needed. There were no drug-drug interaction trials conducted with the fixed-dose combination tablet. Drug interaction studies were conducted with emtricitabine, rilpivirine, or tenofovir DF, the components of Complera.

Drugs Inducing or Inhibiting CYP3A Enzymes
Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.  Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

Drugs Increasing Gastric pH
Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.

Drugs Affecting Renal Function
Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of Complera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.

QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

  • Antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate). The combination of Complera and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after Complera.
  • Azole Antifungal Agents: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole. Concomitant use of Complera with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when Complera is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with Complera.
  • H2-Receptor Antagonists: cimetidine, famotidine, nizatidine, ranitidine. The combination of Complera and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after Complera.
  • Macrolide Antibiotics: clarithromycin, erythromycin, troleandomycin. Concomitant use of Complera with clarithromycin, erythromycin and troleandomycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
  • Narcotic Analgesics: methadone. No dose adjustments are required when initiating coadministration of methadone with Complera. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Drugs with No Observed or Predicted Interactions with Complera
No clinically significant drug interactions have been observed between emtricitabine and the following medications: famciclovir or tenofovir DF. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, or tacrolimus in studies conducted in healthy subjects. No clinically significant drug interactions have been observed between rilpivirine and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, sildenafil, or tenofovir DF. No clinically relevant drug-drug interaction is expected when rilpivirine is coadministered with ribavirin.

]]>
Complera should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:
 

  • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
  • the antimycobacterials rifabutin, rifampin, rifapentine
  • proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
  • the glucocorticoid systemic dexamethasone (more than a single dose)
  • St. John’s wort (Hypericum perforatum[#]
]]>
Emtricitabine: C8H10FN3O3S

Rilpivirine hydrochloride: C22H18N6 • HCl

Tenofovir disoproxil fumarate: C19H30N5O10P • C4H4O4
 

]]>
Emtricitabine: 247.24

Rilpivirine hydrochloride: 402.88

Tenofovir disoproxil fumarate: 635.52
 

]]>
Emtricitabine: white to off-white crystalline powder

Rilpivirine hydrochloride: white to almost white powder

Tenofovir disoproxil fumarate: white to off-white crystalline powder
 

]]>
Emtricitabine: solubility of approximately 112 mg per mL in water at 25°C

Rilpivirine hydrochloride: practically insoluble in water over a wide pH range

Tenofovir disoproxil fumarate: 13.4 mg per mL in water at 25°C
 

]]>
PDF]. A more current version may be available on the manufacturer's web site.]]> Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264
]]>
Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264
]]>
<![CDATA[Enfuvirtide]]>[#]]]>[#]]]>[#] [#]

Enfuvirtide continues to be studied to determine if it will decrease the level of HIV in resting CD4 cells in patients already on antiretroviral therapy or starting an antiretroviral drug regimen for the first time. [#] [#]]]>
[#]]]>[#]

The recommended dose of enfuvirtide for adults is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen. [#] For children age 6 to 16 years, the recommended dose is 2 mg/kg twice daily (maximum dose 90 mg twice daily). The manufacturer's prescribing information provides pediatric dosing guidelines by weight. Insufficient data are available to establish a recommended dose for children younger than 6 years of age. [#]

Each injection should be given at a different site from the preceeding injection site and only where there is no ongoing injection site reaction from a previous dose. Enfuvirtide should not be injected near any areas of the body where large nerves course close to the skin, such as near the elbow, knee, groin, or the inferior or medial sections of the buttocks; skin abnormalities, including directly over a blood vessel; into moles, scar tissue, or bruises; or near the navel, surgical scars, tattoos, or burn sites. [#]]]>
[#]

Store reconstituted solution under refrigeration at 2°C to 8°C (36°F to 46°F) and
use within 24 hours. [#]]]>
[#]

The initial step of HIV-1 entry into the human host cell is the binding of virions with the CD4 molecule and chemokine coreceptor molecules (CXCR4 or CCR5) on the surface of the target cell. Entry of HIV-1 into the target cell is mediated by two viral envelope glycoproteins, gp120 and gp41, which form complexes that facilitate entry of the virion into the host cell. The surface glycoprotein gp120 mediates CD4 and coreceptor binding. The function of the transmembrane glycoprotein gp41 is to anchor the gp120-gp41 glycoprotein complex within the viral envelope and mediate envelope-host cell membrane fusion. [#]

After gp120 interactions with CD4 and the coreceptors, conformational changes occur in gp41 that expose a fusion peptide located near the N-terminus, which is believed to insert into the target cell membrane. It is thought that the bridged target cell and viral membranes are brought together via two heptad repeats (HR1 and HR2) within gp41. Studies have shown that HR1 and HR2 are essential for virus-host cell fusion to occur. Enfuvirtide corresponds to a linear 36-amino acid sequence within HR2 and likely interacts with a target sequence in HR1, inhibiting association with native HR2 and preventing apposition of the viral and cellular membranes. [#]

The mean maximum plasma concentration (Cmax) following a single 90-mg subcutaneous (SQ) injection of enfuvirtide into the abdomen in 12 HIV-1-infected subjects was approximately 4.59 mcg/mL; area under the plasma concentration-time curve (AUC) was approximately 55.8 mcg hr/mL; the median time to maximum plasma concentration (Tmax) was 8 hours (ranging from 3 to 12 h). The absolute bioavailability (using a 90-mg IV dose as a reference) was approximately 84.3%. Following 90-mg twice-daily dosing of SQ enfuvirtide in combination with other antiretroviral agents in 11 HIV-1-infected patients, the mean steady-state Cmax was approximately 5.0 mcg/mL and AUC from zero to 12 hours was approximately 48.7 mcg hr/mL. The median Tmax was 4 hours (ranging from 4 to 8 h). Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh, or arm. [#]

The mean steady-state volume of distribution after IV administration of a 90-mg dose of enfuvirtide was approximately 5.5 liters. Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 mcg/mL. It is bound predominantly to albumin and to a lower extent to alpha-1 acid glycoprotein. [#]

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. Mass balance studies to determine elimination pathways of enfuvirtide have not been performed in humans. In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC. [#]

After a 90-mg single SQ dose of enfuvirtide in 12 patients, the mean elimination half-life was approximately 3.8 hours and the mean apparent clearance was approximately 24.8 +/- 4.1 mL/h/kg. Following 90-mg twice-daily dosing of enfuvirtide SQ in combination with other antiretroviral agents in 11 HIV-1-infected patients, the mean apparent clearance was approximately 30.6 +/- 10.6 mL/h/kg. [#]

Enfuvirtide is in FDA Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Enfuvirtide should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to enfuvirtide and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by either calling 1-800-258-4263 or accessing the Web site at http://www.APRegistry.com. It is not known whether enfuvirtide is distributed into human milk; however, because of the potential for HIV transmission and serious adverse effects in nursing infants, mothers should be instructed not to breastfeed while they are taking enfuvirtide. [#]

Formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with hepatic insufficiency. Analysis of plasma concentration data from participants in clinical trials indicated the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. No dose adjustment is recommended for patients with impaired renal function. [#]

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro. Genotypic analysis of the in vitro-selected resistant isolates showed mutations resulting in amino acid substitutions at the enfuvirtide binding HR1 domain (positions 36 to 38) of the HIV-1 envelope gp41. Phenotypic analysis of site-directed mutants at positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide. [#]

Enfuvirtide exhibited additive to synergistic effects in vitro when combined with individual members of various antiretroviral classes, including zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz. In vitro studies of enfuvirtide in combination with an investigational HIV-1 entry inhibitor, PRO542, and with an investigational CXCR4 blocker, AMD-3100, indicated that these compounds show synergistic antiviral activity. It is unknown whether this synergy will translate into clinical benefit. [#] [#]

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from patients failing an enfuvirtide-containing regimen. Post-treatment HIV-1 virus from 227 patients experiencing virologic failure at 48 weeks exhibited decreases in susceptibility to enfuvirtide. The decreased susceptibility ranged from 0.4- to 6318-fold (median 33.4-fold) relative to their respective baseline virus and coincided with genotypic changes in the codons encoding gp41 HR1 domain amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45. [#]

HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, and protease inhibitors were susceptible to enfuvirtide in cell culture. [#]]]>
[#]

The majority of local injection site reactions were associated with mild to moderate pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Infection at the injection site, including abscess and cellulitis, was reported in 1.7% of study patients receiving enfuvirtide. Ninety-eight percent of patients had at least one local injection site reaction, and 7% of patients discontinued enfuvirtide treatment due to these reactions. [#]

Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course through the skin, bruising, and hematomas have occurred with use of the needle-free device provided with the product. Individuals taking anticoagulants or who have hemophilia or other coagulation disorders may have a higher risk of postinjection bleeding after enfuvirtide use. [#]

An increased rate of bacterial pneumonia was observed in trial patients treated with enfuvirtide compared to control patients. Risk factors for pneumonia included low initial CD4 count, high initial viral load, IV drug use, smoking, and a prior history of lung disease. [#] Because it was unclear whether the higher incidence rate of pneumonia was related to enfuvirtide use, an observational study in 1,850 HIV-infected patients (740 enfuvirtide-treated patients and 1,110 nonenfuvirtide-treated patients) was conducted to evaluate the risk of pneumonia in patients treated with enfuvirtide. Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with enfuvirtide compared to nonenfuvirtide-treated patients. It is unclear if the increased incidence of pneumonia is related to enfuvirtide use. However, because of these findings, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions that may predispose them to pneumonia. [#]

Hypersensitivity reactions have been associated with enfuvirtide therapy and may recur on rechallenge. Hypersensitivity reactions have included rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in patients receiving enfuvirtide include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue enfuvirtide and should seek medical evaluation immediately. Therapy with enfuvirtide should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified. [#]

There is a theoretical risk that enfuvirtide use may lead to the production of anti-enfuvirtide antibodies that cross react with HIV gp41. This could result in a false-positive enzyme-linked immunosorbent assay (ELISA) diagnostic HIV test in HIV-uninfected patients. A confirmatory western blot test would be expected to be negative in such cases. [#]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including enfuvirtide. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis, which may necessitate further evaluation and treatment. [#]]]>
in vitro study, enfuvirtide is not an inhibitor of CYP450 enzymes. In a human metabolism study, enfuvirtide, at the recommended dose of 90 mg twice daily, did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19, or CYP2E1 substrates. [#]

Coadministration of ritonavir, saquinavir/ritonavir, and rifampin did not result in clinically significant pharmacokinetic interactions with enfuvirtide. No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral medication. [#]

Enfuvirtide exhibited additive to synergistic effects in vitro when combined with individual members of various antiretroviral classes, including zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz. In vitro studies of enfuvirtide in combination with an investigational HIV-1 entry inhibitor, PRO542 [#], and with an investigational CXCR4 blocker, AMD-3100 [#] indicated that these compounds show synergistic antiviral activity. It is unknown whether this synergy will translate into clinical benefit.]]>
[#]]]>[#] ]]>[#] 262434-79-7 [#] ]]>[#]]]>[#]]]>[#]]]> Fuzeon Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, Goodgame JC, Gallant JE, Volberding P, Murphy RL, Valentine F, Saag MS, Nelson EL, Sista PR, Dusek A. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses. 2002 Jul 1;18(10):685-93.
Lazzarin A. Enfuvirtide: the first HIV fusion inhibitor. Expert Opin Pharmacother. 2005 Mar;6(3):453-64.
Manfredi R, Sabbatani S. A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20). Curr Med Chem. 2006;13(20):2369-84. Review.
Oldfield V, Keating GM, Plosker G. Enfuvirtide: a review of its use in the management of HIV infection. Drugs. 2005;65(8):1139-60.
Price RW, Parham R, Kroll JL, Wring SA, Baker B, Sailstad J, Hoh R, Liegler T, Spudich S, Kuritzkes DR, Deeks SG. Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin. Antivir Ther. 2008;13(3):369-74.
Rockstroh JK, Mauss S. Clinical perspective of fusion inhibitors for treatment of HIV. J Antimicrob Chemother. Epub 2004 Mar 24.
Shalit P, True A, Thommes JA; QUALITE Investigators. Quality of life and tolerability after administration of enfuvirtide with a thin-walled needle: QUALITE Study. HIV Clin Trials. 2007 Jan-Feb;8(1):24-35.
Wright D, Rodriguez A, Godofsky E, Walmsley S, Labriola-Tompkins E, Donatacci L, Shikhman A, Tucker E, Chiu YY, Chung J, Rowell L, Demasi R, Graham N, Salgo M. Efficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patients. HIV Clin Trials. 2008 Mar-Apr;9(2):73-82.]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
Durham, NC 27707
Phone: 919-419-6050
Fax: 919-419-1816]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
<![CDATA[Maraviroc]]>[#]]]>[#]]]>[#] In April 2007, the FDA's Antiviral Drugs Evaluation Committee unanimously recommended accelerated approval of maraviroc for treatment-experienced patients. [#] Maraviroc received accelerated approval by the FDA on August 6, 2007. The accelerated approval was based on 24-week, interim data from two ongoing trials. [#] [#] After evaluation of longer-term safety and efficacy data, the FDA granted full approval of maraviroc on November 25, 2008. [#] On November 20, 2009, the FDA approved a supplemental new drug application (NDA) to expand the indication for maraviroc to include combination antiretroviral treatment of therapy-naïve adults infected with CCR5-tropic HIV-1 virus. [#]

The expanded indication of maraviroc to treatment-naïve adults is based upon data collected through 96 weeks from Study A4001026, demonstrating safety and efficacy. In this Phase 2b/3 study of treatment-naïve subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was lower for maraviroc compared to efavirenz (1.8 compared to 2.4 events per 100 patient-years of exposure). [#]

Maraviroc is approved for use in combination with other antiretroviral (ARV) medications for the treatment of adults infected with only CCR5-tropic HIV-1 (R5 virus). In treatment-naïve subjects, more subjects treated with maraviroc experienced virologic failure and developed lamivudine resistance compared to efavirenz. The safety and efficacy of maraviroc have not been established in pediatric patients. Maraviroc is not approved for use in patients 16 years of age or younger. [#] [#] [#] Safety and efficacy are not established in treatment-naive HIV infected people or in those with dual- or mixed-tropic or with CXCR4-tropic virus. [#] Tropism testing with a highly sensitive tropism assay is required for the appropriate use of maraviroc. [#]]]>
[#]]]>
- When given with potent CYP3A inhibitors (with or without a CYP3A inducer)--including protease inhibitors (except tipranavir/ritonavir); delavirdine; ketoconazole, itraconazole, clarithromycin; and other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)--the recommended dose is maraviroc 150 mg twice daily.
- When given with NRTIs, tipranavir/ritonavir, nevirapine, raltegravir, and other drugs that are not potent CYP3A inhibitors or CYP3A inducers, the recommended dose is maraviroc 300 mg twice daily.
- When given with potent CYP3A inducers (without a potent CYP3A inhibitor)--including efavirenz; rifampin; etravirine; and carbamazepine, phenobarbital, and phenytoin--the recommended dose is maraviroc 600 mg twice daily. [#]

Safety and efficacy have not been established in pediatric patients; therefore, maraviroc should not be used in patients younger than 16 years of age. [#]

For patients with impaired renal function (CrCl ≤ 80 mL/min), recommended doses of maraviroc are based on the results of a pharmacokinetic study conducted in healthy subjects with various degrees of renal impairment. The pharmacokinetics of maraviroc in subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function. No dose adjustment is recommended for patients with mild or moderate renal impairment receiving maraviroc with or without a potent CYP3A inhibitor or inducer. [#]

If patients with severe renal impairment or end-stage renal disease (ESRD) not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and it is contraindicated for these patients. [#]]]>
[#]]]>
[#] Maraviroc did not display efficacy against CXCR4-tropic or mixed- or dual-tropic virus in Phase II efficacy studies. [#]

Peak plasma concentrations (Cmax) of maraviroc are achieved between 0.5 and 4 hours after single oral doses of maraviroc 1,200 mg in healthy volunteers. Maraviroc pharmacokinetics are not dose proportional. The absolute bioavailability of a 100-mg dose is 23% and is predicted to be 33% after a 300-mg dose. [#]

Maraviroc is metabolized by the cytochrome P450 (CYP) liver enzyme system, primarily by CPY3A; metabolites of maraviroc are inactive against HIV-1. The terminal half-life of maraviroc at steady-state is between 14 and 18 hours. Maraviroc, rather than metabolites, was the main component recovered. [#]

Maraviroc is moderately protein bound (approximately 76%) and has a volume of distribution of approximately 194 liters. Renal clearance accounts for approximately 25% of total clearance of maraviroc. [#] A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in subjects with severe renal impairment and end-stage renal disease (ESRD) to healthy volunteers.  Geometric mean ratios for maraviroc Cmax and AUCinf were 2.4-fold and 3.2-fold higher respectively for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher respectively for subjects with ESRD as compared to subjects with normal renal function in this study. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous maraviroc 300 mg single-dose studies in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this study were 50% lower than that observed in previous studies. Based on the results of this study, no dose adjustment is recommended for patients with renal impairment receiving maraviroc without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, their dose should be reduced to 150 mg twice daily. [#] 

In addition, the study compared the pharmacokinetics of multiple dose maraviroc in combination with saquinavir/ritonavir 1000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment and moderate renal impairment to healthy volunteers with normal renal function. Subjects received 150 mg of maraviroc at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared to healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 50% higher, 20% higher, and 43% lower, respectively for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax, and Cmin were 16% higher, 29% lower, and 85% lower, respectively for subjects with moderate renal impairment (dosed every 48 hours) compared to healthy volunteers (dosed every 12 hours). Based on the data from this study, no adjustment in dose is recommended for patients with mild or moderate renal impairment. [#]

Maraviroc is in Pregnancy Category B. No adequate and well-controlled studies have been conducted in pregnant women. However, the incidence of fetal malformations in animal studies, conducted at doses up to 20-fold higher than recommended human doses, was not increased. To monitor maternal-fetal outcomes of pregnant women exposed to maraviroc and other ARV medications, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 800-258-4263. [#]

In a small, Phase I study conducted in 2003, 24 HIV infected adults with CCR5-tropic HIV were randomized to receive maraviroc 25 mg once daily, 100 mg twice daily, or placebo. Steady-state drug levels were reached within 7 days, with more favorable drug levels achieved in the fasted state. By Day 14, those receiving 100 mg doses had experienced a viral load decline of more than 20-fold compared with a nearly threefold reduction in the 25-mg group. The drug was well tolerated, and viral load did not rebound immediately upon cessation of the drug, indicating that a proportion of the receptors remain blocked for some time. [#]

Interim Week 24 results of the two Phase IIb/III placebo-controlled studies MOTIVATE-1 and -2 indicate that treatment with maraviroc plus optimized background therapy (OBT) leads to superior viral control compared with OBT alone. These studies are following a total of 1,049 participants, residing in Europe, Australia, Canada, and the United States, who are triple class resistant, had baseline viral loads of more than 5,000 copies/ml, and had baseline CD4 counts of approximately 150 cells/mm3. With maraviroc treatment, these participants had viral load reductions of as much as 99% from baseline at a dosage of maraviroc 300 mg once or twice daily while on OBT. CD4 counts in these participants also increased by 56% to 74% from baseline during this time period. [#] Long-term Week 48 data demonstrate that maraviroc plus OBT significantly increase CD4 count compared with OBT alone. In addition, 3 times as many participants receiving maraviroc plus OBT achieved undetectable viral load levels compared with those receiving OBT alone. [#]

Because the impairment of CCR5 could have a negative impact on regular immune function, safety studies have been performed in both healthy and HIV-1 infected people at doses of up to 1,200 mg of maraviroc daily for 10 to 28 days. These studies showed that maraviroc did not have an effect on immune function, and no increased frequency or severity in infections was seen. However, an increase in CD4 count also was not seen over this time period. [#]

In an evaluation of 973 treatment-experienced patients in two ongoing Phase III trials, important predictors of virologic success (viral load less than 400 copies/ml at 24 weeks) included the mean predicted trough concentration of maraviroc, the baseline viral load, and the baseline CD4 count. [#]

In the Phase III MERIT study, maraviroc 300 mg twice daily was compared with efavirenz 600 mg once daily, both in combination with zidovudine/lamivudine. A total of 721 treatment-naïve, HIV-infected patients with CCR5-tropic virus and without evidence of HIV resistance were selected to participate. Rates of virologic suppression to less than 400 copies/mL and less than 50 copies/mL were greater in the efavirenz-treated arm and did not reach criteria for noninferiority of maraviroc. [#] [#]

However, a 2008 reanalysis of the MERIT data that used a newer, more sensitive tropism assay identified 104 of the original 721 patients who actually harbored CXCR4-tropic virus. After their exclusion, analysis of only patients with CCR5-tropic virus resulted in Week 48 virologic suppression rates of 68.5% and 68.3% for maraviroc- and efavirenz-treated arms, respectively, which met criteria for maraviroc noninferiority. [#]

HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell cultures. In an in vitro study using six primary CCR5 HIV-1 isolates, those able to replicate in the presence of high maraviroc concentrations emerged gradually after multiple passages of all isolates. Two isolates resistant to maraviroc continued to use the CCR5 receptor and one isolate developed the ability to use the CXCR4 receptor. In the viruses that remained R5 tropic, two different sets of mutations developed in the gp120 V3 loop region; this and other data suggest that changes in viral tropism are independent of maraviroc. [#] [#] All CCR5 antagonists bind to CCR5 in a pocket formed by transmembrane helices and extracellular loop 2 (ECL2); it appears that subtle differences in occupation of the binding pocket may block replication of some HIV strains. As a result, scientists are optimistic that resistance to an HIV coreceptor antagonist will not necessarily lead to drug class resistance. [#]

Clinical resistance to maraviroc has not yet been fully defined. Virologic failure has been associated with viral tropism switches that occur over time. In an examination of 5 participants who had CCR5-tropic virus at the time of treatment failure while on maraviroc, all 5 had mutations at position 13 or 26 of the V3 loop of CCR5. In an examination of 20 participants who had CXCR4-tropic virus at the time of treatment failure while on maraviroc, 14 participants experienced outgrowth of CXCR4-tropic virus that was undetectable at study entry, whereas 6 experienced a tropism switch. [#] Of the 1,043 patients with R5 virus at screening for the 2 ongoing Phase III trials, 7.6% displayed dual- or mixed-tropism at baseline measurements taken approximately 5 weeks later. In subsequent interim analysis, CXCR4-tropic virus was identified in approximately 60% of patients who failed treatment on maraviroc compared with 6% of patients who experienced treatment failure while on placebo. [#]]]>
[#]

The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. Prescribers should use caution when administering maraviroc to patients with preexisting liver dysfunction or who are co-infected with viral hepatitis B or C. [#]

In the two Phase II/III MOTIVATE-1 and -2 studies, adverse effects at Week 24 interim analysis were similar to those that occurred with optimized background therapy (OBT) alone. In these studies, 5% or fewer study participants in both placebo and treatment groups discontinued treatment because of adverse events. [#]

These two studies showed no increase in mortality or malignancy and no clear evidence of hepatotoxicity. However, an increase in Candida, herpes, and influenza infections were observed in these studies. [#]

In 24-week analysis of these two clinical studies, the most common maraviroc-related adverse effects (occurring in more than 8% of patients and more often than in the placebo group) were cough, fever, upper respiratory infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness. Additional adverse effects noted with greater incidence in the once-daily treatment arm included diarrhea, edema, sleep disorders, rhinitis, and urinary abnormalities. Serious adverse events occurred in less than 2% of maraviroc-treated patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia, myositis, osteonecrosis, and rhabdomyolysis. Grade 3 to 4 treatment-emergent laboratory abnormalities occurring in at least 2% of patients included increased bilirubin, amylase, lipase, AST, and ALT levels. [#] At Week 48 analysis of the same studies, the most commonly observed adverse events in the maraviroc plus OBT arm were diarrhea, nausea, fatigue, and headache, all of which occurred with similar incidence in the OBT-only arm. [#]

One case of possible drug-associated hepatotoxicity with allergy has been reported in a study of healthy volunteers. Systemic allergic reaction prior to the onset of hepatotoxicity may involve pruritic rash, eosinophilia, or increased IgE levels. Although no statistically significant increases in Grade 3 to 4 liver function tests have been reported, an increased rate of hepatic adverse events has been observed in treatment-experienced patients. Immediate evaluation and possible discontinuation of maraviroc are warranted in patients exhibiting signs or symptoms of hepatotoxicity, including systemic rash reactions or abnormal liver function tests. [#] To date, only 6% of patients in clinical studies have been coinfected with hepatitis B or C virus; large-scale clinical trials with coinfected individuals are needed to determine the risk of hepatic adverse events in these patients. Maraviroc should be prescribed to patients with HIV and hepatitis coinfections with caution. [#] [#]

Immune reconstitution syndrome has also been reported. In addition, patients taking maraviroc should be monitored for risk of infection because of CCR5-antagonism effects on some immune cells. [#]

Cardiovascular events, including myocardial ischemia or infarction, have been observed at higher rates in maraviroc-treated patients than in placebo. During Phase 3 studies of treatment-experienced individuals, eleven participants (1.3%) who received maraviroc had cardiovascular events including myocardial ischemia and/or infarction (in a total exposure of 609 patient-years, 300 on once daily and 309 on twice daily maraviroc), while no participants who received placebo had such events (total exposure 111 patient-years). The participants who experienced cardiovascular events generally had cardiac disease or cardiac risk factors prior to maraviroc use, and the relative contribution of maraviroc to these events is not known. [#]

In a Phase 2b/3 study of treatment-naïve adults, 3 subjects (0.8%) who received maraviroc had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for maraviroc and efavirenz, respectively). [#]

An increase in Candida, herpes, and influenza infections were observed in these studies. [#]

Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with end-stage renal disease (ESRD) due to increased maraviroc exposure. Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of maraviroc in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily. [#]

Immune reconstitution syndrome has also been reported. Maraviroc antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. During Phase 3 treatment-experienced studies of maraviroc, the overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups. In maraviroc treatment arms, there were higher rates of certain upper respiratory tract infections and a higher incidence of Herpes virus infections, but a lower rate of pneumonia, compared to placebo. Patients should be monitored closely for evidence of infections while receiving maraviroc. [#]

While no increase in malignancy has been observed with maraviroc, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. [#]

QT prolongation has been observed in animal studies at up to 12 times the recommended human dosage, but no prolongation has been noted in treatment-experienced patients taking recommended dosages. When maraviroc was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when maraviroc was given at the recommended dose to HIV-infected participants in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). [#] The dose-limiting adverse effect in clinical studies, observed at daily doses of maraviroc 600 mg, is postural hypotension. [#] Caution should be used when administering maraviroc in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. [#]]]>
[#]

Maraviroc is a cytochrome P450 (CYP) 3A and p-glycoprotein (Pgp) substrate and may require dosage adjustments when administered with CYP- or Pgp-modulating medications. CYP3A/Pgp inhibitors such as ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir, and atazanavir increase maraviroc Cmax and AUC; CYP3A/Pgp inducers such as carbamazepine, phenytoin, phenobarbital, rifampin, and efavirenz decrease maraviroc Cmax and AUC. Tipranavir/ritonavir, a CPY3A inhibitor but a Pgp inducer, does not affect maraviroc pharmacokinetics. [#]]]>
[#]]]>[#] ]]>[#] ]]>[#]]]>[#]]]> Lieberman-Blum SS, Fung HB, Bandres JC. Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection. Clin Ther. 2008 Jul;30(7):1228-50.
MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis. 2008 Jul 15;47(2):236-41.
Ndegwa S. Maraviroc (Celsentri) for multidrug-resistant human immunodeficiency virus (HIV)-1. Issues Emerg Health Technol. 2007 Dec;(110):1-8.
Vandekerckhove L, Verhofstede C, Vogelaers D. Maraviroc: integration of a new antiretroviral drug class into clinical practice. J Antimicrob Chemother. 2008 Jun;61(6):1187-90. Epub 2008 Apr 9.
Nelson, M, Fatkenheuer, G, Konourina I, Lazzarin, A, Clumeck, N, Horbam, A, Tawadrous M, Sullivan, J, Mayer, H, van der Ryst, E. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic, ART-experienced Patients Infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-Week Results. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 104aLB, 2007.
Lalezare, J, Goodrich, J, DeJesus, E, Lampiris, H, Gulick, R, Saag, M, Redgway, C, McHale, M, van der Ryst, E, Mayer, H. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/3 Study in the US and Canada. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 104bLB, 2007.]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
<![CDATA[Raltegravir]]>ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor.

Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

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ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor.

Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

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ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, 3class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naïve adults.

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

The safety and efficacy of ISENTRESS have not been established in pediatric patients.

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Film-coated tablets containing raltegravir 400 mg.

DOSAGE AND ADMINISTRATION

For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food.

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Mechanism of Action
Raltegravir is an HIV-1 antiviral drug.

Pharmacodynamics
In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.

In the randomized, double-blind, placebo-controlled, dose-ranging trial, Protocol 005, and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.

Effects on Electrocardiogram
In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).

Pharmacokinetics
Absorption
Raltegravir is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.

The absolute bioavailability of raltegravir has not been established.

In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 μM(hr) and C12hr of 142 nM.

Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.

Effect of Food on Oral Absorption
ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

Distribution
Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 μM.

Metabolism and Excretion
The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravirglucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.

Special Populations
Pediatric
The pharmacokinetics of raltegravir in pediatric patients has not been established.

Age
The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Race
The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Gender
A study of the pharmacokinetics of raltegravir was performed in healthy adult males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.

Hepatic Impairment
Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal Impairment
Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.

UGT1A1 Polymorphism
There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).

Drug Interactions
(See Drug and Food Interactions below. For additional information, consult the Isentress complete prescribing information).

Microbiology

Mechanism of Action
Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture
Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.

Resistance
The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N).

Treatment-Naïve Subjects: By Week 96 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 10 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates.

Treatment-Experienced Subjects: By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8- to 159-fold) compared to the wild-type reference.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category C
ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.

Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).

Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5-to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.

Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1800-258-4263.

Nursing Mothers
Breast-feeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1.

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats. There were no effects in rat offspring attributable to exposure of ISENTRESS through the milk.

]]>
Immune Reconstitution Syndrome
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.

Clinical Trials Experience
The most common adverse reactions of moderate to severe intensity (≥2%) which occurred at a higher rate than the comparator are insomnia and headache.

Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

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ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

Effect of Raltegravir on the Pharmacokinetics of Other Agents
Raltegravir does not inhibit (IC50>100 μM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50>50 μM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine, darunavir/ritonavir.

Effect of Other Agents on the Pharmacokinetics of Raltegravir
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS should be increased during coadministration with rifampin. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

Selected Drug Interactions:

HIV-1-Antiviral Agents
• Atazanavir: Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.

• Atazanavir/ritonavir: Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.

• Efavirenz: Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.

• Etravirine: Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.

• Tipranavir/ritonavir: Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.

Other Agents
• Omeprazole: Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.

• Rifampin: Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

]]>
[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]> Isentress Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Anker M, Corales RB. Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs. 2008 Jan;17(1):97-103.
Evering TH, Markowitz M. Raltegravir: an integrase inhibitor for HIV-1. Expert Opin Investig Drugs. 2008 Mar;17(3):413-22.
Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-9.
Harris M, Larsen G, Montaner JS. Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. AIDS. 2008 Jun 19;22(10):1224-6.
Cooper D, Gatell J, Rockstroh J, Katlama C, Yeni P, Lazzarin A, Chen J, Xu X, Isaacs R, Teppler H, Nguyen BY, and the BENCHMRK-1 Study Group. 48-Week Results from BENCHMRK-1, a Phase III Study of Raltegravir in Patients Failing ART With Triple-Class Resistant Virus. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, Abstract 788, 2008.
Steigbigel R, Kumar P, Eron J, Schechter M, Markowitz M, Loufty M, Zhao J, Isaacs R, Nguyen B, Teppler H, and the BENCHMRK-2 Study Group. 48-Week Results from BENCHMRK-2, a Phase III Study of Raltegravir in Patients Failing ART With Triple-Class Resistant Virus. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, Abstract 789, 2008.
A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies. Available at: http://clinicaltrials.gov/show/NCT00293267. Accessed 02/06/09.
A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies. Available at: http://clinicaltrials.gov/show/NCT00293254. Accessed 02/06/09.]]>
West Point,  PA 19486
Phone: 800-672-6372]]>
West Point,  PA 19486
Phone: 800-672-6372]]>
<![CDATA[Delavirdine]]>[#] ]]>[#] ]]>[#] [#] ]]>[#] ]]>
The recommended dose of delavirdine for adults is 400 mg (four 100 mg or two 200 mg tablets) three times daily, used in combination with other antiretroviral therapy. [#] ]]>
[#] ]]>
[#]

Delavirdine is rapidly absorbed following oral administration. [#] The bioavailability of delavirdine 100 mg tablets is increased by approximately 20% when the medication is dissolved in water prior to administration; however, this is not necessarily a preferred method of administration in patients able to swallow oral tablets. Delavirdine 200 mg tablets do not readily disperse in water and should be swallowed intact. [#] When multiple doses of delavirdine were administered with food, peak plasma concentration (Cmax) was reduced by approximately 25%, but area under the plasma concentration-time curve (AUC) and minimum plasma concentration (Cmin) were not altered. [#]

Delavirdine is distributed predominantly into blood plasma. [#] Delavirdine is approximately 98% bound to plasma proteins, principally albumin. The percentage that is protein bound is constant over delavirdine concentrations of 0.23 to 89.5 mcg/mL. [#] In HIV-1 infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in the saliva of HIV-infected patients and in the semen of healthy volunteers were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval. [#]

Delavirdine is in FDA Pregnancy Category C; no adequate and well-controlled studies of delavirdine have been conducted in pregnant women. [#] It is not known whether delavirdine crosses the placenta in humans, but this does occur in laboratory animals. Delavirdine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to delavirdine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. [#] It is not known whether delavirdine is distributed into human breast milk; however, it is distributed into milk in rats. Breastfeeding is not recommended for HIV-infected mothers because of the potential for HIV transmission to the breastfed infant. [#]

Delavirdine is extensively converted to several inactive metabolites. It is primarily metabolized by cytochrome P(CYP) 450 3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Delavirdine reduces the activity of CYP3A, thereby inhibiting its own metabolism. Inhibition of CYP3A by delavirdine is reversible within 1 week after discontinuation of therapy. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. [#] [#]

Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. [#] Mean elimination time from plasma is approximately 5.8 hours following treatment with 400 mg three times a day. The apparent half-life increases with dose. The time to peak plasma concentration is approximately 1 hour. The mean steady-state concentration in plasma is approximately 16.1 mcg/mL following doses of 400 mg three times a day. Systemic exposure as measured by the AUC is approximately 82.8 mcg/mL per hour; trough concentration is approximately 6.9 mcg/mL. The median AUC in female patients is 31% higher than in male patients. [#]

In a study of six healthy adults who received multiple doses of delavirdine, approximately 44% of the radiolabeled dose was recovered in feces and approximately 51% of the dose was excreted in urine as metabolites. Less than 5% of the dose was recovered unchanged in urine. [#] The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated; however, delavirdine is metabolized primarily by the liver and should be used with caution in patients with impaired hepatic function. [#]

Resistant virus emerges rapidly when delavirdine is used as monotherapy. Acquisition of a single mutation can confer resistance to delavirdine. Genotypic analysis of viral isolates from patients receiving delavirdine and zidovudine revealed that 84% had resistance-associated mutations after 24 weeks of therapy. Mutations occurred predominantly at HIV RT amino acid position 103, and to a lesser extent, at positions 181 and 236. [#]

Delavirdine may confer cross-resistance to other NNRTIs when used alone or in combination. [#] Cross-resistance between nucleoside reverse transcriptase inhibitors or protease inhibitors (PIs) is unlikely. [#] ]]>
[#]

Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving delavirdine. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue delavirdine and consult a physician.

Adverse events of moderate to severe intensity reported by at least 5% of patients receiving delavirdine in clinical trials involved the following systems: body as a whole (generalized abdominal pain, asthenia, fatigue, fever, flu syndrome, headache, and localized pain); digestive (diarrhea, nausea, and vomiting); nervous (anxiety, depressive symptoms, and insomnia); and respiratory (bronchitis, cough, pharyngitis, sinusitis, and upper respiratory tract infections. [#]

Postmarketing adverse events not reported in clinical trials have included hepatic failure, hemolytic anemia, rhabdomyolysis, and acute kidney failure. Because these events were observed during clinical practice, their frequency cannot be determined. [#] ]]>
[#]

Dose adjustment of delavirdine and/or other drugs may be necessary in patients receiving concomitant therapy with drugs that are extensively metabolized by, induce or inhibit CYP3A, CYP2C9, CYP2D6, and CYP2C19. Delavirdine may inhibit the metabolism of and is predicted to result in clinically important plasma concentration increases in certain amphetamines; anticoagulants (warfarin); anti-infectives (clarithromycin, dapsone, rifabutin, and saquinavir); sedative hypnotics (alprazolam, midazolam, triazolam); cardiovascular agents (nifedipine, quinidine); ergot alkaloids and derivatives; GI drugs (cisapride); HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin); immunosuppressive agents (cyclosporine, sirolimus, tacrolimus); methadone; or sildenafil. [#]

Due to the potential for serious reactions such as risk of myopathy including rhabdomyolysis, concomitant use of lovastatin or simvastatin with delavirdine is not recommended. [#]

Because delavirdine is an inhibitor of CYP3A, concomitant use with an HIV PI may result in increased plasma concentrations of the PI. Delavirdine may inhibit metabolism of indinavir, increasing the Cmax and AUC of indinavir. Although no pharmacokinetic studies have been performed, the possibility exists that delavirdine may increase plasma concentrations of amprenavir and lopinavir. Concomitant use of delavirdine with nelfinavir may result in increased concentration of nelfinavir and decreased concentration of delavirdine and the active nelfinavir metabolite (nelfinavir hydroxy-t-butylamide). Concomitant use of delavirdine with saquinavir may result in increased AUC of saquinavir. Recent studies indicate that concomitant administration of delavirdine and ritonavir may result in a 70% increase of ritonavir trough concentrations and ritonavir systemic exposure. [#]

Pharmacokinetic studies evaluating concomitant use of delavirdine and other NNRTIs have not been performed. [#]

Doses of delavirdine and buffered preparations of didanosine should be separated by at least 1 hour. [#]

Concurrent administration of delavirdine with aluminum and magnesium oral suspension decreased the AUC for delavirdine by approximately 44%; patients should be advised not to take antacids within 1 hour of taking delavirdine. [#]

Coadministration of St. John's wort or St. John's wort-containing products with NNRTIs, including delavirdine, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of delavirdine and lead to loss of virologic response and possible resistance to delavirdine and other NNRTIs. [#]

Concurrent use of delavirdine with carbamazepine, phenobarbital, or phenytoin substantially decreases the trough plasma concentration of delavirdine. [#]

Cimetidine, famotidine, nizatidine, and ranitidine increase gastric pH and may reduce absorption of delavirdine; long-term use of these medications with delavirdine is not recommended. [#]

Concurrent administration of delavirdine with clarithromycin increases the AUC for delavirdine by approximately 44%. The AUC for clarithromycin increases by approximately 100%. [#]

Concurrent administration of delavirdine and fluoxetine increases the trough plasma concentration of delavirdine by approximately 50%. [#]

Concurrent administration of delavirdine and ketoconazole increases the trough plasma concentration of delavirdine by approximately 50%. [#]

Concurrent administration of delavirdine with rifabutin or rifampin decreases the AUC for delavirdine by approximately 80% and 96%, respectively, and increases the AUC for rifabutin by at least 100%. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#]

100 mg: white, capsule-shaped tablets marked with "U3761."
200 mg: white, capsule-shaped tablets marked with "RESCRIPTOR200mg." [#] ]]>
[#] ]]>
Rescriptor Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Engelhorn C, Hoffmann F, Kurowski M, Stocker H, Kruse G, Notheis G, Belohradsky BH, Wintergerst U. Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children. AIDS. 2004 Jul 2;18(10):1473-5.
Harrigan PR, Hertogs K, Verbiest W, Larder B, Yip B, Brumme ZL, Alexander C, Tilley J, O'Shaughnessy MV, Montaner JS. Modest decreases in NNRTI susceptibility do not influence virological outcome in patients receiving initial NNRTI-containing triple therapy. Antivir Ther. 2003 Oct; 8(5):395-402.
Smith PF, Dicenzo R, Forrest A, Shelton M, Friedland G, Para M, Pollard R, Fischl M, DiFrancesco R, Morse GD. Population pharmacokinetics of delavirdine and N-delavirdine in HIV-infected individuals. Clin Pharmacokinet. 2005;44(1):99-109.
Yazdanpanah Y, Sissoko D, Egger M, Mouton Y, Zwahlen M, Chene G. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. BMJ. 2004 Jan 31;328(7434):249. Epub 2004 Jan 23.]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
<![CDATA[Efavirenz]]>[#]]]>[#]]]>Efavirenz was approved by the U.S. Food and Drug Administration (FDA) on September 17, 1998, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Efavirenz was approved under the FDA's accelerated review process, which allows approval based on analysis of surrogate markers or response, such as T-cell counts and HIV RNA viral levels, rather than clinical endpoints such as disease progression or survival. The safety and efficacy of efavirenz in children less than 3 years of age have not been established. [#]

Efavirenz should not be used as a single agent or add on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as a monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance. [#]

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[#] ]]>Capsules containing efavirenz 50 mg or 200 mg
Tablets (film-coated) containing efavirenz 600 mg. [#]

Adult Patients
The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms. [#]

Efavirenz must be given in combination with other antiretroviral medications. [#]

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or six 50-mg capsules). Efavirenz tablets should not be broken. [#]

Pediatric Patients
It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The recommended dose of efavirenz for pediatric patients 3 years of age or older weighing between 10 kg and 40 kg is shown below. The recommended dosage of efavirenz for pediatric patients weighing greater than 40 kg is 600 mg once daily. [#]

Pediatric Dose to be Given Once Daily [#]

Body Weight                                                                     Dose (mg)
10 to less than 15 kg  (22 to less than 33 lbs)            200
15 to less than 20 kg  (33 to less than 44 lbs)            250
20 to less than 25 kg  (44 to less than 55 lbs)            300
25 to less than 32.5 kg  (55 to less than 71.5 lbs)     350
32.5 to less than 40 kg  (71.5 to less than 88 lbs)     400
at least 40 kg  (at least 88 lbs)                                       600

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[#]]]>
Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase (RT). It has no inhibitory effect on HIV-2 RT or human cellular DNA polymerases alpha, beta, gamma, or delta. [#]

Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in peak plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady state, mean Cmax, mean trough plasma drug concentration (Cmin), and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time-to-peak plasma concentrations were approximately 3to 5 hours and steady-state plasma concentrations were reached in 6 to10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM(h). [#]

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Administration of a single 600-mg dose of efavirenz capsules with a high-fat/highcaloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [#]

Efavirenz is highly bound (approximately 99.5% to 99.75%) to human plasma proteins, principally albumin. In HIV infected patients who received 200 mg to 600 mg of efavirenz once a day for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26% to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately threefold higher than the nonprotein-bound (free) fraction of efavirenz in plasma. [#]

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 mg to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22% to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). [#]

Efavirenz has a terminal half-life of 52 to76 hours after single doses and 40 to 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14% to 34% of the radiolabel was recovered in the urine and 16% to 61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. [#]

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. [#]

Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values (8.5 to 17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82 to 160 μM) only at concentrations well above those achieved clinically. The inhibitory effect on CYP3A is expected to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. [#]

Efavirenz is in FDA Pregnancy Category D. Efavirenz may cause fetal harm when administered during pregnancy, especially in the first trimester of pregnancy. If efavirenz is used during the first trimester of pregnancy or if pregnancy occurs while the patient is taking efavirenz, the patient should be appraised of the potential harm to the fetus. No adequate and well-controlled studies have been performed in pregnant women. In prospective reports, birth defects have occurred in 14 of 501 live births (first-trimester exposure) and 2 of 55 live births (second/third-trimester exposure). One of these reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been reported: however, this case included severe oblique facial clefts and amniotic banding, a known association with anopthalmia. Six retrospective reports identified findings consistent with neural tube defects, including meningomyelocele, in mothers exposed to efavirenz during the mother's first trimester. Although a causal relationship has not been established, similar defects have been observed in preclinical studies of efavirenz. [#]

Pregnancy should be avoided in women receiving efavirenz. Two methods of birth control, with a barrier method in combination with a nonbarrier method such as an oral or other hormonal contraceptive, should be used to avoid pregnancy in women taking efavirenz. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of the drug is recommended. Before initiating therapy with efavirenz, women of childbearing potential should undergo pregnancy testing. It is recommended that efavirenz not be given to pregnant women except in situations in which there are no therapeutic alternatives. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to efavirenz. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known if efavirenz is secreted in human milk, efavirenz is secreted into the milk of lactating rats. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breastfeed if they are receiving efavirenz. [#]

In cell culture, HIV-1 isolates with reduced susceptibility to EFV (>380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT. [#]

Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 were observed in patients failing treatment with EFV in combination with IDV, or with ZDV plus LAM. The mutation K103N was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4 to106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased EFV susceptibility in cell culture with a median 88-fold change in EFV susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). [#]

Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as EFV-resistant were also phenotypically resistant in cell culture to DLV and NVP compared to baseline. DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to EFV. [#]

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Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits. [#]

Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 weeks to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms. Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm. Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. [#]

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). Efavirenz can be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Rash was reported in 26 of 57 pediatric patients (46%) treated with efavirenz capsules. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered. [#]

Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity. [#]

Convulsions have been observed in patients being treated with efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels. [#]

Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating efavirenz therapy and at periodic intervals during therapy. [#]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. During the first phase of combination antiretroviral treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may require further evaluation and treatment. [#]

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients. [#]

The most common (greater than 5%) efavirenz-associated adverse reactions of at least moderate severity are rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. [#]

Clinical adverse experiences observed in greater than 10% of 57 pediatric patients aged 3 to 16 years who received efavirenz capsules, nelfinavir, and one or more NRTIs in Study ACTG 382 were rash (46%), diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting (16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%). The incidence of nervous system symptoms was 18% (10/57). One patient experienced Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued because of rash. [#]

]]>
It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Administration of a single 600-mg dose of efavirenz capsules with a high-fat/highcaloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [#]

Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions must be considered before and during therapy. [#]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). [#]

Drugs That Are Contraindicated or Not Recommended for Use With Efavirenz:

  • Antimigraine: ergot derivatives dihydroergotamine, ergonovine, ergotamine, acute ergot toxicity characterized by peripheral vasospasm and methylergonovine. Potential for serious and/or life-threatening reactions such as ischemia of the extremities and other tissues.
  • Benzodiazepines: midazolam, triazolam. Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
  • Calcium channel blocker: bepridil. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • GI motility agent: cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • Neuroleptic: pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • St. John’s wort (Hypericum perforatum). May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). [#]

Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs. Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. [#]

Established and Other Potentially Significant Drug Interactions:

  • Fosamprenavir calcium. Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.
  • Atazanavir. Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime).Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended.
  • Indinavir. The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. When indinavir at an increased dose (1000 mg every 8 hours) was given with efavirenz (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
  • Lopinavir/ritonavir. Lopinavir/ritonavir tablets should not be administered once-daily in combination with efavirenz. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with efavirenz with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with efavirenz.
  • Ritonavir. When ritonavir 500 mg q12h was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz is used in combination with ritonavir.
  • Saquinavir. Should not be used as sole protease inhibitor in combination with efavirenz.
  • Maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
  • Warfarin. Plasma concentrations and effects potentially increased or decreased by efavirenz.
  • Carbamazepine. There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
  • Anticonvulsants (phenytoin, phenobarbital). Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
  • Sertraline. Increases in sertraline dosage should be guided by clinical response.
  • Voriconazole. Efavirenz and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz  tablets should not be broken.
  • Itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
  • Ketoconazole. Drug interaction studies with efavirenz and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
  • Posaconazole. Avoid concomitant use unless the benefit outweighs the risks.
  • Clarithromycin. Plasma concentrations decreased by efavirenz; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with efavirenz.
  • Rifabutin. Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
  • Rifampin. Clinical significance of reduced efavirenz concentrations is unknown. Dosing recommendations for concomitant use of efavirenz and rifampin have not been established.
  • Diltiazem. Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
  • Other Calcium Channel Blockers (eg, felodipine, nicardipine, nifedipine, verapamil). No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
  • HMG-CoA reductase inhibitors (atorvastatin pravastatin simvastatin). Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
  • Ethinyl estradiol/ Norgestimate, oral. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
  • Etonogestrel, implant. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
  • Immunosuppressants (cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A). Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
  • Methadone. Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. [#]

Based on the results of drug interaction studies, no dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir disoproxil fumarate, and zidovudine. [#]

Specific drug interaction studies have not been performed with efavirenz and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. [#]

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics CEDIA DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAU Multi-Level THC assay showed false-positive results. The other two assays provided true-negative results. The effects of efavirenz on cannabinoid screening tests other than these three are unknown. The manufacturers of cannabinoid assays should be contacted for additional information regarding the use of their assays with patients receiving efavirenz. [#]

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Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of its components. [#]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). [#]

Drugs That Are Contraindicated or Not Recommended for Use With Efavirenz:

  • Antimigraine: ergot derivatives dihydroergotamine, ergonovine, ergotamine, acute ergot toxicity characterized by peripheral vasospasm and methylergonovine. Potential for serious and/or life-threatening reactions such as ischemia of the extremities and other tissues.
  • Benzodiazepines: midazolam, triazolam. Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
  • Calcium channel blocker: bepridil. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • GI motility agent: cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • Neuroleptic: pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • St. John’s wort (Hypericum perforatum). May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). [#]
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[#] ]]>[#] ]]>[#]]]>[#]]]> Sustiva Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Arendt G, de Nocker D, von Giesen HJ, Nolting T. Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf. 2007 Mar;6(2):147-54.
Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J, Riddler SA, Reichman R, Shikuma C, Meyer WA 3rd, Klingman KL, Gulick RM; ACTG A5166s Protocol Team. Plasma HIV-1 RNA Dynamics in Antiretroviral-Naive Subjects Receiving either Triple-Nucleoside or Efavirenz-Containing Regimens: ACTG A5166s. J Infect Dis. 2007 Apr 15;195(8):1169-76. Epub 2007 Mar 6.
Landovitz RJ, Angel JB, Hoffmann C, Horst H, Opravil M, Long J, Greaves W, Fätkenheuer G. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis. 2008 Oct 15;198(8):1113-22.
Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, Maartens G. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS. 2008 Oct 18;22(16):2117-25.
ter Heine R, Scherpbier HJ, Crommentuyn KM, Bekker V, Beijnen JH, Kuijpers TW, Huitema AD. A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations. Antivir Ther. 2008;13(6):779-87.
Wintergerst U, Hoffmann F, Jansson A, Notheis G, Huss K, Kurowski M, Burger D. Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J Antimicrob Chemother. 2008 Jun;61(6):1336-9. Epub 2008 Mar 13.]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Etravirine]]>[#]

In vitro, etravirine has equipotent activity against wild-type HIV and NNRTI-resistant variants that encode L100I, K103N, Y181C, Y188L, and G190A/S mutations. [#]]]>
[#]

In vitro, etravirine has equipotent activity against wild-type HIV and NNRTI-resistant variants that encode L100I, K103N, Y181C, Y188L, and G190A/S mutations. [#]]]>
[#] The required confirmatory data for traditional approval of etravirine was approved by the FDA on November 24, 2009. The etravirine labeling was updated to include results through 48 weeks of dosing for the two Phase 3 trials TMC125-C206 and TMC125-C216 in treatment-experienced patients. [#]]]>[#]]]>Tablets containing etravirine 100 mg or 200 mg. [#]

Treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents:

  • The recommended oral dose of etravirine tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. [#]
     
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[#] TMC125 is a highly flexible compound with low in vitro toxicity. [#] TMC125 has garnered attention because of its activity against NNRTI-resistant HIV strains. [#]

A substantial improvement in the relative oral bioavailabililty of TMC125 was achieved with new tablet formulation, compared with tablet formulations used in initial studies. In the TMC125-C170 trial, all 45 HIV uninfected participants received 1 reference dose of 400 mg TMC125. After a 2-week washout period, participants received 1 of 4 test formulations of TMC125. Pharmacokinetics of TMC125 were assessed for 96 hours postdose. Results indicated marked increases in the area under the concentration-time curve (AUC) and the maximum serum concentration (Cmax) for all test formulations compared with the reference dose. The time to maximum concentration (Tmax) and the elimination half-life were similar for all treatments. Less intersubject variability was observed for the test formulations compared with the reference dose. Treatment with TMC125 was generally safe and well tolerated. The new tablet formulation also reduces pill burden. [#]

Several studies of TMC125 in HIV infected people have been promising. In the TMC125-C207 study conducted in London, England, TMC125's effectiveness in HIV infected men with documented efavirenz resistance taking an NNRTI-containing regimen was evaluated. In this open-label, Phase IIa study of 16 HIV infected men with 10- to 500-fold resistance to efavirenz, treatment with TMC125 for 7 days resulted in a median decrease in viral load of slightly less than 10-fold. Seven patients (44%) had a viral load decrease greater than 10-fold. There was no relationship between response to the drug and patient genotype or phenotype. [#] [#]

In the TMC125-C208 trial conducted in the Russian Federation in 2001, a 7-day monotherapy course of TMC125 at a dosage of 900 mg twice daily was given to 12 HIV infected, antiretroviral therapy (ART)-naive patients. The treatment duration was limited to 7 days to prevent the selection of NNRTI-resistant mutants, because a rapid emergence of resistance has been observed for first-generation NNRTIs when given as monotherapy. TMC125-C208's results were compared to the Dutch ERA study that took place between 1997 and 2000, which evaluated the effect of a 5-drug, triple-class ART regimen in ART-naive individuals with either primary or chronic HIV-1 infection. Analysis indicated that 1 week of TMC125 monotherapy resulted in a similar decline in viral load compared with 1 week of therapy with a 5-drug regimen. The apparent ability of TMC125 to substantially reduce HIV viral load in only 7 days of monotherapy suggests that starting treatment with a TMC125-containing regimen could provide better long-term suppression of HIV replication. [#]

In the TMC125-C223 trial, 199 HIV infected patients with NNRTI- and PI-resistant HIV were randomly assigned to receive an investigator-selected background therapy of TMC125 at either 400 mg or 800 mg twice daily or a standard-of-care regimen. At Week 24, viral load was reduced by more than 90% in the 2 TMC125 treatment arms compared with less than 50% in the control arm. These reductions in each treatment arm were statistically significant when compared individually with the control arm. [#] [#] Week 48 analysis indicated mean HIV viral load log10 reductions of -0.88, 1.01, and -0.14 for the 400-mg, 800-mg, and standard-of-care groups, respectively. At Week 48, TMC125 showed high rates of sustained efficacy in these heavily pretreated patients. Analysis of response compared with baseline resistance suggests that TMC125 retains activity in the presence of multiple NNRTI mutations, a situation in which current NNRTIs are not expected to be effective. [#]

Updated results from the two Phase 3 trials TMC125-C206 and TMC125-C216 confirm the efficacy of etravirine. At Week 48, 70.8% of etravirine-treated patients achieved HIV-1 RNA less than 400 copies/mL as compared to 46.4% of placebo-treated patients. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log10 copies/mL for etravirine-treated patients and -1.46 log10 copies/mL for placebo-treated patients. The mean CD4+ cell count increase from baseline for etravirine-treated patients was 96 cells/mm3 and 68 cells/mm3 for placebo-treated patients. [#]

Highly treatment-experienced HIV infected patients with drug-resistant HIV may benefit from using TMC125 together with darunavir, a protease inhibitor (PI) approved by the FDA in 2006. Five men started taking twice-daily darunavir 600 mg with ritonavir 100 mg, and twice-daily 20-mg TMC125, with a combination of nucleoside reverse transcriptase inhibitors and/or enfuvirtide. Viral load, CD4 count, and safety parameters were followed from baseline to Week 24; genotypic resistance was assessed at baseline and on the most recent blood sample with detectable viral load. About a month after initiating study treatment, TMC125 coadministered with ritonavir-boosted darunavir were well tolerated. Interim results at Week 4 for the first four study participants indicate that viral load decreased and CD4 count increased, with no PI-associated mutations observed by Week 4. [#]

DUET-1 and DUET-2 are two randomized, double-blind, Phase III trials that evaluated the safety and efficacy of etravirine compared with placebo. Both treatment and control arms were administered in combination with background antiretroviral therapy that contains ritonavir-boosted darunavir, nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. All enrolled patients have documented, treatment-resistant HIV. At Week 24 analysis of 591 patients enrolled in DUET-2, TMC125 was statistically superior to the control arm; 75% of patients receiving TMC125 had a viral load less than 400 copies/ml compared with 54% of patients in the control arm. [#] Of the 612 patients enrolled in DUET-1, Week 24 analysis was similar, with a more than 100-fold reduction in viral load seen in the TMC125 arm compared with a 50-fold reduction in the control arm. [#]

In the ongoing Phase III trials of TMC125 combined with ritonavir-boosted darunavir, 13 NNRTI-associated mutations that decreased viral response to TMC125 were observed during interim analyses. V179F, Y181V, Y106I, and V179O appeared in the patients who were considered the worst responders to treatment. The V179F and Y181C mutations always appeared together; this combination has been observed in approved NNRTIs, such as efavirenz and nevirapine, as well. Virologic response, measured by the 50% effective concentration (EC50), decreased proportionally with the increasing number of mutations. Complete resistance appears rare, but intermediate resistance to TMC125 may be likely. Only 15% of trial participants displayed 3 or more resistance-associated mutations; these participants displayed the largest decrease in virologic response. [#] [#]]]>
[#]

Nausea and rash are the most frequently reported adverse events of etravirine. [#] Peripheral neuropathy and rash are reported in at least 2% of subjects treated with etravirine and occur at a higher rate than placebo. [#]

In the TMC125-C223 trial, approximately 15% of patients receiving etravirine developed rash, and several of these individuals had to discontinue therapy. [#]

Other less common adverse events of etravirine include hepatic failure, acute renal failure, abdominal pain, fatigue, peripheral neuropathy, headache and hypertension. [#]

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving etravirine compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected subjects receiving etravirine discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy.


Discontinue etravirine immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia or angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction. [#] [#]

The potential for etravirine to cause cancer was evaluated in studies of mice and rats. In these studies, which lasted approximately 104 weeks, mice received daily doses of 50, 200, and 400 mg/kg of etravirine and rats received doses of 70, 200, and 600 mg/kg. Because of poor tolerability, after the first 41 to 52 weeks the high and middle doses were reduced by 50% in mice and by 50-66% in rats to complete the studies. In the mouse study, females treated with etravirine experienced statistically significant increases in incidences of hepatocellular carcinoma and hepatocellular adenomas or carcinomas combined. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold in mice and 0.2 to 0.7-fold in rats. [#]]]>
[#] [#]

Because etravirine is an inducer of CYP3A4, coadministration of CYP3A4 substrates with etravirine may result in altered plasma concentrations of the coadministered substrate drug. Etravirine interacts with numerous boosted and unboosted PIs, which results in altered concentrations of etravirine and of the PI. Increased concentrations of amprenavir and nelfinavir, but decreased concentrations of atazanavir and indinavir, have been observed when these PIs were coadministered with etravirine. Concentrations of etravirine may decrease with concomitant administration of ritonavir alone. Therefore, etravirine should not be administered with any unboosted PI or with the following boosted PIs: tipranavir or fosamprenavir.. Etravirine may be administered at normal dosages with boosted darunavir and saquinavir and may be administered with lopinavir/ritonavir.. [#] [#] Coadministration of atazanavir/ritonavir with etravirine causes the concentration of atazanavir to decrease and the concentration of etravirine to increase. Atazanavir may lose its therapeutic effect if taken in combination with etravirne. Etravirine and atazanavir/ritonavir should no be co-administered. [#]

The mean systemic exposure (defined as area under the curve) of etravirine was reduced after co-administration of etravirine with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, etravirine and lopinavir/ritonavir can be co-administered without dose adjustments. [#] 

Combining etravirine with another NNRTI has not been shown to be beneficial and use of etravirine with efavirenz or nevirapine may cause a significant decrease in the plasma concentration of etravirine. Combining etravirine with delavirdine may cause a significant increase in the plasma concentration of etravirine. Therefore, etravirine and other NNRTIs should not be coadministered. [#]

When etravirine is co-administered with maraviroc, maraviroc dosing depends on whether a potent CYP3A inhibitor (like a ritonavir-boosted protease inhibitor) is also being co-administered. When a potent CYP3A inhibitor is included, the recommended dose of maraviroc is 150 mg twice daily; when not included, the recommended dose is 600 mg twice daily. No dose adjustment of etravirine is needed either way. [#]

If a person taking etravirine is beginning treatment with digoxin, the lowest dose of digoxin should be prescribed initially. If a person taking digoxin is beginning treatment with etravirine, no dose adjustment of either medication is necessary. Serum digoxin concentrations should be monitored and used to titrate the digoxin dose to obtain the desired clinical effect. [#]

Activation of clopidogrel, a platelet aggregation inhibitor, to its active metabolite may be decreased when clopidogrel is co-administered with extravirine. Alternatives to clopidogrel should be considered. [#]

Co-administration of etravirine and the antifungals fluconazole or voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited; therefore, etravirine and fluconazole or voriconazole should be co-adminstered with caution. No dose adjustments of extravirine, fluconazole or voriconazole is needed. [#]]]>
[#] ]]>[#] ]]>[#]]]> Intelence Prescribing Information from the FDA Web site: http://www.fda.gov/cder/foi/label/2008/022187lbl.pdf. A more current version may be available on the manufacturer's Web site.
Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, Trottier B, Peeters M, Vingerhoets J, de Smedt G, Baeten B, Beets G, Sinha R, Woodfall B; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):39-48.
Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, Wilkin T, Peeters M, Vingerhoets J, de Smedt G, Leopold L, Trefiglio R, Woodfall B; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised,double-blind, placebo-controlled trial.Lancet. 2007 Jul 7;370(9581):29-38.
Nadler JP. Efficacy and Safety of Etravirine (TMC125) in Patients With Highly Resistant HIV-1: Primary 24-Week Analysis. AIDS. 2007;21(6):F1-F10.
Scholler-Gyure M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, Peeters M, Hoetelmans RM. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther. 2007;12(5):789-96.]]>
Suite 300
Yardley, PA 19067
Phone: 877-732-2488]]>
Suite 300
Yardley, PA 19067
Phone: 877-732-2488]]>
<![CDATA[Nevirapine]]>[#]]]>[#]]]>[#] Nevirapine is approved for use in adults and in pediatic patients 15 days and older. [#] Nevirapine extended-release tablets received FDA approval on March 25, 2011. [#]

Administration of single-dose nevirapine to the mother intrapartum and to the infant postpartum effectively reduces vertical transmission of HIV-1. [#] This regimen, recommended only for use in HIV-infected treatment-naive women in labor who have had no prior therapy for HIV, includes a single nevirapine dose given to the mother at the onset of labor and a single nevirapine dose given to the neonate 48 to 72 hours after birth. [#]]]>
[#] [#]]]>Tablets containing nevirapine 200 mg. [#]

Extended-release tablets containing nevirapine 400 mg. [#]

Oral suspension containing nevirapine 50 mg (as nevirapine hemihydrate) per 5 ml. [#]


Dosage and Administration of Nevirapine (Immediate-Release)

The recommended adult dose of nevirapine is one 200 mg tablet once daily for the first 14 days, followed by one 200 mg tablet twice daily. As of June 2008, the recommended dose of nevirapine 50 mg/5 ml oral suspension for pediatric patients is based on body surface area (BSA) rather than on weight. Pediatric patients who are 15 days and older should receive 150 mg/m2 once daily for 14 days (lead-in period) and 150mg/m2 twice daily thereafter, with a maximum total daily dose of 400 mg. The decision to calculate pediatric dosing by BSA instead of weight was based on pharmacokinetic data from more than 600 participants in a 48-week pediatric trial and in an analysis of five Pediatric AIDS Clinical Trial Group protocols. BSA-calculated doses for these studies provided nevirapine trough concentrations that were comparable to those achieved with weight-based doses; however, BSA dosing was found to allow for smoother dose transitions between pediatric age groups. [#] [#] [#]


Dosage and Administration of Extended-Release Nevirapine

Patients Not Currently Taking Immediate-Release Nevirapine:

Patients must initiate therapy with one 200 mg tablet of immediate-release nevirapine daily for the first 14 days in combination with other antiretroviral agents (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of  extended release nevirapine once daily. Patients must swallow nevirapine extended-release tablets whole. They must not be chewed, crushed, or divided. For concomitantly administered therapy, the manufacturer’s recommended dosage and monitoring should be followed. Nevirapine extended-release tablets can be taken with or without food. [#]

Switching Patients from Immediate-Release Nevirapine to Extended-Release Nevirapine:

Patients already on a regimen of immediate-release nevirapine twice daily in combination with other antiretroviral agents can be switched to extended-release nevirapine 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of immediate-release nevirapine. [#]


Patients must never take more than one form of nevirapine at the same time. [#]

Monitoring of patients receiving extended-release nevirapine is the same as immediate-release nevirapine and includes intensive clinical and laboratory monitoring, including liver enzyme tests at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release nevirapine, prior to initiation of extended-release nevirapine, and at two weeks after initiation of extended-release nevirapine therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout extended-release nevirapine treatment. [#]

Patients already on a regimen of immediate-release nevirapine twice daily who switch to extended-release nevirapine once daily should continue with their ongoing clinical and laboratory monitoring. [#]
 



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[#]]]>
[#]

Nevirapine is more than 90% absorbed after oral administration in healthy adults and adults with HIV-1 infection. Absolute bioavailability in a trial of 12 healthy adults following single-dose administration was 93% for a 50 mg oral tablet and 91% for 5 mL (nevirapine hemihydrate 50 mg) of oral suspension. When nevirapine was administered to 24 healthy adults with either a high-fat breakfast or an antacid, the extent of absorption was comparable to that seen under fasting conditions. [#]

Although distribution of nevirapine into body tissues and fluids has not been fully characterized, animal studies indicate that nevirapine is widely distributed into most tissues after administration. Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. A nevirapine peak plasma concentration (Cmax) of approximately 2 mcg/mL was measured by 4 hours after a single 200 mg dose. Following IV administration of nevirapine in healthy adults, the apparent volume of distribution is 1.21 L/kg, suggesting that the drug is widely distributed in humans. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/mL. [#] Nevirapine concentrations in cerebrospinal fluid were 45% of the concentrations in plasma at a ratio approximately equal to the fraction not bound to plasma protein. [#] [#]

Nevirapine is extensively biotransformed via cytochrome P450 (CYP) metabolism to several hydroxylated metabolites. Biotransformation is primarily by isozymes from the CYP3A family, but other isozymes may be involved with nevirapine metabolism. [#] In a pharmacokinetic study, approximately 81% of a radiolabeled dose was recovered in the urine, with greater than 80% of that made up of glucuronide conjugates of hydroxylated metabolites. Approximately 10% of a radiolabeled dose was recovered in the feces. Less than 5% of the recovered radiolabeled dose was made up of the parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound. [#] In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. [#]

Nevirapine is in FDA Pregnancy Category B. There are no adequate and well-controlled studies of nevirapine in pregnant women. Nevirapine readily crosses the placenta and achieves neonatal blood concentrations comparable to those in the mother (cord-to-maternal blood ratio approximately 0.9). Evidence of impaired fertility was seen in female rats at doses providing systemic exposure approximately equivalent to that attained with the recommended clinical dose of nevirapine. Teratogenic effects of nevirapine have not been observed in reproductive studies with rats and rabbits. However, in rats, a significant decrease in fetal weight occurred at doses producing systemic concentrations approximately 50% higher than human therapeutic exposure. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In order to monitor maternal-fetal outcomes of pregnant women exposed to nevirapine and other antiretrovirals, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by either calling 800-258-4263 or accessing the website at http://www.APRegistry.com. [#] [#]

Nevirapine is readily distributed into breast milk. Following administration of a single 100- to 200-mg dose of nevirapine to pregnant women several hours prior to delivery, postpartum concentrations of nevirapine in milk have been reported to be 25% to 122% of maternal serum concentrations. HIV infected mothers should not breastfeed their infants in order to avoid risk of HIV transmission and the potential for serious nevirapine-related adverse reactions in the nursing infant. [#]

The mechanism of resistance or reduced susceptibility to nevirapine has not been fully determined, but mutation of HIV RT appears to be involved. A single mutation may be sufficient to result in high-level resistance to nevirapine. Drug-resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Mutations conferring resistance to nevirapine could be observed after a single dose, even with a low level of viral replication. Therefore, nevirapine should always be administered in combination with at least one other antiretroviral agent. [#] Resistance to nevirapine usually confers class resistance to other NNRTIs (efavirenz and delavirdine). However, nevirapine-resistant isolates were susceptible to the nucleoside analogues zidovudine and didanosine. Similarly, zidovudine-resistant isolates were susceptible to nevirapine in vitro. [#]

Nevirapine demonstrated additive to synergistic in vitro activity against HIV-1 in combination regimens with zidovudine, didanosine, stavudine, lamivudine, saquinavir, and indinavir. [#] Because nevirapine and HIV protease inhibitors (PIs), such as amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, have different enzyme targets, cross resistance between nevirapine and these drugs is unlikely. [#]

The clinical efficacy of extended-release nevirapine is based on 48-week data from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 24-week data in an ongoing, randomized, open-label trial in subjects who switched from immediate-release nevirapine tablets administered twice daily to extended-release nevirapine tablets administered once daily (Trial 1100.1526, TRANxITION). [#]]]>
Granulocytopenia (occurring more frequently in children), skin rash, fever, hepatitis prodromal symptoms, hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, gastrointestinal effects, fatigue, and headache are the most common adverse effects seen with nevirapine use. [#]

Clinically symptomatic hepatotoxicity has been observed with initiation of and during continued use of nevirapine. Among the NNRTIs, nevirapine has the greatest potential for causing clinical hepatitis. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. [#] The greatest risk of severe and potentially fatal hepatic events, often associated with rash, occurs in the first 6 weeks of nevirapine treatment. Approximately two-thirds of the cases of nevirapine-associated clinical hepatitis occur within the first 12 weeks of use. [#] However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment. Clinical hepatitis and hepatic failure may be isolated or associated with signs of hypersensitivity, which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction. Patients who experience a clinical hepatitis event must seek medical evaluation immediately and should be advised to permanently discontinue nevirapine. In some cases, hepatic injury progresses despite discontinuation of treatment. [#] [#]

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine, including extended-release nevirapine, should not be initiated in adult females with CD4 counts greater than 250 cells/mm3 or in adult males with CD4 counts greater than 400 cells/mm3 unless the benefit outweighs the risk. [#] [#]

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Severe or life-threatening rash occurred in approximately 2% of clinically treated patients. [#] Fever, in the absence of any apparent cause, is a significant predictor for the development of rash in patients receiving nevirapine. [#] Patients who develop signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine as soon as possible and must limit the nevirapine-only treatment time to 28 days. [#] [#]

The first 18 weeks of therapy with nevirapine is a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18 week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash. [#]

Patients starting extended-release nevirapine and who are not currently taking immediate-release nevirapine, must strictly follow the 14-day lead-in period with immediate-release nevirapine 200 mg daily dosing to reduce the occurrence of rash. If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with extended-release nevirapine. The lead-in dosing with 200 mg once-daily immediate-release nevirapine should not be continued beyond 28 days, at which point an alternative regimen should be sought. [#]

Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing postexposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agents used for postexposure prophylaxis. In many circumstances, the risks associated with nevirapine as part of a postexposure prophylaxis regimen outweigh the anticipated benefits. However, no serious toxicity has been reported in women or infants receiving two-dose nevirapine (the HIVNET 012 clinical trial regimen) for prevention of perinatal transmission of HIV. [#]

Additional adverse reaction information related to extended-release nevirapine can be found in clinical trial data. In Trial 1100.1486 (VERxVE) treatment-naïve subjects received a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release nevirapine 200 mg twice daily (n=506) or extended-release nevirapine 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for men. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subjects’s completion of the 48 week primary endpoint in the trial (mean observation period 61 weeks). [#]

After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine group and 6% in the extended-release nevirapine group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 7% in the immediate-release nevirapine group and 6% in the extended-release nevirapine group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE. [#]

Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release nevirapine, and in 1% of subjects in either treatment group during the randomization phase. In addition, five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of nevirapine treatment. [#]

No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release nevirapine (200 mg once daily), with the exception of rash which occurred in 4% of subjects. [#]

Adverse reactions of at least moderate intensity (Grades 2 or above) and considered to be related to treatment by the investigator in at least 2% of treatment-naive subjects receiving either immediate-release nevirapine or extended-release nevirapine after randomization in Trial 1100.1486 are rash – 3% for each for nevirapine immediate release and extended-release nevirapine and clinical hepatitis 3% for nevirapine immediate release vs 2% extended-release nevirapine.[#]
 

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[#]

Caution is required when nevirapine is administered concurrently with a PI, as the plasma concentrations of PIs may be reduced to subtherapeutic concentrations due to nevirapine-induced hepatic metabolism. Nevirapine decreases the area under the plasma concentration-time curve (AUC) and Cmax of indinavir, saquinavir, and ritonavir; nevirapine and nelfinavir do not appear to interact significantly. In contrast, PIs do not appear to affect the pharmacokinetics of nevirapine. No dosage adjustments are required when nevirapine is concurrently administered with ritonavir or nelfinavir. [#]

Concomitant use of nevirapine and hormonal contraceptives containing ethinyl estradiol or norethindrone may result in decreased plasma concentrations of the contraceptive. Therefore, hormonal contraceptives should not be used as the primary means of contraception when nevirapine is prescribed to women of childbearing potential. [#]

Concurrent use of ketoconazole with nevirapine is not recommended, as it results in significantly reduced plasma concentrations of ketoconazole and a modest increase in plasma concentrations of nevirapine. Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concurrently. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Concurrent use of prednisone with nevirapine has resulted in increased incidence and severity of rash in the first 6 weeks of nevirapine therapy; concurrent use is not recommended. [#]

Rifampin and rifabutin accelerate the metabolism of NNRTIs through induction of CYP isoenzymes, resulting in subtherapeutic levels of nevirapine. Nevirapine retards the metabolism of rifampin and rifabutin, resulting in increased serum levels of these drugs. A dosage adjustment may be necessary when these drugs are administered with nevirapine. [#]

Concurrent use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products with nevirapine is expected to substantially decrease nevirapine concentrations and may result in suboptimal levels of nevirapine, loss of virologic response, and development of nevirapine resistance; concurrent use is not recommended. [#]

Based on data from an open-label randomized study and retrospective database analysis demonstrating the potential for early virologic failure, clinicians are advised to use caution when co-administering tenofovir disoproxil fumarate, enteric-coated didanosine, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads. [#]]]>
[#]

Nevirapine is contraindicated in patients with moderate or severe (child Pugh Class B or C, respectively) hepatic impairment. [#] Nevirapine is hepatotoxic and extensively metabolized by the liver. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. Risk-benefit should be considered in patients with renal function impairment, as nevirapine metabolites are extensively eliminated by the kidneys. [#]]]>
[#] ]]>[#] ]]>[#]
Suspension: White to off-white suspension. [#]]]>
[#]]]>
Viramune Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.
Giaquinto C, Rampon O, De Rossi A. Antiretroviral therapy for prevention of mother-to-child HIV transmission: focus on single-dose nevirapine. Clin Drug Investig. 2006;26(11):611-27.
Gray GE, Urban M, Chersich MF, Bolton C, van Niekerk R, Violari A, Stevens W, McIntyre JA; for the PEP Study Group. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. 2005 Aug 12;19(12):1289-97.
Wit FW, Kesselring AM, Gras L, Richter C, van der Ende ME, Brinkman K, Lange JM, de Wolf F, Reiss P. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study. Clin Infect Dis. 2008 Mar 15;46(6):933-40.
Verweel G, Sharland M, Lyall H, Novelli V, Gibb DM, Dumont G, Ball C, Wilkins E, Walters S, Tudor-Williams G. Nevirapine use in HIV-1-infected children. AIDS. 2003 Jul 25; 17(11): 1639-47.
Bannister WP, Ruiz L, Cozzi-Lepri A, Mocroft A, Kirk O, Staszewski S, Loveday C, Karlsson A, Monforte A, Clotet B, Lundgren JD; EuroSIDA study group. Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA. AIDS. 2008 Jan 30;22(3):367-76.]]>
Ridgefield, CT 06877-0368
Phone: 800-542-6257]]>
Ridgefield, CT 06877-0368
Phone: 800-542-6257]]>
Ridgefield, CT 06877-0368
Phone: 800-542-6257]]>
Ridgefield, CT 06877-0368
Phone: 800-542-6257]]>
<![CDATA[Rilpivirine]]>[#]]]>[#]]]>Rilpivirine was approved by the U.S. Food and Drug Administration (FDA) on May 20, 2011, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve adult patients. [#]

As of August 10, 2011 rilpivirine has been approved as part of a fixed dose combination tablet containing 200 mg/25mg/300 mg emtricitabine/rilpivirine/tenofovir DF for treatment of HIV in treatment-naive adults. [#]

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[#]]]>[#]


Recommended Dose


The recommended dose of rilpivirine, in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment- naïve adult patients, is one 25 mg tablet once daily taken orally with a meal. 

The following points should be considered when initiating therapy with rilpivirine:

  • More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
  • The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
  • More subjects treated with rilpivirine developed lamivudine/emtricitabine-associated resistance compared to efavirenz. [#]

No dose adjustment is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution and with increased monitoring for adverse effects, because rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. Because rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. [#]

The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established. [#] ]]>
[#]]]>
Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.  [#]

Pooled data from Phase III trials through Week 48 of rilpivirine 25 mg administered once daily in antiretroviral treatment-naïve HIV-1-infected subjects (n = 679) demonstrate a mean area under the plasma concentration-time curve from time of administration up to 24 hours (AUC24h) of 2397 ± 1032 ng(h)/mL and a mean pre-dose plasma concentration (C0h) of 80 ± 37 ng/mL. [#]

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4 to 5 hours. The absolute bioavailability of rilpivirine is unknown. The exposure to rilpivirine was approximately 40% lower when rilpivirine was taken in a fasted condition compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. [#]

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine. [#]

Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Rilpivirine has not been studied in subjects with
severe hepatic impairment (Child-Pugh score C). [#]

Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1-infected subjects with mild renal impairment compared to HIV-1-infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. Because rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. [#]

Rilpivirine is in FDA Pregnancy Category B. No adequate and well-controlled or pharmacokinetic studies of rilpivirine use in pregnant women have been conducted. Studies in animals have shown no evidence of relevant embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal no observed adverse effects levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Rilpivirine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to rilpivirine, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients either online at http://www.APRegistry.com or by calling 1-800-258-4263. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving rilpivirine. [#]

Two Phase III trials (TMC278-C209: ECHO and TMC278-C215: THRIVE) compared rilpivirine to efavirenz in antiretroviral-naïve HIV-1 infected subjects with HIV-1 RNA ≥ 5000 copies/mL and no NNRTI resistance. Both trials were identical in design, with the exception of the background regimen. In TMC278-C209, the background regimen was fixed to the nucleoside (tide) reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the background regimen consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278 C215, randomization was also stratified by N(t)RTI background regimen. In the pooled resistance analysis from the Phase III Studies C209 and C215, the emergence of resistance among subjects was greater in the rilpivirine arm compared to the efavirenz arm. In the combined studies, 41% (38/92) of the virologic failures in the rilpivirine arms had genotypic and phenotypic resistance to rilpivirine compared to 25% (15/60) of the virologic failures in the efavirenz arms who had genotypic and phenotypic resistance to efavirenz. Moreover, resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in 48% (44/92) of the virologic failures in the rilpivirine arms compared to 15% (9/60) in the efavirenz arms. [#]

Emerging NNRTI substitutions in the rilpivirine virologic failures included V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L, and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 to 621. The E138K substitution emerged most frequently on rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and the tenofovir resistance-associated substitutions K65R or N emerged more frequently in rilpivirine virologic failures compared to efavirenz virologic failures. [#]

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the pooled analyses of the Phase III clinical trials, 38 rilpivirine virologic failure subjects had evidence of rilpivirine resistance. Of these subjects, 89% (n = 34) were resistant to etravirine and efavirenz, and 63% (n = 24) were resistant to nevirapine. In the efavirenz arm, none of the 15 efavirenz-resistant virologic failures were resistant to etravirine at failure. Subjects experiencing virologic failure on rilpivirine developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz. [#] ]]>
The safety assessment, based on pooled data from 1368 patients in the Phase III controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE), found that the most common adverse drug reactions to rilpivirine (incidence > 2%) of at least moderate to severe intensity (> Grade 2) were depression, insomnia, headache, and rash. The most common adverse drug reactions leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the rilpivirine arm and 15 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the rilpivirine arm and 10 (1.5%) subjects in the efavirenz arm. [#]

The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase III trials (n = 1,368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (n = 686) or efavirenz (n = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm and suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to rilpivirine, and, if so, to determine whether the risks of continued therapy outweigh the benefits. [#]

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including rilpivirine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia, and tuberculosis), which may necessitate further evaluation and treatment. [#]]]>
The exposure to rilpivirine was approximately 40% lower when rilpivirine was taken in a fasted condition compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. [#]

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A. Drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. [#]

Coadministration of rilpivirine is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. Rilpivirine should not be coadministered with the following drugs because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs:

  • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin
  • the antimycobacterials rifabutin, rifampin, and rifapentine
  • proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole
  • the glucocorticoid systemic dexamethasone (more than a single dose)
  • St John’s wort (Hypericum perforatum) [#]

The following are established and potentially significant drug interactions:

  • Didanosine: No dose adjustment is required when rilpivirine is coadministered with didanosine. Didanosine is to be administered on an empty stomach and at least 2 hours before or at least 4 hours after rilpivirine (which should be administered with a meal).
     
  • NNRTIs (delavirdine, efavirenz, etravirine, nevirapine): It is not recommended to coadminister rilpivirine with other NNRTIs.
     
  • Darunavir/ritonavir: Concomitant use of rilpivirine with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when rilpivirine is coadministered with darunavir/ritonavir.
     
  • Lopinavir/ritonavir: Concomitant use of rilpivirine with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when rilpivirine is coadministered with lopinavir/ritonavir.
     
  • Other boosted protease inhibitors (PIs) (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir): Concomitant use of rilpivirine with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of coadministered PIs.
     
  • Unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir): Concomitant use of rilpivirine with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of coadministered PIs.
     
  • Antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate): The combination of rilpivirine and antacids should be used with caution because co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after rilpivirine.
     
  • Azole antifungal agents (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole): Concomitant use of rilpivirine with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when rilpivirine is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with rilpivirine.
     
  • H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine): The combination of rilpivirine and H2-receptor antagonists should be used with caution because coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after rilpivirine.
     
  • Macrolide antibiotics (clarithromycin, erythromycin, troleandomycin): Concomitant use of rilpivirine with clarithromycin, erythromycin and troleandomycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
     
  • Methadone: No dose adjustments are required when initiating coadministration of methadone with rilpivirine. However, clinical monitoring is recommended because methadone maintenance therapy may need to be adjusted in some patients. [#]
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when coadministered with a drug with a known risk of torsade de pointes. [#] ]]>
Coadministration of rilpivirine is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. [#]

Rilpivirine should not be coadministered with the following drugs, because significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs:

  • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin
  • the antimycobacterials rifabutin, rifampin, and rifapentine
  • proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole
  • the glucocorticoid systemic dexamethasone (more than a single dose)
  • St John’s wort (Hypericum perforatum) [#]
]]>
[#] ]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>FDA Edurant Prescribing Information, May 2011. Available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf. Accessed 05/20/2011.

Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Bethune MP, Peeters M, Woodfall B. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects. AIDS. 2006 Aug 22;20(13):1721-6.

Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Bethune MP, Pauwels R, Das K, Clark AD Jr, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl] -2,6-dimethylphenyl] amino]-2-pyrimidinyl]amino] benzonitrile (R278474, rilpivirine). J Med Chem. 2005 Mar 24;48(6):1901-9.

TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 144LB, 2007.

Pooled Week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, Phase III trials comparing TMC278 versus efavirenz in treatment-naïve, HIV-1-infected patients. XVIII International AIDS Conference, Vienna Austria. Abstract THLBB206, 2010.

Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA. Abstract H-1810, 2010.]]>
Titusville, NJ 08560
Phone: 1-877-REACH-IT (1-877-732-2488)]]>
Titusville, NJ 08560
Phone: 1-877-REACH-IT (1-877-732-2488)]]>
<![CDATA[Abacavir]]>[#]]]>[#]]]>[#] A patient's medical history should be reviewed for prior exposure to any abacavir-containing product before abacavir sulfate is administered in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir. [#]

Abacavir is used in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for HIV transmission. [#]]]>
[#]]]>[#]

Oral solution containing abacavir 20 mg/ml. [#]

The recommended dose of abacavir for adults is 600 mg (300 mg twice daily or 600 mg once daily) in combination with other antiretroviral agents. The recommended dosage of abacavir in patients with mild hepatic impairment (Child-Pugh score 5-6) is 200 mg twice daily. The recommended dosage of abacavir for adolescents and pediatric patients age 3 months to 16 years is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents. To enable dose reduction, abacavir oral solution (10 ml twice daily) should be used for the treatment of these patients. [#]]]>
[#]

Oral solution may be refrigerated but should not be frozen. [#]]]>
[#] Abacavir is active in vitro against HIV-1 and -2. [#]

Abacavir sulfate is well absorbed following oral administration. Absorption is rapid and extensive. Abacavir sulfate has an absolute bioavailability of approximately 83%, which is not affected by food. After oral administration of 300 mg twice daily, the mean steady-state peak serum abacavir concentration (Cmax) was 3.0 +/- 0.89 mcg/ml, and the area under the concentration-time curve (AUC) was 6.02 +/- 1.73 mcg(hour)/ml. After oral administration of a single 600 mg dose, the Cmax was 4.26 +/- 1.19 mcg/ml, and the AUC was 11.95 +/- 2.5 mcg(hour)/ml. Systemic absorption is comparable following administration of tablets and oral solution. [#]

Following IV administration of abacavir sulfate, the apparent volume of distribution is 0.86 +/- 0.15 L/kg, suggesting distribution into extravascular spaces. Abacavir is distributed into cerebrospinal fluid (CSF). The steady-state CSF-to-plasma AUC ranges from 27% to 33%. Abacavir also readily distributes into erythrocytes. Plasma protein binding is approximately 50% and is independent of drug concentration. [#]

Abacavir is metabolized in the liver by alcohol dehydrogenase and glucuronyl transferase to form the metabolites 5'-carboxylic acid and 5'-glucuronide, neither of which has antiviral activity. Involvement of cytochrome P450 isoenzymes in metabolizing abacavir is limited. Following oral administration of a 600 mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% is excreted as feces, with unchanged abacavir accounting for 1.2% of recovered radioactivity in urine. The elimination half-life following a single dose is approximately 1.5 hours. [#] It is unknown whether abacavir is removable by hemodialysis or peritoneal dialysis. [#]

Abacavir sulfate is in FDA Pregnancy Category C. No adequate or well-controlled studies of abacavir have been done in pregnant women. Studies in laboratory animals have shown that abacavir crosses the placenta, with evidence of fetal toxicity at dosage levels many times higher than the corresponding dosage for humans. Abacavir should be used in pregnancy only if the potential benefits outweigh the risks. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to abacavir and other antiretroviral agents. Physicians may register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. It is not known whether abacavir is excreted in human milk; it is excreted in the milk of laboratory animals. Because of the potential for HIV transmission and for serious adverse effects from abacavir to the breastfed infant, women should be instructed not to breastfeed while taking abacavir. [#]

In ACTG 5202, a Phase IIIb study in 515 HLA-B*5701--negative patients, abacavir plus lamivudine combined with ritonavir-boosted atazanvir was evaluated as part of initial treatment regimens. At Week 36 analysis, 80% experienced virologic suppression; i the subset of patients with high viral loads, 76^ achieved virologic suppression. However, a 12-trial meta-analysis reported lower rates of suppression with protease inhibitor--based regimens that included abacavir plus lamivudine compared with tenofovir/emtricitabine. [#] [#] [#]

HIV-1 isolates with reduced sensitivity to abacavir have been selected in vitro and also have been obtained from patients treated with abacavir. Genetic analysis of isolates from abacavir-treated patients showed point mutations in the RT gene resulting in amino acid substitutions of K65R, L74V, Y115F, and M184V. The mutation M184V/I was the commonly observed mutation in virologic failure isolates from patients receiving abacavir. In vitro, abacavir has synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity in combination with didanosine, lamivudine, stavudine, and zalcitabine. [#]

Recombinant laboratory strains of HIV-1 containing multiple RT abacavir resistance mutations exhibited cross resistance to didanosine, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and zalcitabine in vitro. An increasing number of thymidine analogue mutations (TAMs) are associated with a progressive reduction in abacavir susceptibility. There is evidence that HIV isolates that are highly resistant to multiple dideoxynucleoside reverse transcriptase inhibitors have reduced susceptibility to abacavir. [#]

Cross resistance between abacavir and protease inhibitors (PIs) is unlikely because the drugs target different enzymes; cross resistance between abacavir and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is also unlikely because of different binding sites and mechanisms of action. [#]]]>
[#]

In clinical studies, hypersensitivity reactions have been reported in approximately 8% of adult and pediatric patients receiving abacavir in conjunction with lamivudine and zidovudine. Hypersensitivity-related fatalities have also been reported with abacavir use. Hypersensitivity reactions are characterized by symptoms indicating involvement of multiple organ and body systems and usually appear within the first 6 weeks of abacavir therapy, although they may appear at any time. [#] Signs and symptoms of hypersensitivity include skin rash or a combination of two or more of the following: fever; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, and cough. [#] Other signs and symptoms include malaise, lethargy, myalgia, myolysis, headache, arthralgia, edema, paresthesia, lymphadenopathy, and mucous membrane lesions such as conjunctivitis and mouth ulcerations. Laboratory abnormalities indicating hypersensitivity reaction include lymphopenia and increases in serum concentrations of liver enzymes, creatine kinase, or creatinine. Anaphylaxis, liver failure, renal failure, hypotension, and death have occurred in association with hypersensitivity reactions. [#]

Recently, the genetic HLA B*5701 allele variant has been associated with an increased likelihood of abacavir hypersensitivity reaction. New research indicates that a positive result in a genetic test for this variant accurately predicts the hypersensitivity reaction of patients to abacavir, which therefore allows these patients to avoid abacavir use (and hypersensitivity reaction risk) altogether. In the PREDICT-1 study, in which 5.6% of participants were positive for the HLA B*5701 allele, the screening test had a 100% negative predictive value. Screening for HLA B*5701 and removing positive-testing participants from the abacavir treatment arm completely eliminated hypersensitivity reactions in that arm (0% vs. 2.7% in the non-tested control group; p < 0.001). An additional study suggests that, although the variant is more common in white than black patients, genetic screening is equally useful in both populations; all five black patients who had confirmed hypersensitivity reactions were positive for the HLA B*5701 allele, which supports the use of testing in this population for the prevention of hypersensitivity reaction. [#] [#] Current recommendations from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents are to administer genetic testing for the HLA B*5701 variant before beginning treatment (or re-treatment) with abacavir in HIV infected patients. In addition, abacavir should be permanently discontinued in patients who experience hypersensitivity, and the reactions should be reported to the Abacavir Hypersensitivity Reaction Registry at 800-270-0425. [#] [#]

Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretroviral agents. These conditions are sometimes fatal. The majority of cases have occurred in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised in any patient who has known risk factors for liver disease; however, cases have been reported in patients with no known risk factors. Treatment with abacavir sulfate should be suspended in any patient who develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity. [#]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment. [#]

Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. [#]

In a clinical trial performed in treatment-naive adults given abacavir, lamivudine, and zidovudine twice daily, the most common adverse effects observed were nausea, headache, malaise and fatigue, and vomiting. [#] In this clinical study, laboratory abnormalities (e.g., creatine phosphokinase elevations, liver function test [specifically, ALT] abnormalities, neutropenia) were observed with similar frequencies as in treatment-naive adults who received indinavir three times daily and lamivudine and zidovudine twice daily. [#]

In an ongoing study of more than 33,000 HIV-infected patients, recent use of abacavir and didanosine in multidrug regimens were linked to significant increases in the risk of myocardial infarction (MI; relative risks of 1.49 [P=0.003] and 1.90 [P=0.0001], respectively). The association was noted in patients who were most likely to develop future heart disease; the association remained even after analyses were adjusted for those patients; and the association did not increase with cumulative or long-term (greater than 6 months) use of the drugs. In 54 manufacturer-conducted trials of abacavir, no risk association was observed with abacavir use compared with placebo; however, these manufacturer results are considered inconclusive by the FDA. No mechanism of action has been identified for the increased risk of MI. Current recommendations are to continue abacavir use in patients who have a low to moderate risk of MI and to carefully consider use of abacavir in patients who are at high risk for MI. [#]]]>
[#]

Concurrent use of abacavir and ethanol or other alcohol-containing products may result in increased concentrations and an increased half-life of abacavir as a result of competition for common metabolic pathways via alcohol dehydrogenase. [#]

Concomitant use of abacavir and methadone resulted in a methadone clearance increase by 22% in patients stabilized on oral methadone maintenance therapy who started abacavir therapy with abacavir 600 mg twice daily. Increases in clearance may not be clinically significant in a majority of patients, but methadone dosage increases may be required in some patients. [#] [#]

In human liver microsomes, abacavir did not significantly inhibit cytochrome P450 isoforms 2C9, 2D6, or 3A4; therefore, clinically important interactions between abacavir and drugs metabolized through these pathways are not expected. [#]]]>
[#] A Medication Guide and Warning Card summarizing the symptoms of abacavir hypersensitivity reactions should be dispensed by the pharmacist with each new prescription and refill of abacavir (or abacavir-containing products, such as Epzicom and Trizivir). Patients being treated with abacavir sulfate should carry the warning card with them. [#]

Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate. Hypersensitivity to abacavir is a multiorgan clinical syndrome usually characterized by a sign or symptom in two or more of the following groups: fever, rash, gastrointestinal problems (including nausea, vomiting, diarrhea, or abdominal pain), constitutional problems (including generalized malaise, fatigue, or achiness), and respiratory problems (including dyspnea, cough, or pharyngitis). Abacavir should not be restarted following a hypersensitivity reaction to abacavir, because more severe symptoms can occur within hours and may include life-threatening hypotension and death. [#] Recent research has concluded that positivity for the HLA B*5701 genetic allele is a marker for abacavir hypersensitivity; patients who test positive for this variant are at risk for developing hypersensitivity reaction and should not receive abacavir. [#] [#]

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir sulfate and other antiretroviral agents. [#]]]>
[#] ]]>[#] ]]>[#]

Oral solution: clear to opalescent, yellowish, strawberry-banana flavored liquid. [#]]]>
[#]]]>
Ziagen Tablets and Oral Solution Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26
Gatanaga H, Honda H, Oka S. Pharmacogenetic information derived from analysis of HLA alleles. Pharmacogenomics. 2008 Feb;9(2):207-14.
Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, Stancil B, Mosteller M, Brothers C, Wannamaker P, Hughes A, Sutherland-Phillips D, Mallal S, Shaefer M; Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation Study Team. High Sensitivity of Human Leukocyte Antigen-B*5701 as a Marker for Immunologically Confirmed Abacavir Hypersensitivity in White and Black Patients. Clin Infect Dis - 2008;46:1111-1118. Available at: http://www.journals.uchicago.edu/doi/pdf/10.1086/529382. Accessed 07/01/08.
Stürmer M, Staszewski S, Doerr HW. Quadruple nucleoside therapy with zidovudine, lamivudine, abacavir and tenofovir in the treatment of HIV.Antivir Ther. 2007;12(5):695-703.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
<![CDATA[Abacavir/Lamivudine]]>EPZICOM Tablets contain the following 2 synthetic nucleoside analogues: abacavir sulfate (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1.

EPZICOM Tablets are for oral administration. Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY® orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

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EPZICOM Tablets contain the following 2 synthetic nucleoside analogues: abacavir sulfate (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1.

EPZICOM Tablets are for oral administration. Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY® orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

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EPZICOM Tablets, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection. Additional important information on the use of EPZICOM for treatment of HIV-1 infection:

• EPZICOM is one of multiple products containing abacavir. Before starting EPZICOM, review medical history for prior exposure to any abacavir-containing product in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir.

• As part of a triple-drug regimen, EPZICOM Tablets are recommended for use with antiretroviral agents from different pharmacological classes and not with other nucleoside/nucleotide reverse transcriptase inhibitors.

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Film-coated tablet containing 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine.

DOSAGE AND ADMINISTRATION

• A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

• To facilitate reporting of hypersensitivity reactions and collection of information on each case, an Abacavir Hypersensitivity Registry has been established. Physicians should register patients by calling 1-800-270-0425.

• EPZICOM can be taken with or without food.

Adult Patients
The recommended oral dose of EPZICOM for adults is one tablet daily, in combination with other antiretroviral agents.

Dosage Adjustment
Because it is a fixed-dose combination, EPZICOM should not be prescribed for:

• patients requiring dosage adjustment such as those with creatinine clearance <50 mL/min,
• patients with hepatic impairment.

Use of EPIVIR® (lamivudine) Oral Solution or Tablets and ZIAGEN® (abacavir sulfate) Oral Solution may be considered.

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Mechanism of Action
EPZICOM is an antiviral agent.

Pharmacokinetics
Pharmacokinetics in Adults:
EPZICOM: In a single-dose, 3-way crossover bioavailability study of 1 EPZICOM Tablet versus 2 ZIAGEN Tablets (2 x 300 mg) and 2 EPIVIR Tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.

Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUCwas 11.95 ± 2.51 mcg•hr/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy volunteers, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hr/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

In humans, abacavir and lamivudine are not significantly metabolized by cytochromeP450 enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized below.

Pharmacokinetic Parametersa for Abacavir and Lamivudine in Adults

Oral bioavailability (%) – Abacavir: 86 ± 25, n=6; Lamivudine: 86 ± 16, n=12
Apparent volume of distribution (L/kg) – Abacavir: 0.86 ± 0.15, n=6; Lamivudine: 1.3 ± 0.4, n=20
Systemic clearance (L/hr/kg) – Abacavir: 0.80 ± 0.24, n=6; Lamivudine: 0.33 ± 0.06, n=20
Renal clearance (L/hr/kg) – Abacavir: .007 ± .008, n=6; Lamivudine: 0.22 ± 0.06, n=20
Elimination half-life (hr) – Abacavir: 1.45 ± 0.32, n=20; Lamivudine: 5 to 7b

a Data presented as mean ± standard deviation except where noted.
b Approximate range.

Effect of Food on Absorption of EPZICOM:
EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUClast, AUC, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately.

Special Populations:
Renal Impairment: EPZICOM: Because lamivudine requires dose adjustment in the presence of renal insufficiency, EPZICOM is not recommended for use in patients with creatinine clearance <50 mL/min.

Hepatic Impairment: EPZICOM: EPZICOM is contraindicated for patients with hepatic impairment because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. Abacavir is contraindicated in patients with moderate to severe hepatic impairment, and dose reduction is required in patients with mild hepatic impairment.

Pregnancy: Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.

Nursing Mothers: Abacavir: No data are available on the pharmacokinetics of abacavir in nursing mothers.
Lamivudine: Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Pediatric Patients: EPZICOM: The pharmacokinetics of EPZICOM in pediatric subjects are under investigation. There are insufficient data at this time to recommend a dose.

Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.

Gender: Abacavir: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.

Lamivudine: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in lamivudine AUC normalized for body weight.

Race: Abacavir: There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions:
The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Abacavir: Lamivudine and Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction study evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Methadone: In a study of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% 557 to 42%).

Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
(For additional information, consult the Epzicom complete prescribing information).

Microbiology
Mechanism of Action:
Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.
 
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases α, β, and γ.

Antiviral Activity:
Abacavir: The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV-1BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0.26 ± 0.18 μM 595 against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. Ribavirin (50 μM) had no effect on the anti–HIV-1 activity of abacavir in cell culture.

Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 μM (1 μM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 μM (range: 0.200 to 2.007 μM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 μM (1.37 to 3.68 μM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 μM, and against HIV-2 isolates from 0.003 to 0.120 μM in peripheral blood mononuclear cells. Ribavirin (50 μM) decreased the anti–HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Abacavir/lamivudine had additive to synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine, stavudine, tenofovir, zalcitabine, zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, efavirenz, nevirapine; the protease inhibitors (PIs) amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir; or the fusion inhibitor, enfuvirtide. Ribavirin, used in combination with interferon for the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.

Resistance:
HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture and have also been obtained from subjects failing abacavir/lamivudine-containing regimens. Genotypic characterization of abacavir/lamivudine-resistant viruses selected in cell culture identified amino acid substitutions M184V/I, K65R, L74V, and Y115F in HIV-1 RT.

Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT contributed to abacavir resistance. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated subjects showed that the resistance was due to a specific amino acid substitution in HIV-1 RT at codon 184 changing the methionine to either isoleucine or valine (M184V/I). In a study of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the RT substitutions that emerged during abacavir/lamivudine once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The abacavir- and lamivudine-associated resistance substitution M184V/I was the most commonly observed substitution in virologic failure isolates from subjects receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 636 8/20).

Thirty-nine percent (7/18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared with 41% (7/17) of the failure isolates in the twice-daily abacavir group had a >2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range: 0.79 to >116) and 1.1 (range: 0.68 to >116) in the once-daily and twice-daily abacavir arms, respectively.

Cross-Resistance:
Cross-resistance has been observed among NRTIs. Viruses containing abacavir and lamivudine resistance-associated amino acid substitutions, namely, K65R, L74V, M184V, and Y115F, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine.

The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

USE IN SPECIFIC POPULATIONS
Pregnancy
EPZICOM: Pregnancy Category C. There are no adequate and well-controlled studies of EPZICOM in pregnant women. Reproduction studies with abacavir and lamivudine have been performed in animals (see Abacavir and Lamivudine sections below). EPZICOM should be used during pregnancy only if the potential benefits outweigh the risks.

Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.

Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to EPZICOM or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Abacavir: Abacavir is secreted into the milk of lactating rats.
Lamivudine: Lamivudine is excreted in human breast milk and into the milk of lactating rats.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving EPZICOM.

Pediatric Use
Safety and effectiveness of EPZICOM in pediatric patients have not been established. EPZICOM is not recommended for use in patients aged <18 years because it cannot be dose adjusted.

Geriatric Use
Clinical studies of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients With Impaired Renal Function
EPZICOM is not recommended for patients with impaired renal function (creatinine clearance <50 mL/min) because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted.

Patients With Impaired Hepatic Function
EPZICOM is contraindicated for patients with hepatic impairment because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted.

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WARNING: RISK OF HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, AND EXACERBATIONS OF HEPATITIS B

  • Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of EPZICOM® (abacavir sulfate and lamivudine) Tablets. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue EPZICOM as soon as a hypersensitivity reaction is suspected.

    Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.

    Regardless of HLA-B*5701 status, permanently discontinue EPZICOM if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

    Following a hypersensitivity reaction to abacavir, NEVER restart EPZICOM or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
    Reintroduction of EPZICOM or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours.

    • Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, and other antiretrovirals.

    • Exacerbations of Hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, which is one component of EPZICOM. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPZICOM and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Hypersensitivity Reaction
Serious and sometimes fatal hypersensitivity reactions have been associated with EPZICOM and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.

HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue EPZICOM if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below.

Signs and Symptoms of Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups.

Group 1: Fever
Group 2: Rash
Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
Group 4: Constitutional (including generalized malaise, fatigue, or achiness)
Group 5: Respiratory (including dyspnea, cough, or pharyngitis)

Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.

Hypersensitivity to abacavir was reported in approximately 8% of 2,670 subjects (n = 206) in 9 clinical studies (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. [To view Firgure 1, please consult the Epzicom full prescribing information]. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of subjects reported symptoms from 2 or more of the 5 groups listed above.

Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions. In one study, 4 subjects (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 subjects receiving ZIAGEN 300 mg twice daily.

Physical findings associated with hypersensitivity to abacavir in some subjects include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.

Laboratory abnormalities associated with hypersensitivity to abacavir in some subjects include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.

Clinical Management of Hypersensitivity: Discontinue EPZICOM as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue EPZICOM if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis,  pharyngitis, or influenza; gastroenteritis; or reactions to other medications).

Following a hypersensitivity reaction to abacavir, NEVER restart EPZICOM or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.

When therapy with EPZICOM has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of EPZICOM or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of EPZICOM to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of EPZICOM.

If hypersensitivity cannot be ruled out, DO NOT reintroduce EPZICOM or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of EPZICOM or any other abacavir-containing product and that reintroduction of EPZICOM or introduction of any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.

Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.

Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.

Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.
 
In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

Abacavir Hypersensitivity Reaction Registry: An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions and collection of information on each case. Physicians should register patients by calling 1-800-270-0425.

Lactic Acidosis and Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering EPZICOM to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with EPZICOM should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients With HIV-1 and Hepatitis B Virus Co-Infection
Posttreatment Exacerbations of Hepatitis: In clinical studies in non-HIV-1-infected subjects treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

Emergence of Lamivudine-Resistant HBV: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. In non–HIV-1-infected subjects treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV® [lamivudine] Tablets and Oral Solution for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPZICOM. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Myocardial Infarction
In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI).1 In a sponsor-conducted pooled analysis of clinical studies, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical studies are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking).

Clinical Trials Experience
Treatment-emergent (all causality) adverse reactions of at least moderate intensity (Grades 2-4, ≥5% frequency) in therapy-naive adults (CNA30021) through 48 weeks of treatment include drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, diarrhea, rash, pyrexia, abdominal pain/gastritis, abnormal dreams, and anxiety.

]]>
Effect of Food on Absorption of EPZICOM: EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUClast, AUC∞, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately.

Use With Interferon- and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine, a component of EPZICOM. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected subjects, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and EPZICOM should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of EPZICOM should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Use With Other Abacavir-, Lamivudine-, and/or Emtricitabine-Containing Products
EPZICOM contains fixed doses of 2 nucleoside analogues, abacavir and lamivudine, and should not be administered concomitantly with other abacavir-containing and/or lamivudine-containing products (ZIAGEN, EPIVIR, COMBIVIR® [lamivudine and zidovudine] Tablets, or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets); or emtricitabine-containing products, including ATRIPLA® (efavirenz,emtricitabine, and tenofovir disoproxil fumarate) Tablets, EMTRIVA® (emtricitabine) Capsules and Oral Solution, or TRUVADA® (emtricitabine and tenofovir disoproxil fumarate) Tablets.

The complete prescribing information for all agents being considered for use with EPZICOM should be consulted before combination therapy with EPZICOM is initiated.

DRUG INTERACTIONS
No drug interaction studies have been conducted using EPZICOM Tablets.

Ethanol
Abacavir: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Interferon- and Ribavirin-Based Regimens
Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamics interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected subjects, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.

Methadone
Abacavir: The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

Trimethoprim/Sulfamethoxazole (TMP/SMX)
Lamivudine: No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

]]>
EPZICOM Tablets are contraindicated in patients with:

• previously demonstrated hypersensitivity to abacavir or to any other component of the product. NEVER restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.

• hepatic impairment. [#]

]]>
[#]Lamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis) [#] ]]>[#] Lamivudine: 134678-17-4 [#]]]>[#]]]>[#]]]>[#]

Lamivudine: white to off-white crystalline solid. [#]]]>
[#]

Lamivudine: 70 mg/mL in water at 20°C. [#]]]>
Epzicom Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26.
Dando TM, Scott LJ. Abacavir plus lamivudine: a review of their combined use in the management of HIV infection. Drugs. 2005;65(2):285-302. Review.
DeJesus E, McCarty D, Farthing CF, Shortino DD, Grinsztejn B, Thomas DA, Schrader SR, Castillo SA, Sension MG, Gough K, Madison SJ; EPV20001 International Study Team. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis. 2004 Aug 1;39(3):411-8. Epub 2004 Jul 15.
Waters L, Moyle G. Abacavir/lamividune combination in the treatment of HIV-1 infection: a review. Expert Opin Pharmacother. 2006 Dec;7(18):2571-80.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
<![CDATA[Abacavir/Lamivudine/ Zidovudine]]>[#] ]]>[#] ]]>[#] When used as part of a three-drug HIV treatment regimen, Trizivir should be used with antiretroviral agents from different pharmacological classes and not with other NRTIs. [#] ]]>[#] ]]>
The recommended dosage for adults and adolescents is one tablet twice daily. Because it is in a fixed-dose tablet, Trizivir is not recommended for use in adults or adolescents who weigh less than 40 kg (88 lbs) or in patients who require dosage adjustment, such as those who have creatinine clearance less than 50 ml/min or those who experience dose-limiting adverse events. [#] ]]>
[#] ]]>

Abacavir is a carbocyclic nucleoside analogue that is converted by cellular enzymes to the active metabolite, carbovir triphosphate. Carbovir triphosphate is an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits RT by competing with the natural substrate dGTP and by incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation. In vitro, abacavir had synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity with didanosine, lamivudine, stavudine, and zalcitabine. Following oral dosing, abacavir is rapidly absorbed and extensively distributed. Binding of abacavir to human plasma proteins is about 50%, independent of concentration. Abacavir is primarily eliminated by metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide. [#]

Lamivudine is a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). L-TP inhibits viral RT by DNA chain termination. In vitro, lamivudine had synergistic antiretroviral activity with zidovudine. Following oral dosing, lamivudine is rapidly absorbed and extensively distributed. Plasma protein binding is low and about 70% of an intravenous dose is excreted unchanged in the urine. Metabolism is a minor route of elimination. [#]

Zidovudine is phosphorylated intracellularly to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). ZDV-TP also inhibits RT by DNA chain termination. In vitro, zidovudine demonstrates synergistic activity with delavirdine, didanosine, indinavir, nelfinavir, nevirapine, ritonavir, saquinavir, and zalcitabine and additive activity with interferon alfa. Following oral dosing, zidovudine is rapidly absorbed and extensively distributed. Plasma protein binding is low and elimination is primarily by hepatic metabolism. The major metabolite is 3'-azido-3'-deoxy-5'-O-beta-D- glucopyranuronosylthymidine. A second metabolite, 3'-amino-3'-deoxythymidine, has been identified. [#]

In a bioavailability study of Trizivir, compared to separate tablets of the three components given simultaneously to healthy adults, there was no difference in absorption. One Trizivir tablet was bioequivalent to dosing with one tablet each of abacavir sulfate 300 mg, lamivudine 150 mg, and zidovudine 300 mg in healthy, fasting adults. [#]

Trizivir is in FDA Pregnancy Category C. No adequate or well-controlled studies of the combination drug have been done in pregnant women. A study of zidovudine therapy in women, in the last trimester of pregnancy, showed that although this drug does cross the placenta, there was no evidence of drug accumulation, and zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Studies in laboratory animals have shown that abacavir and lamivudine cross the placenta, with evidence of fetal toxicity at dosage levels many times higher than the corresponding dose for humans. Trizivir should be used in pregnancy only if the potential benefits outweigh the risks. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to Trizivir and other antiretrovirals. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. Zidovudine is excreted in human milk, and abacavir and lamivudine are excreted in the milk of laboratory animals. [#]

HIV-1 isolates with reduced sensitivity to abacavir, lamivudine, or zidovudine have been selected in vitro and have also been obtained from patients treated with that combination or lamivudine plus zidovudine. Treatment for 12 weeks with lamivudine and zidovudine restored sensitivity to zidovudine in some patients with zidovudine-resistant virus. Combination therapy delayed the emergence of mutations conferring resistance to zidovudine. Higher levels of resistance were associated with greater numbers of mutations. Laboratory strains of HIV-1 containing multiple RT mutations that confer abacavir resistance exhibited cross resistance to lamivudine, didanosine, and zalcitabine in vitro. Cross resistance to didanosine and zalcitabine has been observed in some patients who harbor lamivudine-resistant HIV-1 isolates. Multiple drug resistance, including resistance to lamivudine and stavudine, has been observed in HIV isolates from patients treated for more than 1 year with zidovudine plus didanosine or zalcitabine. [#]

Cross resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine has been seen in patients treated with abacavir. Cross resistance to abacavir, didanosine, tenofovir, and zalcitabine has been seen in patients treated with lamivudine. Multiple drug resistance, including resistance to lamivudine, didanosine, stavudine, zalcitabine, and zidovudine, has been observed in HIV isolates from some patients treated for more than 1 year with zidovudine plus didanosine or zalcitabine. [#] ]]>
[#] An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions. Physicians should register patients by calling 1-800-270-0425. [#]

Recently, the genetic HLA B*5701 allele variant has been associated with an increased likelihood of abacavir hypersensitivity reaction. New research indicates that a positive result in a genetic test for this variant accurately predicts the hypersensitivity reaction of patients to abacavir, which therefore allows these patients to avoid abacavir use (and hypersensitivity reaction risk) altogether. In the PREDICT-1 study, in which 5.6% of participants were positive for the HLA B*5701 allele, the screening test had a 100% negative predictive value. Screening for HLA B*5701 and removing positive-testing participants from the abacavir treatment arm completely eliminated hypersensitivity reactions in that arm (0% vs. 2.7% in the non-tested control group; p < 0.001). An additional study suggests that, although the variant is more common in white than black patients, genetic screening is equally useful in both populations; all five black patients who had confirmed hypersensitivity reactions were positive for the HLA B*5701 allele, which supports the use of testing in this population for the prevention of hypersensitivity reaction. [#] [#] The current recommendations from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents is to administer genetic testing for the HLA B*5701 variant before beginning treatment with abacavir in HIV infected patients. [#]

Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination. These conditions are sometimes fatal. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, liver problems have been reported in patients with no known risk factors. Treatment with Trizivir should be suspended in any patient who develops clinical or laboratory findings that suggest the presence of lactic acidosis or pronounced hepatotoxicity. [#] Neutropenia and anemia are the most frequent adverse effects associated with zidovudine therapy. [#] Myopathy and myositis have occurred with prolonged use of zidovudine and may occur during therapy with Trizivir. [#] Peripheral neuropathy has been reported in adults who receive lamivudine but has rarely resulted in interruption or discontinuance of treatment. [#] Post-treatment exacerbations of hepatitis B virus (HBV) infections have been reported in both HIV infected and uninfected participants treated with lamivudine for chronic HBV when lamivudine therapy was discontinued. [#]

Immune reconstitution syndrome has been reported with the use of combination anti-HIV therapy, including abacavir/lamivudine/zidovudine. Patients who develop immune system responses to anti-HIV therapy may develop an inflammatory response to residual opportunisitic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, tuberculosis). [#]

Other adverse effects occurring in clinical trials of Trizivir or its component drugs include nausea, vomiting, diarrhea, abdominal pain or cramping, dyspepsia, anorexia, insomnia and other sleep disorders, fever and/or chills, headache, dizziness, malaise and/or fatigue, depressive disorders, neuropathy, musculoskeletal pain, myalgia, arthralgia, and skin rashes. Adverse events reported during post-approval use of abacavir, lamivudine, and/or zidovudine that may potentially be related to these drugs include cardiomyopathy, stomatitis, oral mucosal pigmentation, gynecomastia, hyperglycemia, vasculitis, weakness, anemia, aplastic anemia, lymphadenopathy, pure red cell aplasia, splenomegaly, lactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbation of hepatitis B, sensitization reactions and urticaria, muscle weakness, creatine phosphokinase (CPK) elevation, rhabdomyolysis, paresthesia, peripheral neuropathy, seizures, abnormal breath sounds/wheezing, alopecia, erythema multiforme, and Stevens-Johnson syndrome. [#] ]]>
[#]

Abacavir, lamivudine, and zidovudine (studied as individual drugs) are not significantly metabolized by the cytochrome P 450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. [#]

Abacavir administered at twice the recommended dose increased methadone clearance by 22%. A small number of patients receiving both abacavir and methadone may need a methadone dosage adjustment. Because abacavir elimination is decreased by alcohol, consumption of alcohol may cause an increase in abacavir exposure. [#]

Because lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another, Trizivir should not be coadministered with zalcitabine. [#] The AUC of lamivudine was increased by 43% and renal clearance was decreased by 30% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and zidovudine in one small study resulted in a 39% increase in the Cmax of zidovudine with no change observed in the AUC. Concurrent administration of lamivudine with indinavir and zidovudine resulted in a 6% decrease in the AUC of lamivudine, no change in the AUC of indinavir, and a 36% increase in the AUC of zidovudine. No adjustment in dose is necessary. Concurrent administration of lamivudine with drugs associated with pancreatitis (alcohol, didanosine, IV pentamidine, sulfonamides, and zalcitabine) or with drugs associated with peripheral neuropathy (dapsone, didanosine, isoniazid, stavudine, and zalcitabine) should be avoided or used cautiously. [#]

Zidovudine may interact with atovaquone, fluconazole, methadone, probenecid, ribavirin, valproic acid, [#] nelfinavir, and ritonavir. [#] The hematologic toxicity of zidovudine may be increased when zidovudine is coadministered with bone marrow depressant agents such as ganciclovir or interferon alfa, blood dyscrasia-causing medications, cytotoxic agents, or radiation therapy. [#] [#] Medications that are metabolized by hepatic glucuronidation such as acetaminophen, aspirin, benzodiazepines, cimetidine, indomethacin, lorazepam, and oxazepam may in theory increase the risk of toxicity of zidovudine or the coadministered medication. [#] Antagonistic relationships between zidovudine and stavudine, doxorubicin, and ribavirin have been reported in vitro. Concomitant use of zidovudine with any of these three drugs should be avoided. [#]

Results of in vitro studies indicate that ribavirin reduces the phosphorylation of pyrimidine nucleoside analogues, including lamivudine. Liver decompensation has occurred in patients coinfected with HIV and hepatitis C virus receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. [#] ]]>
[#] Recent research has concluded that positivity for the HLA B*5701 genetic allele is a marker for abacavir hypersensitivity; patients who test positive for this variant are at risk for developing hypersensitivity reaction and should not receive abacavir. [#] [#] Due to the fixed-dose formulation of Trizivir, there is no way to accommodate the dosage reduction of zidovudine that may be necessary in individuals with impaired liver function or the dosage adjustment of both lamivudine and zidovudine that may be necessary in those with renal insufficiency (creatinine clearance less than 50 ml/min). Additionally, dosage adjustments cannot be made for pediatric or geriatric patients, for patients who weigh less than 40 kg, or for any patient who has special dosing requirements. Trizivir is not recommended for these patients. [#] ]]>[#] Lamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis)- [#] Zidovudine: Thymidine, 3'-azido-3'-deoxy- [#] ]]>[#] Lamivudine: 134678-17-4 [#] Zidovudine: 30516-87-1 [#] ]]>[#]

Lamivudine: white to off-white crystalline solid. [#]

Zidovudine: white to beige crystalline solid. [#] ]]>
[#]

Lamivudine: 70 mg/ml in water at 20 C. [#]

Zidovudine: 20.1 mg/ml in water at 25 C. [#] ]]>
Trizivir Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Keiser P, Nassar N. Abacavir sulfate/lamivudine/zidovudine fixed combination in the treatment of HIV infection. Expert Opin Pharmacother. 2007 Mar;8(4):477-83.
Ferrer E, Gatell JM, Sanchez P, Domingo P, Puig T, Niubo J, Cortes C, Veloso S, Pedrol E, Leon A, Gutierrez M, Podzamczer D. Zidovudine/lamivudine/abacavir plus tenofovir in HIV-infected naive patients: a 96-week prospective one-arm pilot study. AIDS Res Hum Retroviruses. 2008 Jul;24(7):931-4.
Mastroianni CM, d'Ettorre G, Vullo V. Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir. Expert Opin Pharmacother. 2006 Nov;7(16):2233-41.
d'Ettorre G, Zaffiri L, Ceccarelli G, Andreotti M, Massetti AP, Vella S, Mastroianni CM, Vullo V. Simplified maintenance therapy with abacavir/lamivudine/zidovudine plus tenofovir after sustained HIV load suppression: four years of follow-up. HIV Clin Trials. 2007 May-Jun;8(3):182-8.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
<![CDATA[Didanosine]]>[#] Didanosine, a synthetic antiretroviral agent, is a synthetic analogue of deoxyadenosine, a naturally occurring purine nucleoside. Didanosine differs from deoxyadenosine in that the 3'-hydroxyl group on the ribose moiety is replaced with hydrogen. [#]]]>[#] Didanosine, a synthetic antiretroviral agent, is a synthetic analogue of deoxyadenosine, a naturally occurring purine nucleoside. Didanosine differs from deoxyadenosine in that the 3'-hydroxyl group on the ribose moiety is replaced with hydrogen. [#]]]>[#] A generic delayed-release capsule formulation was approved by the FDA on December 3, 2004. [#] Didanosine is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in adults, adolescents, and pediatric patients. [#]

Didanosine is used with other antiretrovirals for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with tissues or body fluids associated with a risk of HIV transmission. [#]

Because of a decline in clinical demand for the buffered tablet formulation of didanosine, this formulation was discontinued in the U.S. by the manufacturer in February 2006. The discontinuation of the less popular buffered tablets is voluntary and does not reflect any problems with safety or efficacy. [#]]]>
[#]]]>[#]

Buffered powder for oral solution in single-dose packets containing didanosine 100, 167, or 250 mg. [#]

Pediatric powder for oral solution in 4- or 8-ounce bottles containing didanosine 2 or 4 g, respectively. [#]

Delayed-release capsules of enteric-coated beadlets containing didanosine 125, 200, 250, or 400 mg. [#]

Bioequivalent generic delayed-release capsules containing didanosine 200, 250, or 400 mg. [#]

The recommended dose of didanosine in pediatric patients who weigh at least 20 kg and who can swallow capsules is based on body weight according to the following scale: Patients who weigh 20 to <25 kg should receive didanosine 200 mg once daily; 25 to <60 kg, 250 mg once daily; and 60 kg or more, 400 mg once daily. [#] For patients who weigh less than 20 kg, the recommended dose of didanosine powder for oral solution is based on age and body surface area: pediatric patients aged 2 weeks to 8 months should receive 100 mg/m2 twice daily, and pediatric patients older than 8 months should receive 120 mg/m2 twice daily. [#]

In patients with impaired renal function, the doses and dosing intervals of didanosine should be adjusted to compensate for the slower rate of elimination. Recommendations for didanosine dosing in renal impairment are provided in the Videx and Videx EC prescribing information from the manufacturer. [#] In patients who have hepatic impairment, no dosage adjustment is necessary. Similar ranges of maximum plasma concentrations and areas under the concentration-time curve were observed in a study of participants who had impairment and those who were matched controls. [#]]]>
[#]]]>
[#]

Didanosine is acid labile. All oral formulations of didanosine contain or are compounded with buffering agents to increase gastric pH. [#] Didanosine is rapidly absorbed, with peak plasma concentrations (Cmax) observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation (in tablet or powder form) and 2 hours following oral dosing with the enteric-coated formulation. Extent of absorption depends on several factors, including dosage form, gastric pH, and presence of food in the gastrointestinal (GI) tract. There is considerable variation between individuals in Cmax and areas under the plasma concentration curve (AUC) of didanosine attained following oral administration. [#]

Didanosine's Cmax and AUC were decreased by approximately 55% when didanosine buffered tablets were administered up to 2 hours after a meal. Administration of didanosine tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. The Cmax and AUC for the enteric-coated formulation were reduced by approximately 46% and 19%, respectively, in the presence of food. [#]

Because gastric secretions may inactivate didanosine following oral administration, didanosine chewable/dispersible tablets and powder for oral solution either contain buffering agents or must be admixed with antacids prior to administration. Each adult dose of the buffered tablet formulation of didanosine must consist of 2 tablets to ensure adequate acid-neutralizing capacity. [#] The delayed-release capsules contain enteric-coated beadlets, which protect didanosine from degradation by stomach acid. [#]

Didanosine is distributed into cerebrospinal fluid (CSF) following IV administration. CSF concentrations average 19% to 21% of concurrent plasma concentrations in samples obtained 1 hour after a single IV dose. In a study of HIV infected pediatric patients who received oral or intravenous didanosine, CSF concentrations averaged 46% (over a range of 12% to 85%) of concurrent plasma concentrations. [#] Binding of didanosine to plasma proteins in vitro is less than 5%. [#]

Didanosine is in FDA Pregnancy Category B. No adequate or well-controlled studies of didanosine have been done in pregnant women. In animal studies, didanosine and/or its metabolites were transferred to the fetus through the placenta. Animal studies with didanosine have not shown evidence of impaired fertility or harm to the fetus. Nevertheless, the drug should be used during pregnancy only if clearly needed. To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. [#] It is not known whether didanosine or its metabolites are distributed into human milk; however, the drug and/or its metabolites are distributed into milk in laboratory animals. Because of both the potential for HIV transmission and serious adverse reactions in nursing infants, HIV infected mothers should be instructed not to breastfeed their infants if they are receiving didanosine. [#]

The metabolic fate of didanosine has not been fully evaluated in humans. Because didanosine is an analogue of a naturally occurring purine nucleoside, metabolism of the drug is presumed to occur via the same pathways as endogenous purines. The in vivo intracellular half-life of the active metabolite, ddA-TP, has not been determined; the in vitro intracellular half-life of ddA-TP is 8 to 24 hours. In HIV infected adults, the plasma half-life of didanosine averages 0.97 to 1.6 hours. In HIV infected pediatric patients, the plasma half-life averages 0.8 hours. [#]

Didanosine is eliminated in urine by glomerular filtration and active tubular secretion. Following oral dosing in adults, the renal clearance of didanosine is approximately 50% of the total body clearance and averages 400 ml/min. Renal clearance has been reported to average 5.5 ml/min/kg in adult patients and 240 ml/min/m2 in pediatric patients. In HIV infected adults, approximately 20% of the dose is eliminated in the urine; in pediatric patients approximately 18% of the dose is eliminated in the urine. [#]

The half-life of didanosine increases as creatinine clearance decreases. It is recommended that the didanosine dose be modified in patients with renal impairment and reduced creatinine clearance and in patients receiving maintenance hemodialysis. [#] A 4-hour hemodialysis session reduces the serum didanosine concentration by approximately 20%. [#] The effects of impaired hepatic function on the pharmacokinetics of didanosine have not been adequately studied. [#]

HIV-1 isolates with reduced sensitivity to didanosine havebeen selected in vitro and were also obtained from patients treated with didanosine. Phenotypic analysis of HIV-1 isolates from 60 patients receiving from 6 to 24 months of didanosine monotherapy, some with prior exposure to zidovudine, showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. [#]

HIV-1 isolates from 2 of 39 patients receiving combination therapy with zidovudine and didanosine for up to 2 years exhibited cross-resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. The clinical relevance of these observations has not been established. [#]

Further study is needed to evaluate more fully the extent of cross resistance among the dideoxynucleoside reverse transcriptase inhibitors. Although zidovudine-resistant HIV strains are susceptible to didanosine in vitro, some zidovudine-resistant strains may be cross resistant to didanosine or zalcitabine. In addition, some strains of HIV modified in vitro by site-directed mutagenesis have had decreased susceptibility to both didanosine and zalcitabine but were susceptible to zidovudine. [#]

Cross resistance between didanosine and protein inhibitors (PIs), including amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, is highly unlikely since the drugs have different target enzymes. The potential for cross resistance between didanosine and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine) is considered to be low since the drugs bind on different sites of reverse transcriptase and have different mechanisms of action. [#]]]>
[#]

Postmarketing cases of non-cirrhotic portal hypertension have been reported in people taking didanosine, including cases leading to liver transplantation or death. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Patients receiving didanosine should be monitored for early signs of portal hypertension (eg. Thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine should be discontinued in patients with evidence of non-cirrhotic portal hypertension. [#]

The use of didanosine and other nucleoside analogues, either alone or in combination with other antiretrovirals, has been associated with lactic acidosis and severe hepatomegaly with steatosis, including some fatal cases. Risk factors include female gender, obesity, and prolonged exposure to antiretroviral nucleoside analogues. Fatal lactic acidosis has been reported in pregnant women who received an antiretroviral regimen that included didanosine and stavudine. Cases have occurred in patients with and without known risk factors for liver disease. Didanosine use should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. [#]

Retinal changes and optical neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients taking didanosine. [#]

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients taking didanosine. Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

Common, less serious adverse effects include central nervous system effects (anxiety, headache, insomnia, irritability, and restlessness), dry mouth, GI disturbances (diarrhea, dyspepsia, flatulence, nausea, vomiting), and skin rash. [#]]]>
[#]

The manufacturer suggests that didanosine be discontinued in patients who require life-sustaining treatment with other drugs known to cause pancreatitis. Patients receiving didanosine in combination with stavudine, with or without hydroxyurea, may be at an increased risk for potentially fatal pancreatitis. [#]

Didanosine and some (PIs), including amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir, have additive or synergistic activity against HIV-1, probably due to the different stages of virus replication at which these drugs are active. However, due to the buffering agents in some didanosine dosage forms and the requirement that most PIs be administered with food, dosing of these drugs should be separated. [#]

Concomitant use of didanosine and drugs associated with pancreatic toxicity, such as alcohol, asparaginase, azathioprine, estrogens, furosemide, methyldopa, nitrofurantoin, pentamidine (IV), sulfonamides, sulindac, tetracyclines, thiazide diuretics, and valproic acid, may increase the risk of pancreatitis. Didanosine should be used with extreme caution and only when other alternatives are not available in patients receiving these drugs. [#]

Didanosine should be avoided or used with caution in patients receiving other drugs that have been associated with peripheral neuropathy, such as chloramphenicol, cisplatin, dapsone, ethambutol, ethionamide, hydralazine, isoniazid, lithium, metronidazole, nitrofurantoin, nitrous oxide, phenytoin, stavudine, vincristine, and zalcitabine. [#]

When buffered preparations of didanosine are administered with medications that require an acidic environment, didanosine may cause decreased absorption of the coadministered drug. Drugs that depend on gastric acidity for optimal absorption, including dapsone, itraconazole, and ketoconazole, should be administered at least 2 hours before or 2 hours after didanosine is given. [#]

Concurrent administration of delavirdine or indinavir and didanosine may decrease absorption of these drugs. If either of these drugs are taken together, delavirdine or indinavir should be given 1 hour prior to didanosine administration. [#]

Coadministration of tenofovir disoproxil fumarate (tenofovir DF) with didanosine causes increased absorption of didanosine. Increased exposure may cause or worsen didanosine-related toxicities, including pancreatitis, hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir DF with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. [#]

In vitro studies demonstrate that concurrent administration of didanosine and oral ganciclovir resulted in a 111% increase in the steady-state AUC of didanosine and may result in increased didanosine-related toxicities. Because valganciclovir is rapidly and completely converted to ganciclovir, drug interactions associated with ganciclovir are expected to occur with valganciclovir as well. If there is no suitable alternative to ganciclovir, then use in combination with enteric-coated didanosine with caution. Patients receiving concomitant therapy with didanosine and ganciclovir or valganciclovir should be monitored for didanosine toxicity. [#] [#]

The oral absorption and plasma concentrations of fluoroquinolone antibiotics or tetracyclines may be decreased in the presence of antacids such as those present in the buffering agents of certain oral didanosine dosage forms. Dosages of didanosine and quinolones should be separated by at least 2 hours. [#]

Based on data from an open-label randomized study and retrospective database analyses, clinicians are advised to use caution when administering enteric-coated didanosine, tenofovir DF, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads. [#]

Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is enteric-coated. Patients should be closely monitored for adequate clinical response when enteric-coated didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. [#]]]>
[#]

Coadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. [#]

Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity. Coadministration of allopurinol with didanosine increases didanosine AUC by 113% and Cmax by 69% in healthy subjects. [#]

Risk-benefit should be considered in patients with peripheral neuropathy; active alcoholism; history of or current hypertriglyceridemia; history of pancreatitis; or conditions requiring a low-sodium diet, including cardiac failure, cirrhosis of the liver, severe hepatic disease, peripheral or pulmonary edema, hypernatremia, hypertension, renal function impairment, toxemia of pregnancy, gouty arthritis, hepatic function impairment, or phenylketonuria. [#]

Patients with phenylketonuria should be made aware that didanosine chewable buffered tablets contain up to 73 mg of phenylalanine per two-tablet dose. [#]]]>
[#] ]]>[#] ]]>[#]]]>[#] To provide adequate buffering, at least two of the appropriate strength tablets of the buffered formulation (but no more than 4 tablets) should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption. Solutions made from didanosine chewable/dispersible buffered tablets that have been dispersed in water or dispersed in clear apple juice are stable for 1 hour at room temperature. The dispersion should be stirred just prior to consumption. [#]

After reconstitution with the appropriate admixture of water and liquid antacid by a pharmacist, the resulting suspension of didanosine pediatric powder for oral solution may be stored for up to 30 days in a refrigerator at 2 C to 8 C (36 F to 46 F). Discard any unused portion after 30 days. [#]]]>
[#]]]>
Videx EC and Videx Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Cooper DA. Update on didanosine. J Int Assoc Physicians AIDS Care (Chic Ill). 2002 Winter; 1(1): 15-2Crespo M, Ribera E, Suárez-Lozano I, Domingo P, Pedrol E, López-Aldeguer J, Muñoz A, Viladés C, Sánchez T, Viciana P, Teira R, García-Alcalde ML, Vergara A, Lozano F, Galindo MJ, Cosin J, Roca B, Terrón A, Geijo P, Vidal F, Garrido M; VACH Cohort Study Group. Effectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohort. J Antimicrob Chemother. 2009 Jan;63(1):189-96. Epub 2008 Nov 6.5.
Lewis W. Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy. Antivir Ther. 2005;10 Suppl 2:M13-27. Review.
Marcelin AG, Flandre P, Furco A, Wirden M, Molina JM, Calvez V; AI454-176 Jaguar Study Team. Impact of HIV-1 reverse transcriptase polymorphism at codons 211 and 228 on virological response to didanosine. Antivir Ther. 2006;11(6):693-9.
Masia M, Gutierrez F, Padilla S, Ramos JM, Pascual J. Severe toxicity associated with the combination of tenofovir and didanosine: case report and review. Int J STD AIDS. 2005 Sep;16(9):646-8. Review.
Ntemgwa ML, Toni TD, Brenner BG, Oliveira M, Asahchop EL, Moisi D, Wainberg MA. Nucleoside and nucleotide analogs select in culture for different patterns of drug resistance in human immunodeficiency viruses 1 and 2. Antimicrob Agents Chemother. 2008 Dec 8. [Epub ahead of print].
Torti C, Lapadula G, Barreiro P, Soriano V, Mandalia S, De Silvestri A, Suter F, Maggiolo F, Antinori A, Antonucci F, Maserati R, El Hamad I, Pierotti P, Sighinolfi L, Migliorino G, Ladisa N, Carosi G. CD4+ T cell evolution and predictors of its trend before and after tenofovir/didanosine backbone in the presence of sustained undetectable HIV plasma viral load. J Antimicrob Chemother. 2007 Apr 13.]]>
Pomona, NY 10970
Phone: 800-227-7522
Fax: 914-353-3843]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Emtricitabine]]>EMTRIVA® is the brand name of emtricitabine, a synthetic nucleoside analog with activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

EMTRIVA is available as capsules or as an oral solution.

EMTRIVA Capsules are for oral administration. Each capsule contains 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.

EMTRIVA Oral Solution is for oral administration. One milliliter (1 mL) of EMTRIVA Oral Solution contains 10 mg of emtricitabine in an aqueous solution with the following inactive ingredients: cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben, and propylparaben (added as preservatives), sodium phosphate (monobasic), propylene glycol, water, and xylitol (added as a sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH.

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EMTRIVA® is the brand name of emtricitabine, a synthetic nucleoside analog with activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

EMTRIVA is available as capsules or as an oral solution.

EMTRIVA Capsules are for oral administration. Each capsule contains 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.

EMTRIVA Oral Solution is for oral administration. One milliliter (1 mL) of EMTRIVA Oral Solution contains 10 mg of emtricitabine in an aqueous solution with the following inactive ingredients: cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben, and propylparaben (added as preservatives), sodium phosphate (monobasic), propylene glycol, water, and xylitol (added as a sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH.

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INDICATION AND USAGE

EMTRIVA is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection.

Additional important information regarding the use of EMTRIVA for the treatment of HIV-1 Infection:

  • EMTRIVA should not be coadministered with ATRIPLA, TRUVADA®, or Lamivudine-containing products.
  • In treatment-experienced patients, the use of EMTRIVA should be guided by laboratory testing and treatment history.

Description of Clinical Studies:

Treatment-Naive Adult Patients

Study 934: EMTRIVA + VIREAD + Efavirenz Compared with Zidovudine/Lamivudine + Efavirenz
Data through 48 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing EMTRIVA + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive patients. Patients had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4 cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was
5.01 log10 copies/mL (range 3.56–6.54). Patients were stratified by baseline CD4 count (< or ≥200 cells/mm3); 41% had CD4 cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 weeks for those patients who did not have efavirenz resistance at baseline are presented below.

Outcomes of Randomized Treatment at Week 48 (Study 934)

EMTRIVA + TDF + EFV (N=244) – Responder1: 84%; Virologic failure2: 2% (Rebound: 1%; Never Suppressed: 0%; Change in Antiretroviral Regimen: 1%); Death: <1%; Discontinued Due to Adverse event: 4%; Discontinued for Other Reasons3: 10%.

AZT/3TC + EFV (N=243) – Responder1: 73%; Virologic failure2: 4% (Rebound: 3%; Never Suppressed: 0%; Change in Antiretroviral Regimen: 1%); Death: 1%; Discontinued Due to Adverse event: 9%; Discontinued for Other Reasons3: 14%.

1. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.
2. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
3. Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.

The difference in the proportion of patients who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the EMTRIVA + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm3 in the EMTRIVA + VIREAD group and 158 cells/mm3 in the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the EMTRIVA + VIREAD group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

Study 301A: EMTRIVA QD + Didanosine QD + Efavirenz QD Compared to Stavudine BID + Didanosine QD + Efavirenz QD
Study 301A was a 48 week double-blind, active-controlled multicenter study comparing EMTRIVA (200 mg QD) administered in combination with didanosine and efavirenz versus stavudine, didanosine and efavirenz in 571 antiretroviral naive adult patients. Patients had a mean age of 36 years (range 18–69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients had a mean baseline CD4 cell count of 318 cells/mm3 (range 5–1317) and a median baseline plasma HIV RNA of 4.9 log10 copies/mL (range 2.6–7.0). Thirty-eight percent of patients had baseline viral loads >100,000 copies/mL and 31% had CD4 cell counts <200 cells/mL. Treatment outcomes are presented below.

Outcomes of Randomized Treatment at Week 48 (Study 301A)

EMTRIVA + Didanosine + Efavirenz (N=286) – Responder1: 81% (78%); Virologic failure2: 3%; Death: 0%; Study Discontinuation Due to Adverse Event: 7%; Study Discontinuation for Other Reasons3: 9%.

Stavudine + Didanosine + Efavirenz (N=285) – Responder1: 68% (59%); Virologic failure2: 11%; Death: <1%; Study Discontinuation Due to Adverse Event: 13%; Study Discontinuation for Other Reasons3: 8%.

1. Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
2. Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.
3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

The mean increase from baseline in CD4 cell count was 168 cells/mm3 for the EMTRIVA arm and 134 cells/mm3 for the stavudine arm.
Through 48 weeks in the EMTRIVA group, 5 patients (1.7%) experienced a new CDC Class C event, compared to 7 patients (2.5%) in the stavudine group.
 
Treatment-Experienced Adult Patients

Study 303: EMTRIVA QD + Stable Background Therapy (SBT) Compared to Lamivudine BID + SBT
Study 303 was a 48 week, open-label, active-controlled multicenter study comparing EMTRIVA (200 mg QD) to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 adult patients who were on a lamivudinecontaining triple-antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV-1 RNA ≤400 copies/mL.

Patients were randomized 1:2 to continue therapy with lamivudine (150 mg BID) or to switch to EMTRIVA (200 mg QD). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22–80), 86% were male, 64% Caucasian, 21% African-American and 13% Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm3 (range 37–1909), and a median baseline plasma HIV RNA of 1.7 log10 copies/mL (range 1.7–4.0).

The median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes are presented below.

Outcomes of Randomized Treatment at Week 48 (Study 303)

EMTRIVA + ZDV/d4T + NNRTI/PI (N=294) – Responder1: 77% (67%); Virologic failure2: 7%; Death: 0%; Study Discontinuation Due to Adverse Event: 4%; Study Discontinuation for Other Reasons3: 12%.

Lamivudine + ZDV/d4T + NNRTI/PI (N=146) – Responder1: 82% (72%); Virologic failure2: 8%; Death: <1%; Study Discontinuation Due to Adverse Event: 0%; Study Discontinuation for Other Reasons3: 10%.

1. Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
2. Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression.
3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

The mean increase from baseline in CD4 cell count was 29 cells/mm3 for the EMTRIVA arm and 61 cells/mm3 for the lamivudine arm.
Through 48 weeks, in the EMTRIVA group 2 patients (0.7%) experienced a new CDC Class C event, compared to 2 patients (1.4%) in the lamivudine group.

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Capsules containing emtricitabine 200 mg.

Oral solution containing emtricitabine 10 mg/mL.

DOSAGE AND ADMINISTRATION

EMTRIVA may be taken without regard to food.

Adult Patients (18 years of age and older):

  • EMTRIVA Capsules: one 200 mg capsule administered once daily orally.
  • EMTRIVA Oral Solution: 240 mg (24 mL) administered once daily orally.

Pediatric Patients (0–3 months of age):

  • EMTRIVA Oral Solution: 3 mg/kg administered once daily orally.

Pediatric Patients (3 months through 17 years):

  • EMTRIVA Oral Solution: 6 mg/kg up to a maximum of 240 mg (24 mL) administered once daily orally.
  • EMTRIVA Capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.

Dose Adjustment in Adult Patients with Renal Impairment:

Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment. Therefore, the dosing interval of EMTRIVA should be adjusted in patients with baseline creatinine clearance (CLcr) <50 mL/min using the following guidelines (see below). The safety and effectiveness of these dose adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Dose Adjustment in Adult Patients with Renal Impairment

Capsule (200 mg) – CLcr ≥50 mL/min: 200 mg every 24 hours; CLcr 30–49 mL/min: 200 mg every 48 hours; CLcr 15–29 mL/min: 200 mg every 72 hours; CLcr <15 mL/min or on hemodialysis*: 200 mg every 96 hours.

Oral Solution (10 mg/mL) – CLcr ≥50 mL/min: 240 mg every 24 hours (24 mL); Clcr 30–49 mL/min: 120 mg every 24 hours (12 mL); CLcr 15–29 mL/min: 80 mg every 24 hours (8 mL); CLcr <15 mL/min or on hemodialysis*: 60 mg every 24 hours (6 mL).

* Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.

Although there are insufficient data to recommend a specific dose adjustment of EMTRIVA in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval similar to adjustments for adults should be considered.

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Store oral solution refrigerated, 2–8 °C (36–46 °F). Emtriva oral solution should be used within 3 months if stored by the patient at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F).]]>
Mechanism of Action:
Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5’-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Antiviral Activity:
The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) value for emtricitabine was in the range of 0.0013–0.64 μM (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM).

Resistance:
Emtricitabine−resistant isolates of HIV have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study of treatment-naive patients treated with EMTRIVA, didanosine, and efavirenz, viral isolates from 37.5% of patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I mutations in the HIV reverse transcriptase gene.

In a clinical study of treatment-naive patients treated with either EMTRIVA, VIREAD®, and efavirenz or zidovudine/lamivudine and efavirenz, resistance analysis was performed on HIV isolates from all virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuations. Development of efavirenz resistance-associated mutations occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/12 (17%) analyzed patient isolates in the EMTRIVA + VIREAD group and in 7/22 (32%) analyzed patient isolates in the lamivudine/zidovudine group. Through 48 weeks of Study 934, no patients have developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.

Cross Resistance:
Cross-resistance among certain nucleoside analog reverse transcriptase inhibitors has been recognized. Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R mutation, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N mutation associated with resistance to NNRTIs was susceptible to emtricitabine.

Pharmacodynamics:
The in vivo activity of emtricitabine was evaluated in two clinical trials in which 101 patients were administered 25–400 mg a day of EMTRIVA as monotherapy for 10–14 days. A dose-related antiviral effect was observed, with a median decrease from baseline in plasma HIV-1 RNA of 1.3 log10 at a dose of 25 mg QD and 1.7 log10 to 1.9 log10 at a dose of 200 mg QD or BID.

Pharmacokinetics in Adults:
The pharmacokinetics of emtricitabine were evaluated in healthy volunteers and HIV-infected individuals. Emtricitabine pharmacokinetics are similar between these populations. (For additional information, consult the Emtriva complete prescribing information).

Absorption:
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of EMTRIVA Capsules to 20 HIV-infected subjects, the (mean ± SD) steady-state plasma emtricitabine peak concentration (Cmax) was
1.8 ± 0.7 μg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 hr•μg/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg/mL. The mean absolute bioavailability of EMTRIVA Capsules was 93% while the mean absolute bioavailability of EMTRIVA Oral Solution was 75%. The relative bioavailability of EMTRIVA Oral Solution was approximately 80% of EMTRIVA Capsules.

The multiple dose pharmacokinetics of emtricitabine are dose proportional over a dose range of 25–200 mg.

Effects of Food on Oral Absorption:
EMTRIVA Capsules and Oral Solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA Capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA Oral Solution was administered with either a high-fat or low-fat meal.

Distribution:
In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02–200 μg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.

Metabolism:
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (~4% of dose). No other metabolites were identifiable.

Elimination:
The plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Special Populations:
Race, Gender and Elderly
The pharmacokinetics of emtricitabine were similar in adult male and female patients and no pharmacokinetic differences due to race have been identified. The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.

Hepatic Impairment
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment, however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited.

Pediatrics
The pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-infected children, and the pharmacokinetic profile was characterized in four age groups (see below). The emtricitabine exposure achieved in children receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adults receiving a once-daily dose of 200 mg.

The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg QD x 4 days) during the first 3 months of life. The AUC observed in neonates who received a daily dose of 3 mg/kg of emtricitabine was similar to the AUC observed in pediatric patients ≥3 months to 17 years who received a daily dose of emtricitabine as a 6 mg/kg oral solution up to 240 mg or as a 200 mg capsule (see below).

Mean ± SD Pharmacokinetic Parameters by Age Groups for Pediatric Patients and Neonates Receiving EMTRIVA Capsules or Oral Solution

HIV-exposed Neonates
Age 0–3 mo (N=201; formulation: capsule [n=0], oral solution [n=20]) – Dose (mg/kg)2: 3.1 (2.9-3.4); Cmax (μg/mL): 1.6 ± 0.6; AUC (hr•μg/mL): 11.0 ± 4.2; T1/2 (hr): 12.1 ± 3.1.

HIV-infected Pediatric Patients
Age 3–24 mo (N=14; formulation: capsule [n=0], oral solution [n=14]) – Dose (mg/kg)2: 6.1 (5.5−6.8); Cmax (μg/mL): 1.9 ± 0.6; AUC (hr•μg/mL): 8.7 ± 3.2; T1/2 (hr): 8.9 ± 3.2.

Age 25 mo–6 yr (N=19; formulation: capsule [n=0], oral solution [n=19]) – Dose (mg/kg)2: 6.1 (5.6−6.7); Cmax (μg/mL): 1.9 ± 0.7; AUC (hr•μg/mL): 9.0 ± 3.0; T1/2 (hr): 11.3 ± 6.4.

Age 7–12yr (N=17; formulation: capsule [n=10], oral solution [n=7]) – Dose (mg/kg)2: 5.6 (3.1−6.6); Cmax (μg/mL): 2.7 ± 0.8; AUC (hr•μg/mL): 12.6 ± 3.5; T1/2 (hr): 8.2 ± 3.2.

Age 13–17 yr (N=27; formulation: capsule [n=26], oral solution [n=1]) – Dose (mg/kg)2: 4.4 (1.8−7.0); Cmax (μg/mL): 2.7 ± 0.9; AUC (hr•μg/mL): 12.6 ± 5.4; T1/2 (hr): 8.9 ± 3.3.

1. Two pharmacokinetic evaluations were conducted in 20 neonates over the first 3 months of life. Median (range) age of infant on day of pharmacokinetic evaluation was 26 (5–81) days.
2. Mean (range)

Renal Impairment
The pharmacokinetics of emtricitabine are altered in patients with renal impairment. In adult patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC of emtricitabine were increased due to a reduction in renal clearance (see below). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance <50 mL/min or in adult patients with ESRD who require dialysis. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.

Mean ± SD Pharmacokinetic Parameters in Adult Patients with Varying Degrees of Renal Function

Creatinine Clearance (mL/min) >80 (N=6) – Baseline creatinine clearance (mL/min): 107 ± 21; Cmax (μg/mL): 2.2 ± 0.6; AUC (hr•μg/mL): 11.8 ± 2.9; CL/F (mL/min): 302 ± 94; CLr (mL/min): 213 ± 89.

Creatinine Clearance (mL/min) 50–80 (N=6) – Baseline creatinine clearance (mL/min): 59.8 ± 6.5; Cmax (μg/mL): 3.8 ± 0.9; AUC (hr•μg/mL): 19.9 ± 1.2; CL/F (mL/min): 168 ± 10; CLr (mL/min): 121 ± 39.

Creatinine Clearance (mL/min) 30–49 (N=6) – Baseline creatinine clearance (mL/min): 40.9 ± 5.1; Cmax (μg/mL): 3.2 ± 0.6; AUC (hr•μg/mL): 25.1 ± 5.7; CL/F (mL/min): 138 ± 28; CLr (mL/min): 69 ± 32.

Creatinine Clearance (mL/min) <30 (N=5) – Baseline creatinine clearance (mL/min): 22.9 ± 5.3; Cmax (μg/mL): 2.8 ± 0.7; AUC (hr•μg/mL): 33.7± 2.1; CL/F (mL/min): 99 ± 6; CLr (mL/min): 30 ± 11.

Creatinine Clearance (mL/min) ESRD1 <30 (N=5) – Baseline creatinine clearance (mL/min): 8.8 ± 1.4; Cmax (μg/mL): 2.8 ± 0.5; AUC (hr•μg/mL): 53.2 ± 9.9; CL/F (mL/min 64 ± 12; CLr (mL/min): NA2.

1. ESRD patients requiring dialysis
2. NA = Not Applicable

Hemodialysis: Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Drug Interactions:
At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

EMTRIVA has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. (For additional information, consult the Emtriva complete prescribing information).

Pregnancy:
Emtricitabine is in FDA pregnancy category B. The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed. To monitor fetal outcomes of pregnant women exposed to emtricitabine, an antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1–800–258–4263.

Nursing Mothers:
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV: It is not known whether emtricitabine is secreted into human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving EMTRIVA.

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WARNINGS

  • Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including emtricitabine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. However, cases have also been reported in patients with no known risk factors. Treatment with EMTRIVA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
     
  • Patients Co-infected with HIV and Hepatitis B Virus: It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. EMTRIVA is not approved for the treatment of chronic HBV infection and the safety and efficacy of EMTRIVA have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of EMTRIVA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EMTRIVA and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Patients with Impaired Renal Function:
Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function.

Fat Redistribution:
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome:
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

The most common treatment emergent adverse events that occurred in patients receiving EMTRIVA with other antiretroviral agents in clinical studies 301A and 303 were headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in EMTRIVA and control treatment groups with the exception of skin discoloration which was reported with higher frequency in the EMTRIVA treated group. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

The adverse event profile in pediatric patients was generally comparable to that observed in clinical studies of EMTRIVA in adult patients.

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EMTRIVA Capsules and Oral Solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA Capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA Oral Solution was administered with either a high-fat or low-fat meal.

WARNINGS

  • EMTRIVA is a component of TRUVADA (a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate) and ATRIPLA (a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate). EMTRIVA should not be coadministered with TRUVADA or ATRIPLA. Due to similarities between emtricitabine and lamivudine, EMTRIVA should not be coadministered with other drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir.

Drug Interactions:
The potential for drug interactions with EMTRIVA has been studied in combination with zidovudine, indinavir, stavudine, famciclovir, and tenofovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.

]]>
[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]> Emtriva Prescribing Information from the FDA Web site [PDF] and from the manufacturer's Web site [PDF]. Borroto-Esoda K, Waters JM, Bae AS, Harris JL, Hinkle JE, Quinn JB, Rousseau FS. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses. 2007 Aug;23(8):988-95
Jenny-Avital ER. Tenofovir DF and emtricitabine vs. zidovudine and lamivudine. N Engl J Med. 2006 Jun 8;354(23):2506-8; author reply 2506-8. No abstract available.
McKinney RE Jr, Rodman J, Hu C, Britto P, Hughes M, Smith ME, Serchuck LK, Kraimer J, Ortiz AA, Flynn P, Yogev R, Spector S, Draper L, Tran P, Scites M, Dickover R, Weinberg A, Cunningham C, Abrams E, Blum MR, Chittick GE, Reynolds L, Rathore M; Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. 2007 Aug;120(2):e416-23. Epub 2007 Jul 23.
Molina JM, Journot V, Furco A, Palmer P, De Castro N, Raffi F, Morlat P, May T, Rancinan C, Chene G; Montana (ANRS 091) Study Group. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther. 2007;12(3):417-22.
Saag MS. Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus. Clin Infect Dis. 2006 Jan 1;42(1):126-31. Epub 2005 Nov 23. Review.]]>
<![CDATA[Emtricitabine/Tenofovir disoproxil fumarate]]>TRUVADA tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

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TRUVADA tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

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TRUVADA, a combination of EMTRIVA and VIREAD, is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection:

  • It is not recommended that TRUVADA be used as a component of a triple nucleoside regimen.
  • TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, VIREAD or lamivudine-containing products.
  • In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history.
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TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil).

DOSAGE AND ADMINISTRATION

Recommended Dose
The dose of TRUVADA for adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Dose Adjustment for Renal Impairment
Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment [see EMTRIVA or VIREAD Package Insert]. Therefore, the dosing interval of TRUVADA should be adjusted in patients with baseline creatinine clearance 30–49 mL/min using the recommendations below. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients.

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment.

Dosage Adjustment for Patients with Altered Creatinine Clearance

Recommended Dosing Interval
• Creatinine Clearance (mL/min)a ≥50: Every 24 hours.
• Creatinine Clearance (mL/min)a 30–49: Every 48 hours.
• Creatinine Clearance (mL/min)a <30 (Including Patients Requiring Hemodialysis): TRUVADA should not be administered.

a. Calculated using ideal (lean) body weight

No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.

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• Keep container tightly closed.
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.]]>
For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information.

Mechanism of Action
TRUVADA is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate.

Pharmacokinetics
TRUVADA: One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized below. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized below. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.

Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adultsa

Fasted Oral Bioavailabilityb (%) – Emtricitabine: 92 (83.1–106.4); Tenofovir: 25 (NC–45.0)
Plasma Terminal Elimination Half-Lifeb (hr) – Emtricitabine: 10 (7.4–18.0); Tenofovir: 17 (12.0–25.7)
Cmax c (μg/mL) – Emtricitabine: 1.8 ± 0.72d; Tenofovir: 0.30 ± 0.09
AUCc (μg•hr/mL) – Emtricitabine: 10.0 ± 3.12d; Tenofovir: 2.29 ± 0.69
CL/Fc (mL/min) – Emtricitabine: 302 ± 94; Tenofovir: 1043 ± 115
CLrenal c (mL/min) – Emtricitabine: 213 ± 89; Tenofovir: 243 ± 33

a. NC = Not calculated
b. Median (range)
c. Mean (± SD)
d. Data presented as steady state values.

Effects of Food on Oral Absorption
TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.

Special Populations

Race
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Gender
Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients
TRUVADA should not be administered to pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb).

Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Geriatric Patients
Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis.

Patients with Hepatic Impairment
The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions
The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in trials conducted in healthy volunteers.

Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating lack of clinically significant drug interactions between these agents and VIREAD.

Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown.
(For additional information, consult the Truvada complete prescribing information).

Microbiology

Mechanism of Action
Emtricitabine:
Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity
Emtricitabine and Tenofovir Disoproxil Fumarate:
In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.

Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 μM (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM).

Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5–2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).

Resistance
Emtricitabine and Tenofovir Disoproxil Fumarate:
HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.

In a clinical trial of treatment-naive subjects [Study 934], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subjects isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subjects isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2–4 fold reduction in susceptibility to tenofovir.

In treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed greater than 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.

Cross Resistance
Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

Tenofovir Disoproxil Fumarate: HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category B

Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.

Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1.
Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

(For additional information, consult the Truvada complete prescribing information).

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WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals.
     
  • TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV
It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD.

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.

Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min. No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with creatinine clearance below 30 mL/min or patients requiring hemodialysis.

TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent.

Decreases in Bone Mineral Density
Assessment of bone mineral density (BMD) should be considered for HIV-1 infected adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive adult subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects
receiving VIREAD.

In a clinical trial of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this trial, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD.

Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Early Virologic Failure
Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

The most common adverse reactions associated with Truvada (incidence >10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

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TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.

Coadministration with Other Products
TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

TRUVADA should not be administered with HEPSERA (adefovir dipivoxil).

Drug Interactions

No drug interaction trials have been conducted using TRUVADA tablets. Drug interaction trials have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of TRUVADA.

Didanosine
Coadministration of TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosineassociated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, TRUVADA and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions.

Atazanavir
Atazanavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions.

Tenofovir decreases the AUC and Cmin of atazanavir. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with TRUVADA.

Lopinavir/Ritonavir
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions.

Drugs Affecting Renal Function
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

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[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]

Tenofovir DF: White to off-white crystalline powder. [#]]]>
[#]

Tenofovir DF: 13.4 mg/mL in water at 25°C. [#]]]>
Truvada Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
[No authors listed] Truvada trials hold promise for new HIV prevention strategy. Once-a-day might keep HIV away. AIDS Alert. 2006 May;21(5):49-52.
Gazzard BG. Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients. Expert Opin Pharmacother. 2006 Apr;7(6):793-802.
Muñoz de Benito RM, Arribas López JR. Tenofovir disoproxil fumarate-emtricitabine coformulation for once-daily dual NRTI backbone. Expert Rev Anti Infect Ther. 2006 Aug;4(4):523-35.]]>
<![CDATA[Lamivudine]]>[#] ]]>[#] ]]>[#] [#] Lamivudine should always be used in conjunction with other antiretroviral agents and should not be used alone in the management of HIV infection. Lamivudine usually is used in three- or four-drug regimens that include another nucleoside reverse transcriptase inhibitor (NRTI) and either one or two protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). [#]

Lamivudine has been used in combination with zidovudine for prevention of mother-to-child transmission of HIV. Although the safety and efficacy of this two-drug regimen has not been established, it is considered one of several options used in HIV infected women in labor who have received no prior antiretroviral therapy. Lamivudine is also used in conjunction with zidovudine or, alternatively, with stavudine for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally to blood, body fluids, or tissues associated with a risk for transmission of HIV. [#] ]]>
[#] For HBV therapy, it is administered in doses lower than those used to treat HIV infection. The formulation and dosage of lamivudine used in HBV therapy are not appropriate for patients coinfected with HIV and HBV. [#] Patients with HIV infection should receive only dosing forms appropriate for treatment of HIV. The safety and efficacy of lamivudine have not been established for treatment of chronic HBV in patients coinfected with HIV and HBV. [#] ]]>[#] ]]>[#] Scored, film-coated tablets, appropriate for pediatric dosing, that contain lamivudine 150 mg. [#]

Oral solution containing lamivudine 10 mg/ml in 240 ml bottles. [#]

The recommended dose of lamivudine for HIV infected adults is 300 mg once daily or 150 mg twice daily, in combination with other antiretroviral agents. The recommended dose of lamivudine for HIV infected children age 3 months to 16 years is 4 mg/kg twice daily, up to a maximum of 150 mg twice daily, in combination with other antiretroviral agents. [#]

Lamivudine dosage should be adjusted in accordance with renal function in patients with creatinine clearance below 50 ml/min. No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis. [#] ]]>
[#] ]]>
[#] The principal mode of action of L-TP is inhibition of HIV reverse transcription via viral DNA chain termination after incorporation of the nucleoside analogue. L-TP is a weak inhibitor of mitochondrial DNA polymerase and mammalian DNA polymerases alpha and beta. [#] 3TC-LP is a structural analogue of deoxycytidine triphosphate (dC-TP), the natural substrate for reverse transcriptase. 3TC-TP appears to compete with naturally occurring dC-TP for incorporation into viral DNA by reverse transcriptase. Following incorporation of 3TC-TP into the viral DNA chain instead of dC-TP, viral DNA synthesis is terminated prematurely because the absence of a 3'-hydroxyl group on the oxathiolane ring prevents further 5' to 3' phosphodiester linkages. Lamivudine has in vitro virustatic activity against HIV-1, HIV-2, and HBV, but it appears to be inactive against other common human viruses (e.g., cytomegalovirus, Epstein-Barr virus, influenza virus, herpes simplex virus types 1 and 2, respiratory syncytial virus, varicella-zoster virus). [#]

Lamivudine is rapidly absorbed, with bioavailability from 80% to 88% in adults and adolescents and from 66% to 68% in children. Food delays the peak serum concentration; however, there is no significant difference in bioavailability when lamivudine is taken with food. Time to peak concentration (Tmax) is approximately 0.5 to 2 hours after a single 100 mg dose; with food, it increases to approximately 3.2 hours; with fasting, Tmax is about 1 hour. [#]

Lamivudine is widely distributed after administration. Lamivudine crosses the blood-brain barrier and is distributed into the cerebrospinal fluid (CSF) to a limited extent. In children, CSF concentrations have ranged from 10% to 17% of the corresponding non-steady-state serum concentration. [#] Apparent volume of distribution after intravenous (IV) administration in 20 patients was 1.3 +/- 0.4 l/kg, suggesting that lamivudine distributes into extravascular spaces. The volume of distribution was independent of dose and did not correlate with body weight. [#]

Plasma protein binding is low (36%). [#] Metabolism is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose in six HIV infected adults, 5.2% +/- 1.4% was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined. [#] The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 20 HIV-infected patients given a single IV dose, renal clearance was 280.4 +/- 75.2 ml/min, representing 71% +/- 16% of total clearance of the drug. In most single-dose studies in infected patients, the mean elimination half-life ranged from 5 to 7 hours. Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 mg/kg to 10 mg/kg. [#] The half-life of intracellular lamivudine triphosphate is 11 to 15 hours; serum half-life of lamivudine is about 2.6 hours in adults and 1.7 to 2 hours in children. The renal clearance of lamivudine is greater than the glomerular filtration rate, implying active secretion into the renal tubules. [#] Hemodialysis increases lamivudine clearance by a range of 64 to 88 ml/min, but the length of dialysis treatment (i.e., 4 hours) may not be long enough to alter mean lamivudine exposure. It is not known if lamivudine is removed by continuous (24 hour) hemodialysis. [#]

Resistance to lamivudine can be produced in vitro by serial passage of HIV-1 in the presence of increasing concentrations of the drug, and strains of HIV-1 with in vitro resistance to lamivudine have emerged during therapy with the drug. Primary infection with lamivudine-resistant HIV-1 has been reported rarely in adults who were treatment naive. While some strains of zidovudine-resistant HIV-1 may be susceptible to lamivudine, strains resistant to both zidovudine and lamivudine have been isolated. HIV isolates resistant to zalcitabine, zidovudine, didanosine, lamivudine, and stavudine have been isolated from a limited number of patients who received zidovudine in conjunction with zalcitabine or didanosine for 1 year or longer. Mutations identified in these multidrug-resistant isolates were Ala62 to Val, Val75 to Ile, Phe77 to Leu, Phe116 to Tyr, and Gln151 to Met; the mutation at position 151 appears to play an important role in the development of multidrug resistance. The possibility of cross resistance among lamivudine, didanosine, and zalcitabine based on reverse transcriptase codon 184 mutations also is of concern. [#] ]]>
[#] [#]

Post-treatment exacerbations of HBV infection have been reported in HIV uninfected patients treated with lamivudine for chronic HBV infection when lamivudine therapy was discontinued. Similar exacerbations of HBV infection have been reported in patients infected with both HIV and HBV when lamivudine therapy was switched to a regimen not containing lamivudine. The causal relationship between discontinuation of lamivudine therapy and exacerbation of HBV infection is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether reinitiation of lamivudine alters the course of post-treatment exacerbations of hepatitis. [#]

Adverse effects seen with the use of lamivudine include pancreatitis, paresthesia and peripheral neuropathy, skin rash, or splenomegaly, and are more commonly observed in pediatric patients than in adults. [#] ]]>
[#]

Lamivudine exposure was increased by 44% and lamivudine renal clearance was decreased by 30% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and zidovudine in one small study resulted in a 39% increase in peak plasma concentration of zidovudine with no significant changes in the area under the concentration-time curve (AUC) or total clearance of lamivudine or zidovudine. [#]

Concurrent administration of lamivudine with indinavir and zidovudine resulted in a 6% decrease in AUC of lamivudine, no change in AUC of indinavir, and a 36% increase in AUC of zidovudine. No adjustment in dose is necessary. Concurrent administration of lamivudine with drugs associated with pancreatitis (e.g., alcohol, didanosine, IV pentamidine, sulfonamides) or with drugs associated with peripheral neuropathy (e.g., dapsone, didanosine, isoniazid, stavudine, zalcitabine) should be avoided or done with caution. [#]

The higher and lower dose formulations of lamivudine should not be used concurrently. Concurrent administration of products that also contain lamivudine should be avoided, including the coformulations of abacavir sulfate and lamivudine; lamivudine and zidovudine; and abacavir sulfate, lamivudine, and zidovudine. [#] ]]>
[#]

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Lamivudine for HIV (brand name Epivir) in oral solution or tablet form contains higher doses of the active ingredient (lamivudine) than the lamividune formulation used to treat chronic HBV infection (brand name Epivir-HBV). Patients with HIV infection should receive only dosing forms appropriate for treatment of HIV. [#]

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used in caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur. [#]

Risk-benefit should be considered in HIV infected patients with renal function impairment. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Epivir Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Lehmann C, Wyen C, Fatkenheuer G. Rapid Improvement of Liver Function in a Patient with HIV and Hepatitis B Coinfection Treated with Lamivudine and Tenofovir. Infection. 2006 Aug;34(4):234-5.
LePrevost M, Green H, Flynn J, Head S, Clapson M, Lyall H, Novelli V, Farrelly L, Walker AS, Burger DM, Gibb DM. Pediatric European Network for the Treatment of AIDS 13 Study Group. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. 2006 Jun;25(6):533-7.
Levy V, Grant RM. Antiretroviral Therapy for Hepatitis B Virus-HIV-Coinfected Patients: Promises and Pitfalls. Clin Infect Dis. 2006 Oct 1;43(7):904-10. Epub 2006 Aug 23.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
<![CDATA[Lamivudine/Zidovudine]]>Lamivudine/zidovudine is a fixed-dose combination tablet containing two synthetic nucleoside analogues: lamivudine and zidovudine. Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine, each of which inhibits HIV-1 viral reverse transcriptase. [#]

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Lamivudine/zidovudine is a fixed-dose combination tablet containing two synthetic nucleoside analogues: lamivudine and zidovudine. Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine, each of which inhibits HIV-1 viral reverse transcriptase. [#]

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Lamivudine/zidovudine was originally approved by the U.S. Food and Drug Administration (FDA) on September 27, 1997. Lamivudine/zidovudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. [#] [#]

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Oral. [#]

]]>
Film-coated tablets containing lamivudine 150 mg and zidovudine 300 mg. [#]

The recommended dose of lamivudine/zidovudine for adults and adolescents weighing greater than or equal to 30 kg is one tablet twice daily. [#]

The recommended oral dosage of scored lamivudine/zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is one tablet administered twice daily. Before prescribing lamivudine/zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a lamivudine/zidovudine tablet, the liquid oral formulations should be prescribed: lamivudine oral solution and zidovudine syrup. [#]

Because lamivudine/zidovudine is a fixed-dose combination tablet, it should not be prescribed for pediatric patients weighing less than 30 kg or patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 50 mL/min), those experiencing dose-limiting adverse events, or those with impaired hepatic function or liver cirrhosis. Liquid and solid oral formulations of the individual components of lamivudine/zidovudine are available for these populations. [#]

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[#]]]>
Lamivudine is a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ. In vitro, lamivudine with zidovudine had synergistic antiretroviral activity. [#]

Following oral dosing, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). The mean oral bioavailability, mean apparent volume of distribution, plasma protein binding, median CSF:plasma ratio, mean systemic clearance, mean renal clearance, and elimination half-life (approximate range) of lamivudine in fasting patients are 86%, 1.3 L/kg, less than 36%, 0.12, 0.33 L/hr/kg, 0.22 L/hr/kg and 5 to 7 hrs, respectively. [#]

Zidovudine is also a synthetic nucleoside analogue that is phosphorylated intracellularly to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture. [#]

Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine AUC. The pharmacokinetic properties (mean oral bioavailability, mean apparent volume of distribution, plasma protein binding, median CSF:plasma ratio, mean systemic clearance, mean renal clearance, and elimination half-life [approximate range]) of zidovudine in fasting patients are 64%, 1.6 L/kg, less than 38%, 0.60, 1.6 L/hr/kg, 0.34 L/hr/kg and 0.5 to 3 hrs, respectively. [#]

One lamivudine/zidovudine tablet is bioequivalent to one lamivudine tablet (150 mg) plus one zidovudine tablet (300 mg) following single-dose administration to fasting healthy adults (n = 24). Lamivudine/zidovudine may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine/zidovudine (Combivir) with food was similar when compared to fasting healthy subjects (n = 24). [#]

Lamivudine/zidovudine is in FDA Pregnancy Category C. No adequate or well-controlled studies of the combination drug have been done in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). Lamivudine/zidovudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine/zidovudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry (APR) has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. [#]

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in nonpregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. [#]

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug. [#]

Zidovudine pharmacokinetics were studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. [#]

Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus. [#]

Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one fifth the lethal dose. [#]

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine/zidovudine. Although no studies of lamivudine/zidovudine excretion in breast milk have been performed, lactation studies performed with lamivudine and zidovudine show that both drugs are excreted in human breast milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. In another study, after administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum. [#]

In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with zidovudine and lamivudine. Lamivudine/zidovudine combination therapy delayed the emergence of mutations conferring zidovudine resistance. HIV strains resistant to both lamivudine and zidovudine have been isolated from patients after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown. [#]

Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from patients treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated patients showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I). [#]

HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from patients treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed substitutions in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. [#]

Cross-resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to lamivudine. Cross-resistance to abacavir, didanosine, tenofovir, and zalcitabine has been observed in some patients harboring lamivudine-resistant HIV-1 isolates. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged. [#]

In a study of 167 HIV-1-infected patients, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine. [#]

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Lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other antiretrovirals. These conditions are sometimes fatal. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering lamivudine/zidovudine to any patient with known risk factors for liver disease; however, cases have been reported in patients with no known risk factors. Treatment with lamivudine/zidovudine should be suspended in any patient who develops clinical or laboratory findings that suggest the presence of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). [#]

Zidovudine has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced HIV disease. Lamivudine/zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm3 or hemoglobin less than 9.5 g/dL. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine/zidovudine. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed. [#]

Myopathy and myositis have occurred with prolonged use of zidovudine and may occur during therapy with lamivudine/zidovudine. [#]

Acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine/zidovudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine/zidovudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted. [#]

Post treatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of hepatitis B viral DNA (HBV DNA). Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. [#]

Important Differences Among Lamivudine-Containing Products: Combivir tablets contain a higher dose of the same active ingredient (lamivudine) than Epivir-HBV (lamivudine) tablets and oral solution. Epivir-HBV was developed for treating chronic hepatitis B. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. [#]

Emergence of Lamivudine-Resistant HBV: In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. [#]

Lamivudine/zidovudine should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine/zidovudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur. [#]

Immune reconstitution syndrome has been reported in patients receiving anti-HIV therapy, including lamivudine/zidovudine. Patients who exhibit an inflammatory response to indolent or residual opportunistic infections may require further evaluation before initiating certain anti-HIV regimens. [#]

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

Reported adverse events occurring in clinical trials of lamivudine/zidovudine affected the following body systems: body as a whole (headache, malaise, fatigue, fever, chills); digestive (nausea, diarrhea, vomiting, anorexia and/or decreased appetite, abdominal pain and cramps, dyspepsia); nervous system (neuropathy, insomnia and other sleep disorders, dizziness, depressive disorders); respiratory (nasal signs and symptoms, cough); skin (rash); and musculoskeletal (musculoskeletal pain, myalgia, arthralgia). [#]

Adverse events reported during post-approval use of lamivudine/zidovudine or either of the component drugs occurred in the following body systems: body as a whole (redistribution or accumulation of body fat); cardiovascular (cardiomyopathy); endocrine and metabolic (gynecomastia, hyperglycemia); gastrointestinal (oral mucosal pigmentation, stomatitis); general (vasculitis, weakness); hemic and lymphatic (anemia [including pure red cell aplasia and anemias progressing on therapy], lymphadenopathy, splenomegaly); hepatic and pancreatic (lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B); hypersensitivity (sensitization reactions [including anaphylaxis], urticaria); musculoskeletal (muscle weakness, creatine phosphokinase elevation, rhabdomyolysis); nervous (paresthesia, peripheral neuropathy, seizures); respiratory (abnormal breath sounds, wheezing ); and skin (alopecia, erythema multiform, Stevens-Johnson syndrome). [#]

The most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult and pediatric HIV-1 clinical studies of combination lamivudine and zidovudine were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. [#]

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Lamivudine/zidovudine tablets may be administered with or without food. Administering the drug with food did not alter the area under the concentration-time curve (AUC) for lamivudine or zidovudine, as compared to administration under fasting conditions. [#]

Lamivudine/zidovudine is a fixed-dose combination of lamivudine and zidovudine. Lamivudine/zidovudine should not be administered concomitantly with other lamivudine- or zidovudine-containing products including Epivir (lamivudine) tablets and oral solution, Epivir-HBV tablets and oral solution, Retrovir (zidovudine) tablets, capsules, syrup, and IV infusion, Epzicom (abacavir sulfate and lamivudine) tablets, or Trizivir (abacavir sulfate, lamivudine, and zidovudine) tablets; or emtricitabine-containing products, including Atripla (efavirenz, emtricitabine, and tenofovir), Emtriva (emtricitabine), or Truvada (emtricitabine and tenofovir). [#]

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and lamivudine/zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of lamivudine/zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see the complete prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Co-administration of ribavirin and zidovudine is not advised. [#]

Antiretroviral agents: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine/zidovudine in combination with zalcitabine is not recommended. Concomitant use of lamivudine/zidovudine with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided. [#]

Doxorubicin: Concomitant use of lamivudine/zidovudine with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. [#]

Hematologic/bone marrow suppressive/cytotoxic agents: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. [#]

Trimethoprim/Sulfamethoxazole (TMP/SMX): No change in dose of either TMP/SMX or lamivudine is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP. [#]

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Lamivudine/zidovudine tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the products. [#]

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[#] Zidovudine: Thymidine, 3'-azido-3'-deoxy- [#] ]]>[#] Zidovudine: 30516-87-1 [#]]]>[#]; Zidovudine: C10-H13-N5-O4 [#]]]>[#]; Zidovudine: 267.24 [#]]]>[#]

Zidovudine: White to beige, odorless, crystalline solid [#]]]>
[#]

Zidovudine: 20.1 mg/mL in water at 25°C. [#]]]>
Combivir Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26.
Fischl MA, Burnside AE Jr, Farthing CE, Thompson MA, Bellos NC, Williams VC, Kauf TL, Wannamaker PG, Shaefer MS; ESS40005 Study Team. Twice-daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial. Pharmacotherapy. 2003 Nov;23(11):1432-40.
Kumar P, Rodriguez-French A, Thompson M, Tashima K, Averitt D, Wannamaker P, Williams V, Shaefer M, Pakes G, Pappa K; ESS40002 Study Team. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/staviudine/nelfinavir on lipids, metabolic parameters and efficacy in antiviral-naïve patients: effect of sex and ethnicity. HIV Med. 2006 Mar;7(2):85-98.
Matheron S, Descamps D, Boue F, Livrozet JM, Lafeuillade A, Aquilina C, Troisvallets D, Goetschel A, Brun-Vezinet F, Mamet JP, Thiaux C; CNA3007 Study Group. Triple nucleoside combination zidovudine/lamivudine/abacavir versus zidovudine/lamivudine/nelfinavir as first-line therapy in HIV-1-infected adults: a randomized trial. Antivir Ther. 2003 Apr;8(2):163-71.
Ruane PJ, Parenti DM, Margolis DM, Shepp DH, Babinchak TJ, Van Kempen AS, Kauf TL, Danehower SA, Yau L, Hessenthaler SM, Goodwin D, Hernandez JE; COL30336 Study Team. Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-naive HIV-infected adults. HIV Clin Trials. 2003 Jul-Aug;4(4):231-43.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
North Wales, PA 19454
Phone: 888-TEVA-USA (838-2872)]]>
<![CDATA[Stavudine]]>[#]]]>[#]]]>[#] [#] Additionally, stavudine is indicated for the treatment of patients with HIV infection who have received prolonged previous treatment with zidovudine. The duration of clinical benefit from antiretroviral therapy involving stavudine may be limited. If disease progression occurs during stavudine treatment, an alternative antiretroviral therapy is recommended. [#]

Although stavudine was used as monotherapy in initial studies evaluating the safety and efficacy of the drug, it should not be used alone in the management of HIV infection. Stavudine is also used in conjunction with other antiretroviral agents for postexposure prophylaxis in health care workers and in other individuals exposed occupationally to blood, tissues, or other body fluids associated with a risk for transmission of the HIV virus. [#]]]>
[#]]]>
Oral solution containing stavudine 1 mg/ml. [#]

The recommended dosages based on body weight are as follows: 40 mg twice daily for patients weighing 60 kg (132 lbs) or more and 30 mg twice daily for patients weighing less than 60 kg (132 lbs). The interval between doses of stavudine should be 12 hours. The recommended dose for pediatric patients at least 14 days old and weighing less than 30 kg (66 lbs) is 1 mg/kg/dose, given every 12 hours. Pediatric patients weighing 30 kg (66 lbs) or greater should receive the recommended adult dosage. [#]

Dosing should be adjusted in patients with impaired renal function, according to the recommendations in the manufacturer's prescribing information. For patients on hemodialysis, the recommended dosage is 20 mg every 24 hours for patients weighing more than 60 kg or 15 mg every 24 hours for patients weighing less than 60 kg. [#]
 
Stavudine dose reductions for peripheral neuropathy have not been established. [#]]]>
[#] [#]]]>
[#] A stavudine concentration ranging from 0.009 to 4 micromolar is required to inhibit HIV replication by 50% in vitro. The in vitro potency of stavudine against HIV is similar to that of zidovudine. [#]

Following oral administration to HIV-infected patients, stavudine is rapidly absorbed, with the peak plasma concentration (Cmax) occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration of capsules or solution. [#] Stavudine has an oral bioavailability of 86% in adults and 77% in children. Stavudine may be taken with or without food; administration with food results in a decrease in Cmax and time to Cmax but does not have an appreciable effect on the area under the concentration time curve (AUC) of the drug. [#] Data from single- and multiple-dosing studies indicate that the Cmax and AUC of stavudine increase in proportion to dose over the dose range of 0.03 to 4 mg/kg; there is no evidence that accumulation occurs following multiple doses. [#]

Stavudine distributes equally between red blood cells and plasma. [#] In a study of 8 children, stavudine crossed the blood brain barrier and distributed into the cerebrospinal fluid (CSF) with a mean CSF-to-plasma concentration of 59%. [#] Stavudine is distributed into CSF following oral administration. In a limited number of HIV infected adults receiving oral stavudine at a dosage of 40 mg twice daily in conjunction with other antiretroviral agents, CSF concentrations of the drug averaged 71 ng/ml in samples taken 1 hour after a dose at 8 weeks of therapy; steady-state Cmax at this time averaged 930 ng/ml. Similar CSF and plasma concentrations of stavudine were measured in these patients after almost 2 years of continuous therapy. Following a single intravenous dose in HIV infected individuals, the volume of distribution is 46 l in adults and 0.73 l/kg in pediatric patients 5 weeks to 15 years of age. Results of a study in HIV infected men indicate that stavudine is distributed into semen in concentrations approximating those of concurrent plasma concentrations. [#]

Stavudine is in FDA Pregnancy Category C. [#] Adequate and well-controlled studies have not been done in pregnant women. It is not known whether stavudine crosses the placenta in humans; however, it does cross the placenta in rats. It is not known whether stavudine reduces perinatal transmission of HIV infection as does zidovudine. Stavudine should be used with caution during pregnancy and only if clearly needed. No evidence of impaired fertility was seen in rats given stavudine at doses that resulted in a Cmax that was 216 times that observed in humans who received a clinical dosage of 1 mg/kg per day. Rats and rabbits exposed to levels of stavudine up to 399 and 183 times, respectively, the clinical dosage for humans revealed no evidence of teratogenicity. The incidence of common skeletal variation, incomplete ossification, and neonatal mortality increased in rats exposed to 399 times the human exposure. A slight postimplantation loss was seen at 216 times the human exposure. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including stavudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. [#]

It is not known whether stavudine is distributed into human milk; however, it is distributed into milk in rats. Because of the potential for HIV transmission and for potential adverse effects in breastfed infants, mothers receiving antiretroviral medications should be instructed not to breastfeed. [#]

Binding of stavudine to serum proteins is negligible over the concentration range of 0.01 to 11.4 mcg/ml. The mean elimination half-life of stavudine following a single oral dose is 1.6 hours in HIV infected adults and 0.96 hours in HIV infected pediatric patients (5 weeks to 15 years of age). [#] In patients with renal function impairment (creatinine clearances of less than 25 ml/min), the half-life is approximately 3.7 to 5.5 hours. The time to Cmax is 0.5 to 1.5 hours. The intracellular half-life of stavudine triphosphate is approximately 3.5 hours, with peak serum concentration of approximately 1.4 mcg/ml after a single oral dose of 70 mg stavudine. [#]

Renal elimination accounts for about 40% of overall clearance into urine over a 6 to 24 hour period, regardless of the route of administration. [#] Approximately 50% of an administered dose undergoes nonrenal elimination. The exact metabolic fate of stavudine is unknown. Intracellularly, in both virus-infected and uninfected cells, stavudine is converted to stavudine monophosphate by cellular thymidine kinase. The monophosphate is subsequently converted to stavudine diphosphate and then to stavudine triphosphate. [#] It is not known whether stavudine is removed by peritoneal dialysis. [#] The mean renal clearance is about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. Oral clearance of stavudine decreases and the terminal elimination half-life increases as creatinine clearance decreases; therefore, dosage of stavudine should be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis. [#]

HIV-1 isolates with reduced susceptibility to stavudine have been selected in vitro and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 stavudine-treated patients receiving prolonged, 6 to 29 months, treatment of stavudine monotherapy, showed that post-therapy isolates from four patients exhibited IC50 values more than fourfold (ranging from 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated mutations T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated mutation Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified. [#]]]>
[#]

Studies suggest that lactic acidosis and severe hepatomegaly with steatosis may be more often associated with antiretroviral regimens containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors; however, fatal lactic acidosis has been reported in patients with and without known risk factors for liver disease. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and sudden unexplained weight loss), respiratory symptoms (tachypnea, dyspnea), or neurologic symptoms such as motor weakness might be indicative of lactic acidosis. Therapy with stavudine should be suspended in patients with suspected lactic acidosis. Permanent discontinuation of stavudine should be considered in patients with confirmed lactic acidosis. [#]

An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. Fatal and nonfatal pancreatitis has occurred when stavudine was part of a combination regimen that included didanosine with or without hydroxyurea. Treatment should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with caution. The new regimen should not include either didanosine or hydroxyurea. Fatal lactic acidosis has occurred in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. [#]

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases have occurred in the setting of lactic acidosis. If motor weakness develops, stavudine therapy should be discontinued. Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine. [#] Stavudine dose reductions for peripheral neuropathy have not been established. [#] 

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy and lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered. [#]

Postmarketing adverse events associated with the use of stavudine include the following: abdominal pain, allergic reaction, chills/fever, redistribution/accumulation of body fat, anorexia, pancreatitis, anemia, leukopenia, thrombocytopenia, macrocytosis, symptomatic hyperlactatemia/lactic acidosis,  hepatic steatosis, hepatitis, liver failure, diabetes mellitus,  hyperglycemia, myalgia, insomnia, severe motor weakness (most often reported in the setting of lactic acidosis), neutropenia, lipoatrophy, and lipodystrophy. [#] [#]
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[#] Didanosine with or without hydroxyurea may increase the risk of pancreatitis, peripheral neuropathy, and hepatotoxicity if taken concurrently with stavudine. [#]

Concomitant use of stavudine and zidovudine is not recommended due to possible competitive inhibition of the intracellular phosphorylation of stavudine. In vitro studies detected an antagonistic antiviral effect between stavudine and zidovudine at a molar ratio of 20 to 1, respectively; concurrent use is not recommended until in vivo studies demonstrate that these medications are not antagonistic in their anti-HIV activity. [#] [#]]]>
[#]

Stavudine is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation. [#]

Risk-benefit should be considered in patients with alcoholism, hepatic function impairment, peripheral neuropathy, or renal function impairment. [#]]]>
[#] ]]>[#] ]]>[#]]]>[#]]]>[#]]]> Zerit Prescribing Information from the FDA Web site[PDF]. A more current version may be available on the manufacturer's Web site.
Bakare-Odunola MT, Enemali I, Garba M, Obodozie OO, Mustapha KB. The influence of lamivudine, stavudine and nevirapine on the pharmacokinetics of chlorpropamide in human subjects. Eur J Drug Metab Pharmacokinet. 2008 Jul-Sep;33(3):165-71.
Blanche S. Safety of stavudine during pregnancy. J Infect Dis. 2005 May 1;191(9):1567-8; author reply 1568-9.
Milinkovic A, Martinez E, Lopez S, de Lazzari E, Miro O, Vidal S, Blanco JL, Garrabou G, Laguno M, Arnaiz JA, Leon A, Larrousse M, Lonca M, Mallolas J, Gatell JM. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Antivir Ther. 2007;12(3):407-15.
Paolucci S, Baldanti F, Campanini G, Cancio R, Belfiore A, Maga G, Gerna G. NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine. Antiviral Res. 2007 Jul 2; [Epub ahead of print]]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Tenofovir disoproxil fumarate]]>VIREAD® is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

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VIREAD® is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

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INDICATIONS AND USAGE

HIV-1 Infection
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.
The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:

  • VIREAD should not be used in combination with TRUVADA® or ATRIPLA®.

Chronic Hepatitis B
VIREAD is indicated for the treatment of chronic hepatitis B in adults.

The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:

  • This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease
  • VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease.
  • The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions of efficacy.
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Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil .

DOSAGE AND ADMINISTRATION

Recommended Dose in Adults
For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.

In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.

Recommended Dose in Pediatric Patients (≥12 Years of Age and ≥35 kg)
For the treatment of HIV-1 in pediatric patients 12 years of age and older with body weight ≥35 kg (≥77 lb): The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.

Dose Adjustment for Renal Impairment in Adults
Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations shown below. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients.

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment.

Dosage Adjustment for Patients with Altered Creatinine Clearance

Recommended 300 mg Dosing Interval
  • Creatinine Clearance  ≥50 mL/mina: Every 24 hours
  • Creatinine Clearance  30–49 mL/mina: Every 48 hours
  • Creatinine Clearance  10–29 mL/mina: Every 72 to 96 hours
  • Hemodialysis Patients: Every 7 days or after a total of approximately 12 hours of dialysisb

a. Calculated using ideal (lean) body weight.
b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.

No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.

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Mechanism of Action
Tenofovir disoproxil fumarate is an antiviral drug.

Pharmacokinetics
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Absorption
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg•hr/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.

Distribution
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes. Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Effects of Food on Oral Absorption
Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations

Race:
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.

Gender: Tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients 12 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to <18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg. Pharmacokinetic studies have not been performed in pediatric subjects <12 years of age.

Geriatric Patients: Pharmacokinetic studies have not been performed in the elderly (>65 years).

Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (see below). It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis.

Pharmacokinetic Parameters (Mean ± SD) of Tenofovira in Subjects with Varying Degrees of Renal Function

Baseline Creatinine Clearance >80 mL/min (N=3) – Cmax: 0.34 ± 0.03 μg/mL; AUC0-∞: 2.18 ± 0.26 μg•hr/mL; CL/F: 1043.7 ± 115.4 mL/min; CLrenal: 243.5 ± 33.3 mL/min.

Baseline Creatinine Clearance 50–80 mL/min (N=10) – Cmax: 0.33 ± 0.06 μg/mL; AUC0-∞: 3.06 ± 0.93 μg•hr/mL; CL/F: 807.7 ± 279.2 mL/min; CLrenal: 168.6 ± 27.5 mL/min.

Baseline Creatinine Clearance 30–49 mL/min (N=8) – Cmax: 0.37 ± 0.16 μg/mL; AUC0-∞: 6.01 ± 2.50 μg•hr/mL; CL/F: 444.4 ± 209.8 mL/min; CLrenal: 100.6 ± 27.5 mL/min.

Baseline Creatinine Clearance 12–29 mL/min (N=11) – Cmax: 0.60 ± 0.19 μg/mL; AUC0-∞: 15.98 ± 7.22 μg•hr/mL; CL/F: 177.0 ± 97.1 mL/min; CLrenal: 43.0 ± 31.2 mL/min.

a. 300 mg, single dose of VIREAD

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in VIREAD dosing is required in patients with hepatic impairment.

Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other medicinal products is low.

Microbiology

Mechanism of Action
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Activity against HIV

Antiviral Activity

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 μM to 2.2 μM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).

Resistance
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold reduction in susceptibility to tenofovir.

In Study 903 of treatment-naïve subjects (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to VIREAD were not identified in this study.

In Study 934 of treatment-naïve subjects (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the VIREAD + EMTRIVA group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Cross Resistance
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.

In Studies 902 and 907 conducted in treatment-experienced subjects (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. Virologic responses for subjects in the genotype substudy were similar to the overall study results.

Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. VIREAD-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

In the protocol defined analyses, virologic response to VIREAD was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.

Studies 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 13 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (IntentTo-Treat)a

Baseline VIREAD Susceptibilityb     Change in HIV-1 RNAc (N)
                 <1                                                       -0.74 (35)
                 >1 and ≤3                                          -0.56 (49)
                 >3 and ≤4                                           -0.3 (7)
                 >4                                                       -0.12 (9)

a. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
b. Fold change in susceptibility from wild-type.
c. Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL.

Activity against HBV

Antiviral Activity
The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 μM, with CC50 (50% cytotoxicity concentration) values >100 μM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside anti-HBV reverse transcriptase inhibitors emtricitabine, entecavir, lamivudine and telbivudine, no antagonistic activity was observed.

Resistance
Cumulative VIREAD genotypic resistance was evaluated annually with the paired HBV reverse transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA ≥400 copies/mL at the end of each study year (or at discontinuation of VIREAD monotherapy) using an as-treated analysis. From four ongoing VIREAD trials (Studies 102, 103, and 106 in subjects with compensated liver disease, and Study 108 in subjects with decompensated liver disease), 10% (69/660) of VIREAD recipients with compensated liver disease receiving up to 144 weeks of VIREAD monotherapy and 18% (7/39) of VIREAD recipients with decompensated liver disease receiving up to 48 weeks of VIREAD monotherapy remained viremic at their last time-point on VIREAD monotherapy. In the HEPSERA-naïve HBeAg+ subject population from Study 103, 74% (17/23) of the subjects with HBV DNA ≥400 copies/mL at their last time-point on VIREAD monotherapy had a baseline viral load of >9 log10 copies/mL. Treatment emergent amino acid substitutions in the HBV reverse transcriptase were identified in 46% (32/69) of those subjects in Studies 102, 103, 106, and 108 with evaluable paired genotypic data; no specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD (genotypic or phenotypic analyses).

Cross Resistance
Cross resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.

In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7 to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.

HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6 to 6.9-fold that of wild type virus. An HBV strain expressing rtL180M, rtT184G, rtS202I, and rtM204V together had a 6.9-fold reduction in susceptibility to tenofovir.

HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9 to 1.5-fold that of wild type virus.

In the four VIREAD-treatment studies, prior to treatment with VIREAD, 14, 15, and 2 subjects had HBV harboring either adefovir resistance-associated substitutions (rtA181T/V and/or rtN236T) or lamivudine resistance-associated substitutions (rtM204I/V), or both, respectively. Following up to 144 weeks of VIREAD treatment, 11 of the 14 subjects with adefovir-resistant HBV, 12 of the 15 subjects with lamivudineresistant HBV, and 1 of the 2 subjects with both adefovir- and lamivudine-resistant HBV achieved virologic suppression (HBV DNA <400 copies/mL). Two of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions and one of the 5 subjects whose virus harbored these substitutions and an rtM204I substitution remained viremic following up to 32 weeks of VIREAD monotherapy.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B
Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD.

(For additional information, consult the Viread complete prescribing information). 

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WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals.
     
  • Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Exacerbation of Hepatitis after Discontinuation of Treatment
Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment
Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD.

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA®.

Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.

VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.

Patients Coinfected with HIV-1 and HBV
Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.
HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.

Decreases in Bone Mineral Density
Assessment of bone mineral density (BMD) should be considered for adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range.

In a clinical study of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD.

The bone effects of VIREAD have not been studied in patients with chronic HBV infection.

Fat Redistribution
In HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Early Virologic Failure
Clinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

More than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access studies. The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

In HBV-infected subjects with compensated liver disease, the most common adverse reaction (all grades) was nausea (9%). In HBV-infected subjects with decompensated liver disease, the most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.

]]>
Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Coadministration with Other Products
VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.

VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

Drug Interactions

Didanosine
Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosineassociated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When administered with VIREAD, Cmax and AUC of didanosine (administered as either the buffered or enteric-coated formulation) increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate (tenofovir DF) with didanosine 400 mg daily.

In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing <60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions.

Atazanavir
Atazanavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.

VIREAD decreases the AUC and Cmin of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD.

Lopinavir/Ritonavir
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.

Drugs Affecting Renal Function
Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir.

In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

]]>
[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]>[#]]]> Viread Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, Rozenbaum W, Le Teuff G, Trylesinski A, Piketty C; TECOVIR Study Group. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006 Mar;43(3):548-55.
Gerard L, Chazallon C, Taburet AM, Girard PM, Aboulker JP, Piketty C. Renal function in antiretroviral-experienced patients treated with tenofovir disoproxil fumarate associated with atazanavir/ritonavir. Antivir Ther. 2007;12(1):31-9.
Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, Lazzarin A, Schewe K, Lange J, Wyatt C, Curtis S, Chen SS, Smith S, Bischofberger N, Rooney JF. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007 Jun 19;21(10):1273-81.
Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, Grant R, Clarke EE, Doh AS, Ridzon R, Jaffe HS, Cates W. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007 May 25;2(5):e27.
Pham PA, Gallant JE. Tenofovir disoproxil fumarate for the treatment of HIV infection. Expert Opin Drug Metab Toxicol. 2006 Jun;2(3):459-69.
Squires K, Pozniak AL, Pierone G Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF, Cheng A; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):313-20. Summary for patients in: Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):I22.]]>
Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264
]]>
Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264
]]>
<![CDATA[Zidovudine]]>[#] [#] ]]>[#] [#] ]]>[#] [#]

Zidovudine is also approved for the prevention of vertical transmission of the HIV virus from an HIV infected mother to her fetus, as part of a regimen that includes oral zidovudine administered to the mother beginning at 14 to 34 weeks of gestation, intravenous zidovudine syrup administered to the mother during labor, and zidovudine administered to the neonate for the first 6 weeks of life. However, transmission to infants may still occur in some cases, despite the use of this regimen. [#]

Zidovudine is used in conjunction with lamivudine for postexposure prophylaxis of HIV infection in health care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for HIV transmission. [#] ]]>
[#]

Intravenous injection. [#] ]]>
[#] [#]

Oral solution containing zidovudine 50 mg per 5 ml in 240 ml bottle. [#] [#]

Film-coated tablets containing zidovudine 300 mg. [#] [#]

Intravenous (IV) infusion containing zidovudine 10 mg/ml in 20 ml single-use vials. [#]

The recommended oral dose of zidovudine in adults who are not pregnant is 600 mg daily (either 300 mg twice daily or 200 mg three times daily).

The recommended dose in pediatric patients ages 4 weeks to 18 years should be determined by body weight or body surface area. [#] Dosing by weight is as follows: For pediatric patients who weigh from 4 kg to less than 9 kg, a total daily dose of 24 mg/kg should be given in equal doses twice or three times daily. For pediatric patients who weigh from 9 kg to less than 30 kg, a total daily dose of 18 mg/kg should be given in equal doses twice or three times daily. For pediatric patients who weigh 30 kg or more 600 mg per day should be given in equal doses twice or three times daily. [#] Dosing by body surface area is available in the prescribing information.

The recommended dosing regimen for administration to pregnant women (more than 14 weeks of pregnancy) is 100 mg, five times daily, until the start of labor. During labor and delivery, IV zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous IV infusion of 1 mg/kg/hr (total body weight) until clamping of the umbilical cord. The neonate should receive 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing through 6 weeks of age. In patients maintained on hemodialysis or peritoneal dialysis, the recommended dose of zidovudine is 100 mg every 6 to 8 hours. [#] ]]>
[#] [#]

Store zidovudine oral solution at 15 C to 25 C (59 F to 77 F). [#] [#]

Store zidovudine for injection concentrate for IV infusion at 15 C to 25 C (59 F to 77 F) and protect from light. [#] ]]>
[#] Intracellular (host cell) conversion of zidovudine to the triphosphate derivative is necessary for the antiviral activity of the drug; however, activation for antibacterial action does not depend on phosphorylation within host cells but rather depends on conversion within bacterial cells. [#]

Zidovudine is absorbed rapidly and almost completely from the gastrointestinal tract, with peak serum concentrations (Cmax) occurring in adults within 0.4 to 1.5 hours after an oral dose. Zidovudine appears to undergo first-pass metabolism. In fasting adults, about 64% of an oral dose reaches systemic circulation as unchanged drug. Cmax achieved following administration of zidovudine tablets is equivalent to that following administration of capsules or oral solution; however, absorption following oral administration shows considerable individual variability. [#]

There is limited information on the distribution of zidovudine in the body, but the drug appears to be widely distributed. The apparent volume of distribution for the drug in adults and children with HIV infection is 1.4 to 1.6 l/kg. [#] Zidovudine is distributed into the cerebrospinal fluid (CSF) following both oral and IV administration; distribution to CSF averages 68% of the plasma concentration in children and 60% of the plasma concentration in adults. Time to peak concentration (Tmax) in serum is 0.5 to 1.5 hours. [#]

Zidovudine is in FDA Pregnancy Category C. In humans, treatment with zidovudine during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations. [#] Teratogenic effects were not seen in this experiment at doses of 600 mg/kg per day or less. Zidovudine crosses the placenta and is distributed into cord blood, fetal blood, and amniotic fluid as well as fetal liver, muscle, and central nervous system tissue.

Zidovudine is distributed into human milk. Potential toxicities of antiretroviral agents in infants exposed to the drugs via breast milk are unknown. In addition, efficacy of antiretroviral therapy for prevention of postpartum transmission of HIV through breast milk is unknown. Because of the risk of transmission of HIV to an uninfected infant through breast milk, the U.S. Centers for Disease Control and Prevention (CDC) currently recommends that HIV infected women not breastfeed infants. To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine (or other antiretrovirals), an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. [#]

Plasma protein binding of zidovudine is low (30% to 38%). [#] Zidovudine is rapidly metabolized via glucuronidation in the liver principally to 3'-azido -3'-deoxy- 5'-O-beta-d- glucopyranuronosylthymidine (GZDV). [#]

Following hepatic metabolism, elimination of zidovudine is primarily renal. In adults, 63% to 95% of the dose is excreted in urine, approximately 14% to 18% by glomerular filtration and active tubular secretion. Approximately 72% to 74% of the GZDV metabolite is recovered in urine within 6 hours of administration. [#] The plasma half-life of zidovudine in adults averages approximately 0.5 to 3 hours following oral or IV administration. Following IV administration, plasma concentrations decline in a biphasic manner; half-life in adults is less than 10 minutes in the initial phase and 1 hour in the terminal phase. [#] Current data on the efficacy of removing zidovudine by dialysis vary, but hemodialysis and peritoneal dialysis appear to have a negligible effect. Hemodialysis does enhance the elimination of GZDV; however, dialysis clearance of GZDV is minimal compared to the clearance of GZDV in patients with normal renal function. [#]

Emergence of zidovudine resistance appears to be a function of the duration of zidovudine therapy, the severity of HIV disease, and the overall potency of the regimen in which the drug is used. Resistance is most likely to develop in patients with advanced HIV infection, those with low initial absolute helper/inducer T-cell counts, and those receiving prolonged zidovudine therapy. Although it has been suggested that zidovudine resistance may develop at a slower rate in patients with asymptomatic HIV infection than in those with more advanced disease, high-level zidovudine resistance has emerged in patients with asymptomatic infection, especially in those who have received up to 3 years of zidovudine monotherapy. [#]

Although the mechanisms of resistance or reduced susceptibility to NRTIs have not been fully determined to date, specific mutations of HIV RT at critical codons on the pol gene fragment have been associated with zidovudine resistance. Zidovudine resistance develops in a progressive, stepwise manner, and each reduction in susceptibility appears to be associated with the acquisition of an additional mutation in the HIV RT gene. The degree of resistance appears to depend on the number and combinations of these mutations. [#]

Further study is needed to more fully evaluate the extent of cross resistance among the NRTIs. Some in vitro studies indicate that zidovudine-resistant HIV generally is susceptible to didanosine, zalcitabine, and stavudine; however, some zidovudine-resistant strains may also be cross resistant or have decreased susceptibility to other NRTIs, including didanosine, lamivudine, stavudine, and zalcitabine. The mutation at position 151 appears to play an important role in the development of multidrug resistance. The pattern of mutations with combination therapy is different from that seen with zidovudine monotherapy. Cross resistance between zidovudine and PIs is unlikely, because these drugs have different target enzymes. The potential for cross resistance between zidovudine and NNRTIs is also considered low, because the drugs bind at different sites on the RT enzyme and have different mechanisms of action. [#] ]]>
[#]

The most frequent adverse effects of zidovudine are granulocytopenia and anemia. These are inversely related to the CD4 count at the start of therapy and directly related to dosage and duration of therapy. Significant anemia most commonly occurs after 4 to 6 weeks of therapy. Other adverse effects include changes in platelet count, hepatotoxicity, lactic acidosis, myopathy, neurotoxicity, severe headache, insomnia, myalgia, nausea, changes in pigmentation, hyperpigmentation of nails, and bone marrow depression. [#]

Immune reconstitution syndrome has been reported in some patients treated with combination antiretroviral therapy, including zidovudine. During the initial phase of combination antiretroviral therapy, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection [#] , cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [#]

In monotherapy clinical studies using zidovudine, the most common adverse events reported were headache, malaise, anorexia, and nausea. [#] ]]>

Concurrent administration of ganciclovir or interferon alfa with zidovudine is not recommended because severe hematologic toxicity may occur. Patients receiving these medications concurrently should be monitored frequently for abnormalities in hemoglobin, hematocrit, and white blood cell count; dose reduction or discontinuation of one or both of the medications may be necessary. [#]

Concurrent use of probenecid with zidovudine increases serum concentrations and prolongs elimination half-life for zidovudine, resulting in an increased risk of toxicity. In one small trial, a very high incidence of rash was observed in patients receiving probenecid concurrently with zidovudine. Influenza-like symptoms such as myalgia, malaise, and fever have also occurred. [#]

Concurrent use of doxorubicin or ribavirin and zidovudine is not recommended; in vitro studies indicate an antagonistic relationship between doxorubicin or ribavirin with zidovudine. [#] Ribavirin inhibits the phosphorylation of zidovudine to its active triphosphate form, thus antagonizing the in vitro antiviral activity of zidovudine against HIV. These drugs should not be used concurrently. [#]

Low phenytoin plasma levels have been reported in some patients receiving zidovudine. A pharmacokinetic interaction study showed no effect on phenytoin kinetics, but a 30% decrease of zidovudine clearance was observed with concurrent use of phenytoin and zidovudine. [#]

Total serum concentrations of zidovudine increase when atovaquone, fluconazole, methadone, probenecid, or valproic acid are coadministered with zidovudine. Nelfinavir, rifampin, or ritonavir coadministered with zidovudine decreases the total serum concentration of zidovudine. [#]

Concurrent administration of products that also contain zidovudine, including the coformulations of lamivudine and zidovudine and abacavir sulfate, lamivudine, and zidovudine, should be avoided. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Retrovir Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Retrovir IV Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Arvold ND, Ngo-Giang-Huong N, McIntosh K, Suraseranivong V, Warachit B, Piyaworawong S, Changchit T, Lallemant M, Jourdain G; Perinatal HIV Prevention Trial (PHPT-1), Thailand. Maternal HIV-1 DNA load and mother-to-child transmission. AIDS Patient Care STDS. 2007 Sep;21(9):638-43.
Cressey TR, Leenasirimakul P, Jourdain G, Tawon Y, Sukrakanchana PO, Lallemant M. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1-infected patients weighing less than 60 kg on highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2006 Jul;42(3):387-9.
Dao H, Mofenson LM, Ekpini R, Gilks CF, Barnhart M, Bolu O, Shaffer N. International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S42-55. Review.
Jamieson DJ, Clark J, Kourtis AP, Taylor AW, Lampe MA, Fowler MG, Mofenson LM. Recommendations for human immunodeficiency virus screening, prophylaxis, and treatment for pregnant women in the United States. Am J Obstet Gynecol. 2007 Sep;197(3 Suppl):S26-32.]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
Phone: 614-436-2222
Fax: 614-436-2610]]>
<![CDATA[Acyclovir]]>[#] [#] ]]>[#] [#] ]]>[#] Topical acyclovir is approved for the treatment of initial episodes of genital herpes and HSV infections in immunocompromised patients; however, systemic acyclovir is more effective and may be preferred. [#] ]]>[#] [#] [#] ]]>[#] [#] ]]>[#]

Tablets containing acyclovir 400 mg and 800 mg. [#]

Oral banana-flavored suspension containing acyclovir 200 mg per 5 mL. [#]

Acyclovir sodium in each 10 mL vial contains acyclovir sodium equivalent to 500 mg of acyclovir. Each 20 mL vial contains acyclovir sodium equivalent to 1,000 mg of acyclovir. [#]

5% topical ointment in 3 g and 15 g tubes containing acyclovir 50 mg in a polyethylene glycol base. [#]

5% topical cream in 2 g tubes containing acyclovir 50 mg in an aqueous cream base. [#] ]]>
[#]

Store acyclovir sodium for injection at temperatures between 15 C to 25 C (59 F to 77 F). [#]

Store 5% topical ointment at temperatures between 15 C to 25 C (59 F to 77 F) in a dry place. [#]

Store 5% topical cream at or below a temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [#] ]]>
[#] [#]

Acyclovir's absorption from the gastrointestinal (GI) tract is variable and incomplete; an estimated 10% to 30% of an oral dose is absorbed. Some data suggest that GI absorption of acyclovir may be saturable; in healthy adults, the extent of absorption decreases with increasing dose. Less than dose-proportional plasma concentration increases do not appear to be a function of the dosage form. Food does not appear to affect acyclovir's absorption. Peak plasma concentration of acyclovir usually occurs within 1.5 to 2.5 hours after oral administration. In adults with normal renal function receiving 5 or 10 mg/kg of acyclovir IV over 1 hour every 8 hours, mean steady state peak plasma concentrations were 9.8 or 22.9 mcg/mL, respectively. [#] [#]

Acyclovir is widely distributed into body tissues and fluids, including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, cerebrospinal fluid (CSF), herpetic vesicular fluid, and semen. The reported apparent volume of distribution of acyclovir is 32.4 to 61.8 l/1.73 m2 in adults. Following IV infusion, acyclovir generally diffuses well into CSF; in patients with uninflamed meninges, reported CSF concentrations of acyclovir are approximately 50% of concurrent serum acyclovir concentrations. [#]

Acyclovir is in FDA Pregnancy Category B. There are no adequate and well-controlled studies of acyclovir in pregnant women. When administered to mice, rabbits, and rats during organogenesis at doses up to 22 times normal human plasma levels, acyclovir was not teratogenic. Acyclovir did not impair fertility or reproduction in mice or rats, though at higher doses implantation efficacy decreased in rats and rabbits. Acyclovir crosses the placenta. Limited data indicate that the drug is distributed into milk at concentrations up to 4.1 times greater than concurrent maternal plasma concentrations. As a result, acyclovir should be administered to nursing mothers with caution and only when indicated. [#]

In vitro, acyclovir is approximately 9% to 33% bound to plasma proteins at drug concentrations of 0.41 to 52 mcg/mL. In adults with normal renal function, the half-life of oral acyclovir ranges from 2.5 to 3.3 hours, and the half-life of parenteral acyclovir is approximately 2.5 hours. Acyclovir is excreted principally in urine via glomerular filtration and tubular secretion; most of a single IV dose of the drug is excreted unchanged in urine within 24 hours of administration. Limited data suggest that peritoneal dialysis and blood exchange transfusions do not appreciably remove the drug. Hemodialysis reduces plasma concentrations of acyclovir by about 60%. Doses and frequency of administration of the drug should be modified according to creatinine clearance and age. [#] [#] [#]

Resistance to acyclovir can result from qualitative and quantitative changes in viral TK or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially those with advanced HIV infection. Most acyclovir-resistant mutants are TK-deficient; these TK-negative mutants may cause severe disease in infants and immunocompromised adults. Although acyclovir is apparently unable to eliminate an established latent infection, acyclovir-resistant mutants appear less able of establishing a latent infection. The possibility of viral resistance to acyclovir should only be considered in patients who show poor clinical response during therapy. [#] [#] ]]>
[#]

The most frequent adverse effects observed with acyclovir use are phlebitis (inflammation at the parenteral injection site), symptoms of acute renal failure, headache, malaise, and GI disturbances (e.g., nausea, vomiting, diarrhea). Rare but serious adverse effects include encephalopathy, urticaria, and hematologic abnormalities such as thrombocytopenia or thrombocytosis, hematuria, or anemia. [#] [#]

Adverse effects reported in controlled clinical trials of topical acyclovir ointment include mild pain, transient burning and stinging, and local pruritus. Voluntary reports of adverse reactions that have been received since marketing include edema, pain at the application site, pruritus and rash. [#]

The most common adverse reactions of topical acyclovir cream include dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin. [#] ]]>
[#]

Amphotericin B has strengthened the antiviral effect of acyclovir against pseudorabies virus in vitro. Interferon has also shown additive or synergistic antiviral effects with acyclovir in vitro against HSV-1 cultures. The clinical importance of these interactions is not known. Drugs with the potential for clinically significant interactions with acyclovir include antifungal agents (e.g., ketoconazole), probenecid, interferon, intrathecal methotrexate, and zidovudine. Neurotoxicity has been reported in one case of concurrent acyclovir and zidovudine administration. [#]

Food does not appear to affect acyclovir's absorption; oral dosage forms may be given with or without food. [#] ]]>
[#]

Acyclovir use should be carefully considered in patients with pre-existing renal function impairment or dehydration. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#]

Prior to reconstitution, acyclovir suspension is stable without refrigeration for 24 months. Refrigeration causes formation of a precipitate, which redissolves when the suspension is returned to room temperature. The oral suspension requires shaking before administering a dose. [#] ]]>
[#]

Acyclovir sodium has a maximum solubility of greater than 100 mg/ml in water at 25 C, but at physiologic pH and 37 C, the drug is almost completely unionized and has a maximum solubility of 2.5 mg/ml. [#] ]]>
Zovirax Capsules, Tablets, and Suspension Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Zovirax IV Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Zovirax Cream Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis. 2005 Feb 1;191 Suppl 1:S107-14. Review.
Corey L. Challenges in genital herpes simplex virus management. J Infect Dis. 2002 Oct 15;186 Suppl 1:S29-33. Review.
Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. ClinInfect Dis. 2006 Aug 1;43(3):347-56. Epub 2006 Jun 15.
Villarreal EC. Current and potential therapies for the treatment of herpes-virus infections. Prog Drug Res. 2003;60:263-307.]]>
Pittsburgh, PA 15222
Phone: 800-796-9526]]>
Research Triangle Park, NC 27709
Phone: 888-825-5249]]>
<![CDATA[Adefovir dipivoxil]]>[#] ]]>[#] ]]>[#] In December 1999, Gilead Sciences announced the termination of its adefovir dipivoxil development program for the treatment of HIV. [#] There are limited data to support the use of adefovir dipivoxil in HIV/HBV coinfected individuals. [#] ]]>[#]

Efficacy and safety have also been evaluated in patients with lamivudine-resistant virus and in pre-- and post--liver transplant patients. [#] ]]>
[#] ]]>[#]

Once-daily dosing is recommended by the manufacturer for patients with normal renal function. The manufacturer suggests the following altered dosage regimens for patients with renal impairment: 10 mg every other day for creatinine clearance (CrCl) of 20 to 49 ml/min, 10 mg every 3 days for CrCl of 10 to 19 ml/min, and 10 mg every 7 days after dialysis for patients receiving hemodialysis. [#] ]]>
[#] ]]>
[#] Adefovir is phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Adefovir diphosphate, a nucleotide analogue, inhibits HBV polymerase by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. [#]

The approximate oral bioavailability of adefovir from a single 10-mg dose of adefovir dipivoxil is 59%. Following oral administration of a single dose of adefovir dipivoxil 10 mg, the median peak adefovir plasma concentration (Cmax) was 18.4 ng/ml and occurred at a median 1.75 hours postdose. Terminal elimination half-life of plasma adefovir is approximately 7.48 hours. [#]

In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% or less over the adefovir concentration range of 0.1 to 25 mcg/ml. The volume of distribution at steady state is approximately 392 and 352 ml/kg following IV administration of 1.0 or 3.0 mg/kg/day, respectively. [#]

Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion; 45% of a dose is recovered in the urine over 24 hours. Thirty-five percent of a dose is removed during 4-hour hemodialysis. [#]

Cmax, area under the plasma concentration-time curve (AUC), and half-life are increased in patients with moderately or severely impaired renal function or with end-stage renal disease requiring hemodialysis compared to people with normal renal function. It is recommended that the dosing interval be modified in patients with renal impairment. [#]

Adefovir dipivoxil is in FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Studies in rats and rabbits at doses 23 to 40 times greater than human exposure, respectively, identified no embryotoxicity or teratogenicity. [#] To monitor fetal outcomes of pregnant women exposed to adefovir dipivoxil, an Antiretroviral Pregnancy Registry has been established. Health care providers are encouraged to register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether adefovir is excreted in human milk; breastfeeding is discouraged in women taking adefovir dipivoxil. [#]

There are no data on the effect of adefovir on HBV transmission from mothers to infants. Infant immunization should be used to prevent neonatal HBV infection. The safety and efficacy of adefovir dipivoxil have not been established in the pediatric population. [#]

N236T and A181V mutations have been identified in genotypic analyses as contributors to adefovir resistance. Both mutations have caused a decrease in lamivudine susceptibility in vitro. Recombinant HBV variants containing mutations associated with lamivudine resistance (L180M, M204V, V173L) in the HBV polymerase gene were susceptible to adefovir in vitro. HBV variants with polymerase mutations R or W501Q, both associated with resistance to HBV immunoglobulin, and T128N were susceptible to adefovir in vitro. [#]

Adefovir has activity against HIV but only at much higher doses than those used to treat HBV infection. A chronic HBV patient with unrecognized or untreated HIV infection may develop HIV resistance to adefovir when taken at HBV-approved, non-HIV-suppressive doses. Although adefovir has not been shown to suppress HIV RNA in patients, limited data are available on the use of adefovir to treat patients coinfected with HBV and HIV. [#] [#]

A randomized, double-blind, placebo-controlled trial compared daily tenofovir disoproxil fumarate 300 mg to adefovir dipivoxil 10 mg therapy in 52 HIV/HBV coinfected patients on stable HAART. At baseline, 75% of patients had HIV RNA levels less than 50 copies/ml and 98% had compensated liver disease. During monthly evaluations over 48 weeks, both drugs successfully lowered HBV DNA levels and were considered safe and effective in HIV/HBV coinfected patients. [#] ]]>
[#]

HIV resistance may emerge in HBV-infected individuals with untreated HIV infection who are treated with HBV medications, including adefovir dipivoxil. [#]

Nephrotoxicity, characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus, is the primary dose-limiting toxicity of adefovir dipivoxil therapy at the substantially higher doses required for HIV antiviral activity. This toxicity is also possible at the lower dose required for HBV antiviral activity when given to chronic HBV patients in the long term. [#]

Lactic acidosis and severe hepatomegaly with steatosis, potentially fatal, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Female gender, obesity, and prolonged nucleoside analogue exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases of hepatotoxicity have also been reported in patients with no known risk factors. Treatment with adefovir dipivoxil should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. [#]

Severe adverse effects possible with adefovir treatment include hematuria and glycosuria. Moderate adverse effects that have been reported in patients taking adefovir dipivoxil include asthenia; abdominal pain; headache; and, more rarely, diarrhea, dyspepsia, flatulence, heartburn, and nausea. [#]

Pre-- and post--liver transplantation patients with chronic HBV and clinical evidence of lamivudine resistance and patients with underlying renal insufficiency or other risk factors for renal dysfunction represent special risk groups. Common treatment-related adverse events reported in these patients include hepatic failure, increases in ALT and AST, abnormal liver function, increased coughing, pharyngitis, sinusitis, pruritus, rash, increases in serum creatinine, renal failure, and renal insufficiency. [#] ]]>
[#]

Because adefovir is eliminated by the kidney, coadministration of adefovir dipivoxil with renally excreted drugs or nephrotoxic drugs may cause further nephrotoxicity or may increase serum concentrations of either adefovir or the coadministered drugs. Patients should be monitored closely for adverse events when adefovir dipivoxil is coadministered with drugs that are excreted renally or are known to affect renal function, such as aminoglycosides, cyclosporin, and nonsteroidal anti-inflammatory drugs. Adefovir does not appear to interact with concurrently administered lamivudine, acetaminophen, or sulfamethoxazole/trimethoprim. [#]

When adefovir dipivoxil was coadministered with ibuprofen 800 mg three times daily, adefovir Cmax and AUC increased by 33% and 23%, respectively. The clinical significance of this increase in adefovir exposure is unknown. [#]

Adefovir does not inhibit or act as a substrate for cytochrome P-450 (CYP) enzymes. The potential for adefovir to induce CYP enzymes is not known. Based on the results of in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP-mediated interactions between adefovir and other medicines is low. [#]

Administration of adefovir dipivoxil with nucleoside analogues increases the risk of lactic acidosis and severe hepatomegaly with steatosis. Coadministration of these drugs should be suspended in patients who develop symptoms or laboratory findings indicative of hepatic toxicity. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Hepsera Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Benhamou Y, Bonyhay L. Treatment of hepatitis B virus infection in patients coinfected with HIV. Gastroenterol Clin North Am. 2004 Sep;33(3):617-27. Review.
Gaia S, Barbon V, Smedile A, Olivero A, Carenzi S, Lagget M, Alessandria C, Rizzetto M, Marzano A. Lamivudine-resistant chronic hepatitis B: An observational study on adefovir in monotherapy or in combination with lamivudine. J Hepatol. 2008 Jan 31; [Epub ahead of print].
Murphy MJ, Wilcox RD. Management of the coinfected patient: human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C. Am J Med Sci. 2004 Jul;328(1):26-36.
Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B; ACTG Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006 Nov;44(5):1110-6.
Shepherd J, Jones J, Takeda A, Davidson P, Price A. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation. Health Technol Assess. 2006 Aug;10(28):iii-iv, xi-xiv, 1-183. Review.]]>
<![CDATA[Amphotericin B]]>[#] Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated drug or non-lipid associated drug. [#] ]]>[#] Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated drug or non-lipid associated drug. [#] ]]>[#]

Amphotericin B desoxycholate is used as an alternative agent for long-term suppressive therapy (i.e., secondary prophylaxis) or maintenance therapy to prevent recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV-infected individuals who have received adequate treatment of these infections. Long-term suppressive or maintenance therapy is generally continued for life. The U.S. Public Health Service and Infectious Diseases Society of America make no recommendations for discontinuing therapy in patients receiving antiretroviral therapy who have CD4 cell counts greater than 100 cells/mm3. However, limited data suggest that discontinuing suppressive therapy in HIV-infected adults and adolescents may be associated with low risk for recurrence of cryptococcosis. Individuals who consider discontinuing suppressive therapy should have successfully completed initial therapy for cryptococcosis, remained asymptomatic with respect to cryptococcosis, and have sustained (longer than 6 months) CD4 cell counts greater than 100 to 200 cells/mm3 in response to potent antiretroviral therapy. [#] ]]>
[#]

Although some azole antifungal agents (e.g., itraconazole, fluconazole) are now also recognized as drugs of choice for the treatment of many systemic mycoses, amphotericin B desoxycholate remains the drug of first choice for the initial treatment of severe, life-threatening fungal infections, especially in immunocompromised patients. Because clinical experience with newer amphotericin B formulations is limited, these formulations have generally been reserved for second-line therapy in patients with invasive fungal infections that have not responded to amphotericin B desoxycholate or in patients who cannot tolerate amphotericin B desoxycholate. [#] Specific indications are listed below by formulation.

Amphotericin B cholestryl sulfate complex is indicated for the treatment of invasive aspergillosis in cases where renal impairment or unacceptable toxicity precludes the use of amphotericin B desoxycholate in effective doses and in cases where prior amphotericin B desoxycholate therapy has failed. [#]

Amphotericin B lipid complex is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of amphotericin B desoxycholate therapy. [#]

Amphotericin B liposomal is indicated as empiric therapy for presumed fungal infections in febrile, neutropenic patients; treatment of cryptococcal meningitis in HIV-infected patients; treatment of aspergillosis, candidiasis, or cryptococcosis in patients refractory to amphotericin B desoxycholate or with renal impairment that precludes the use of amphotericin B desoxycholate; and the treatment of leishmaniasis. [#]

Amphotericin B desoxycholate may be the preferred agent for pregnant women with invasive fungal infections due to concerns regarding the use of azole antifungal agents during pregnancy. Intravenous amphotericin B has also been used for empiric therapy in febrile neutropenic patients and for prophylaxis in certain immunosuppressed individuals (e.g., cancer patients and bone marrow or solid organ transplant patients. [#]

Amphotericin B is also used for the treatment of certain protozoal infections, including leishmaniasis and amebic meningoencephalitis. Amphotericin B is not effective against bacteria, rickettsiae, or viruses. [#] ]]>
[#]

May also be given intrathecally, intra-articularly, intrapleurally, and by local instillation or irrigation. [#] ]]>
[#]

The maximum recommended IV total daily dose of Amphoterixin B desoxycholate for adults should not exceed 1.5mg/kg. Prior to initiation of conventional IV amphotericin B therapy, a single test dose of the drug (1 mg in 20 mL of 5% dextrose injection) should be administered IV over 20 to 30 minutes and the patient carefully monitored every 30 minutes for 2 hours. Depending on the patient's cardio-renal status, dosage may gradually be increased by 5 to 10 mg daily to a final daily dosage of 0.5 to 0.7 mg/kg. [#]

Conventional amphotericin B for injection when administered to pediatric patients should be limited to the smallest dose compatibile with an effective therapeutic regimen. [#]

The recommended IV dose of liposomal amphotericin B for infants and small children is 0.2 to 0.5 mg/mL (base) per kg of body weight per day and is administered in 5% dextrose injection over a period of 6 hours. [#] ]]>
[#] ]]>
[#] Cell death occurs in part because of these permeability changes, but other mechanisms may also contribute to amphotericin's antifungal activity. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria). Binding to sterols in mammalian cells (e.g., certain kidney cells, erythrocytes) may be responsible for the toxicities associated with amphotericin B therapy. [#]

Amphotericin B is poorly absorbed from the gastrointestinal (GI) tract and must be given parenterally to treat systemic fungal infections. [#] After completion of IV infusion of amphotericin B 50 mg, the average peak serum concentration was approximately 2 mcg/mL. [#]

Amphotericin B distributes into lungs, liver, spleen, kidneys, adrenal glands, muscle, and other tissues in potentially therapeutic concentrations. The volume of distribution is approximately 4 L/kg in adults. Concentrations attained in inflamed pleural, peritoneal, and synovial fluids and in aqueous humor are reportedly about 60% of concurrent plasma concentrations. [#] Concentrations in cerebrospinal fluid (CSF) are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, amphotericin B must be administered intrathecally. [#]

Amphotericin B is in FDA Pregnancy Category B. Amphotericin B reportedly crosses the placenta, and low concentrations are attained in amniotic fluid. Safe use of amphotericin B during pregnancy has not been established. Animal studies have not revealed evidence of harm to the fetus. It is not known if amphotericin B is distributed into breast milk. [#] [#]

Amphotericin B is highly protein bound (greater than 90%). Metabolism of amphotericin B has not been fully elucidated. The initial plasma elimination half-life is 24 hours and the terminal elimination half-life is approximately 15 days. Amphotericin B is eliminated very slowly (weeks to months) by the kidneys; only about 40% of an administered dose is excreted over 7 days. Only 3% of a dose is excreted in the urine unchanged. Amphotericin B is not removed by hemodialysis. [#]

Resistance to amphotericin B has been produced in vitro, and resistant strains have been isolated from patients who have received long-term therapy with amphotericin B desoxycholate. Fluconazole-resistant strains of Candida albicans that were cross resistant to amphotericin B have been isolated from a few immunocompromised patients. Cryptococcus neoformans isolates resistant to fluconazole and amphotericin B have also been documented. Fungi resistant to amphotericin B desoxycholate may also be resistant to amphotericin B cholestryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal. [#] ]]>
[#]

The majority of patients receiving amphotericin B desoxycholate (50% to 90%) experience some degree of intolerance to initial doses. Acute infusion reactions of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea may occur 1 to 3 hours after initiation of IV infusions. Lipid-based amphotericin B preparations are also associated with acute infusion reactions, although to a lesser degree. Administration of an antipyretic, an antihistamine, meperidine, or a corticosteroid just before the start of the infusion may reduce the incidence or severity of the reaction. [#]

Rapid infusion of amphotericin B desoxycholate has been associated with a more severe reaction consisting of hypotension, bronchospasm, hypokalemia, arrhythmias, and shock. It may be difficult to determine whether these severe reactions indicate intolerance or hypersensitivity to amphotericin B. Anaphylaxis and anaphylactoid reactions have been reported in people taking all formulations of amphotericin B. [#]

Nephrotoxicity is the major dose-limiting toxicity reported with amphotericin B desoxycholate, and nephrotoxicity occurs to some degree in the majority of patients receiving the drug. Adverse renal effects include decreased renal function, azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis. Increased blood urea nitrogen (BUN) and serum creatinine concentrations and decreased creatinine clearance, glomerular filtration rate, and renal plasma flow occur in most patients. Nephrotoxicity associated with amphotericin B desoxycholate appears to involve several mechanisms, including direct vasoconstrictive effects on renal arterioles and lytic action on renal tubular cell membranes. Renal function usually improves within a few months of discontinuing therapy, but some impairment may remain. Lipid-based amphotericin B formulations are generally associated with a lower risk of nephrotoxicity than amphotericin B desoxycholate. However, abnormal renal lab values have been reported in patients using alternate formulations. [#]

Amphotericin B intravenous infusion has also been associated with anemia, headache, thrombophlebitis, and GI effects (indigestion, loss of appetite, nausea, vomiting, diarrhea, stomach pain). Less frequently, blurred or double vision, cardiac arrhythmias, leukopenia, peripheral neuropathy, seizures, and thrombocytopenia have been reported. [#] ]]>
[#]

Concomitant administration of zidovudine and amphotericin B may be associated with increased myelotoxicity and nephrotoxicity. [#]

Concomitant administration of flucytosine and amphotericin B may have additive or slightly synergistic effects. Amphotericin B-induced renal dysfunction may decrease the clearance of flucytosine and result in flucytosine adverse effects, such as bone marrow toxicity. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Prescribing Information from the FDA Web site. More current versions may be available on the manufacturer's Web site.
Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, Harrison T. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25. Erratum in: Clin Infect Dis. 2007 Aug 15;45(4):526.
Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007 Sep;29(9):1980-6.
Herbrecht R, Natarajan-Ame S, Nivoix Y, Letscher-Bru V. The lipid formulations of amphotericin B. Expert Opin Pharmacother. 2003 Aug;4(8):1277-87.
Techapornroong M, Suankratay C. Alternate-day versus once-daily administration of amphotericin B in the treatment of cryptococcal meningitis: a randomized controlled trial.Scand J Infect Dis. 2007;39(10):896-901.]]>
Fax:  888-893-3584]]> Deerfield, IL 60015-2548
Phone:  800-477-6472
Fax:  847-317-7295]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
Mississauga, Ontario,
Canada]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Azithromycin]]>[#] Azithromycin has a broader spectrum of activity than that of erythromycins or clarithromycin. [#] ]]>[#] Azithromycin has a broader spectrum of activity than that of erythromycins or clarithromycin. [#] ]]>[#] ]]>[#] ]]>[#]

Intravenous. [#] ]]>
[#]

Oral suspension containing 100 or 200 mg of anhydrous azithromycin per 5 ml, or 1 g anhydrous azithromycin per single dose packet. [#]

Lyophilized azithromycin in vacuum 10 ml vials containing the equivalent of 500 mg azithromycin. [#] ]]>
[#] ]]>
[#] Azithromycin concentrates in phagocytes; penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus). The site of action appears to be the same as that of the macrolides, clindamycin, lincomycin, and chloramphenicol. [#]

Azithromycin has an expanded spectrum of activity compared with erythromycin and clarithromycin. Azithromycin generally is more active in vitro against gram-negative organisms than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms. Azithromycin is not inactivated by the beta-lactamases produced by Haemophilus influenzae or Moraxella catarrhalis. [#]

Azithromycin is rapidly absorbed from the gastrointestinal (GI) tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34% to 52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms. Limited evidence indicates that the low bioavailability of azithromycin results from incomplete GI absorption rather than acid degradation of the drug or extensive first-pass metabolism. [#] Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. For oral dosage forms, after a 500 mg loading dose on Day 1, then 250 mg once a day for Days 2 to 5, peak plasma concentrations in healthy adults were approximately 0.41 to 0.38 mcg/ml on Day 1 and 0.24 to 0.26 mcg/ml on Day 5. For IV forms, peak plasma concentrations were approximately 1.1 mcg/ml after a 3-hour IV infusion of 500 mg at a concentration of 1 mg/ml and approximately 3.6 mcg/ml after a 1-hour IV infusion of 500 mg at a concentration of 2 mg/ml. [#] Presence of food in the GI tract may affect the extent of absorption of oral azithromycin; however, the effect of food on absorption depends on the dosage form administered. [#]

Azithromycin is rapidly and widely distributed throughout the body. Azithromycin concentrates intracellularly, resulting in tissue concentrations 10 to 100 times higher than those found in plasma or serum. Azithromycin is highly concentrated in fibroblasts and phagocytic cells. [#] In addition to direct tissue uptake, it has been suggested that uptake and release of azithromycin by phagocytic cells contribute to the distribution of the drug into inflamed and infected tissues. Only very low concentrations of azithromycin have been detected in cerebrospinal fluid in patients with noninflamed meninges. [#]

Azithromycin is in FDA Pregnancy Category B. Adequate and well-controlled studies have not been done in pregnant women. Reproduction studies done in rats and mice given azithromycin at doses of up to moderately maternally toxic levels (i.e., 200 mg/kg per day) have found no evidence of harm to the fetus. On a mg/m2 basis, these doses are estimated to be four and two times the human daily dose of 500 mg in rats and mice, respectively. [#] Azithromycin has been detected in human milk. Physicians should exercise caution when administering azithromycin to nursing women. [#]

Protein binding to azithromycin varies with concentration but is generally very low to moderate, with approximately 7% binding at 1 mcg/ml, to 50% at 0.02 to 0.05 mcg/ml. [#] Plasma azithromycin concentrations following a single 500 mg oral or IV dose decline in a polyphasic manner, with a terminal elimination half-life average of 68 hours. [#] More than 50% of azithromycin is eliminated through biliary secretion as unchanged drug. [#] Azithromycin is excreted in feces primarily as unchanged drug. The primary route of biotransformation involves N-demethylation of the desoamine sugar or at the 9a position on the macrolide ring. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation does not occur. [#] Approximately 4.5% of a dose is eliminated in urine as unchanged drug within 72 hours. Approximately 11% to 14% of an IV dose is eliminated in urine as unchanged drug within 24 hours. [#]

Resistance to macrolide antibiotics may be natural or acquired. In studies evaluating prevention of disseminated MAC disease, drug-resistant isolates were detected in 29% to 58% of individuals in whom disease developed while receiving clarithromycin and in 11% of those receiving azithromycin. MAC isolates resistant to azithromycin are resistant to clarithromycin. Erythromycin-resistant staphylococci and streptococci are also resistant to clarithromycin and azithromycin. [#] ]]>
[#] ]]>[#]

Concurrent use of aluminum- and magnesium-containing antacids decreases the Cmax of azithromycin by approximately 24%, but has no effect on AUC. Oral azithromycin should be administered at least 1 hour before or 2 hours after aluminum- and magnesium-containing antacids. [#] ]]>
[#]

Azithromycin should be administered to patients with hepatic function impairment with caution because biliary excretion is the major route of elimination for azithromycin. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>Zithromax Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Zithromax for IV Infusion Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Kadappu KK, Nagaraja MV, Rao PV, Shastry BA. Azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus disease. J Postgrad Med 2002 Jul-Sep;48(3):179-81.
Phillips P, Chan K, Hogg R, Bessuille E, Black W, Talbot J, O'Shaughnessy M, Montaner J. Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002 Feb 1;34(3):371-8.
Pozniak A. Mycobacterial diseases and HIV. J HIV Ther 2002 Feb;7(1):13-6.
Shafran SD, Mashinter LD, Phillips P, Lalonde RG, Gill MJ, Walmsley SL, Toma E, Conway B, Fong IW, Rachlis AR, Williams KE, Garber GE, Schlech WF, Smaill F, Pradier C. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002 Nov 5;137(9):734-7.]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
<![CDATA[Calcium hydroxylapatite]]>[#] [#] ]]>[#] [#] ]]>[#] [#] ]]>[#] Radiesse is approved for use worldwide in facial plastic and reconstructive surgery. [#]

Other FDA-approved soft-tissue augmentation indications of synthetic CaHA include tissue marking, treatment of vocal cord insufficiency, and treatment of oral-maxillofacial defects. Similar products containing CaHA are approved for the treatment of stress urinary incontinence and are used in products for dental ridge augmentation, bone augmentation, and otology implants. [#] [#] ]]>
[#] ]]>[#] Radiesse is injected subcutaneously through a very fine needle. [#] ]]>[#] CaHA in Radiesse is a biocompatible, biodegradable material that is synthetically manufactured to be chemically and biologically identical to the natural substance. [#]

Radiesse contains sterile and nonpyrogenic CaHA microspheres in an aqueous carrier of glycerin, sterile water for injection, and sodium carboxymethylcellulose. [#] [#] After the carrier dissipates in vivo, CaHA particles remain below the skin in the injected area. The active ingredient of Radiesse, CaHA, has been studied extensively in the United States and worldwide; it has been proven safe and effective for various dermal filler uses. [#]

Radiesse is injected subcutaneously to increase skin thickness. Its CaHA microspheres appear in x-rays and CT scans. [#] After Radiesse is injected, the gel carrier dissipates in vivo, and CaHA particles remain at the injection site to provide durable bulking treatment. [#] The CaHA particles act by directly filling space in the soft tissue and by providing a microstructure for tissue infiltration. In addition, Radiesse may promote new collagen binding. [#]

A prospective, open-label study of Radiesse for the treatment of lipoatrophy was conducted in 100 HIV infected patients. The primary endpoint of efficacy and secondary endpoint of safety were evaluated at Months 1, 3, 6, and 12. All patients met the primary endpoint of improved aesthetics at Months 3 and 6, and all patients continued to improve by Month 12. [#] [#] ]]>
[#] [#]

Mild to moderate echymosis, edema, erythema, pain, and pruritis have occurred in HIV infected patients receiving Radiesse in clinical trials. Severe experiences were of short duration, were expected, and did not affect treatment outcome. The most common other adverse effect was mildly uneven skin contours and irregularities, which resolved with additional injections. No systemic or serious adverse effects were reported that were associated with treatment. [#]

In a study of Radiesse for the treatment of HIV-associated lipoatrophy, no clinically significant events occurred. Although 51% of patients in this study were considered people of color, depth of color did not appear to predict the occurrence of adverse effects. Thus, Radiesse is considered safe for use in people of color. [#]

When Radiesse was studied for the correction of nasolabial folds in 117 patients, 82% of nasolabial folds treated with Radiesse improved after 6 months. This was a significantly greater percentage than with the control, which showed improvement in only 27% of treated folds (p less than 0.0001). No granulomas occurred; the rate of nodule formation was low and was the same in control and treatment arms. [#] ]]>
[#] [#] ]]>[#] ]]>Comite SL, Liu JF, Balasubramanian S, Christian MA. Treatment of HIV-associated facial lipoatrophy with Radiance FN (Radiesse). Dermatol Online J. 2004 Oct 15;10(2):2.
Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg. 2006 Sep;118(3 Suppl):34S-45S.]]>
San Mateo, CA 94103
Phone: 650-286-4000
Fax: 650-286-4090]]>
San Mateo, CA 94103
Phone: 650-286-4000
Fax: 650-286-4090]]>
<![CDATA[Clarithromycin]]>[#] ]]>[#] ]]>[#]

The Prevention of Opportunistic Infections Working Group of the U.S. Public Health Service and Infectious Diseases Society of America (USPHS/IDSA) state that HIV infected adults and adolescents with a CD4 count less than 50 cells/mm3 should receive primary chemoprophylaxis against disseminated MAC disease; clarithromycin and azithromycin are the preferred agents. The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone and is associated with a higher rate of adverse effects than either drug alone. This combination should not be used for MAC prophylaxis. In addition to its preventive activity for MAC disease, clarithromycin confers protection against respiratory bacterial infections. [#]

The American Thoracic Society recommends that clarithromycin or azithromycin be used with ethambutol and rifabutin for the treatment of disseminated MAC in HIV infected patients. Limited data from clinical trials indicate that use of ethambutol with clarithromycin may decrease the emergence of clarithromycin-resistant MAC. Adults and adolescents with disseminated MAC should receive lifelong therapy (i.e., secondary prophylaxis, maintenance therapy) unless immune reconstitution occurs as a consequence of highly active antiretroviral therapy (HAART). [#]

Clarithromycin and azithromycin are also the preferred prophylactic agents for disseminated MAC disease in HIV infected children. Prophylaxis should be offered to high-risk children and dosed based on age and CD4 count according to the USPHS/IDSA guidelines. Children with a history of disseminated MAC should be given lifelong prophylaxis to prevent recurrence. [#] ]]>
[#]

Clarithromycin may be used for the treatment of soft tissue infections due to susceptible strains of Staphylococcus aureus or S. pyogenes and as a treatment adjunct for Helicobacter pylori-associated duodenal ulcers. [#] ]]>
[#] ]]>[#]

Oral suspension as granules in sucrose containing 125 and 250 mg per 5 ml. [#] ]]>
[#]

Store extended-release tablets between 20 C and 25 C (68 F and 77 F). Excursions are permitted between 15 C and 30 C (59 F and 86 F). [#]

Store oral suspension in a well-closed container away from light between 15 C and 30 C (59 F and 86 F). [#] ]]>
[#]

Clarithromycin is rapidly absorbed from the gastrointestinal (GI) tract following oral administration. The absolute oral bioavailability of clarithromycin is 50% to 55%. However, this underestimates clarithromycin's systemic activity because of the drug's rapid first-pass metabolism to its active metabolite, 14-hydroxyclarithromycin. [#]

Clarithromycin is extensively metabolized in the liver, primarily by oxidative N-demethylation and hydroxylation at the 14 position. At least seven metabolites have been identified, but the principal metabolite, 14-hydroxyclarithromycin, is the only one with significant antibacterial activity. [#] It is as active or only slightly less active than clarithromycin in vitro against most organisms and enhances the antimicrobial activity of clarithromycin against H. influenzae. However, 14-hydroxyclarithromycin was four to seven times less active than clarithromycin against MAC isolates; the clinical importance of this is unknown. [#]

Clarithromycin is stable in gastric acid. The presence of food delays the rate but not the extent of absorption. Clarithromycin is widely distributed into tissues and fluids; high concentrations are found in nasal mucosa, tonsils, and lungs. [#] Serum concentrations are lower than tissue concentrations because of high intracellular concentrations. Protein binding in vitro is 42% to 72% and decreases with increasing serum drug concentrations. [#]

Elimination of clarithromycin is nonlinear and dose dependent. The elimination half-lives of clarithromycin 250 and 500 mg tablets given every 12 hours are 3 to 4 hours and 5 to 7 hours, respectively. The elimination half-life of 14-hydroxyclarithromycin is slightly longer. [#] Time to peak concentration is 1 to 4 hours for conventional tablets and 5 to 8 hours for extended-release tablets. Clarithromycin is eliminated by both renal and nonrenal mechanisms. Hepatic metabolism is extensive and saturable. After a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in the urine and 40% in feces (4% as clarithromycin) over 5 days. [#]

The serum half-life of clarithromycin is prolonged in patients with impaired renal function. Marked increases in peak serum concentration (Cmax), area under the concentration-time curve (AUC), and half-life of clarithromycin and 14-hydroxyclarithromycin have been reported in patients with creatinine clearances less than 30 ml/min. These patients may require dose reduction. [#]

Clarithromycin is in FDA Pregnancy Category C. No adequate and well-controlled studies in pregnant women have been done. [#] In animal studies, clarithromycin has been associated with fetal loss and embryofetal maldevelopment. Clarithromycin should be used during pregnancy only when safer drugs cannot be used or are ineffective. It is not known whether clarithromycin is distributed in human breast milk. However, it is distributed in the milk of lactating animals, and other macrolides are distributed in human milk. Caution should be exercised when clarithromycin is administered to lactating women. [#]

Resistance to macrolide antibiotics usually involves alteration of the antibiotic target site. Resistant bacteria produce an enzyme that leads to methylation of adenine residues in ribosomal RNA and subsequent inhibition of antibiotic ribosomal binding. Erythromycin-resistant organisms are generally resistant to all 14- and 15-membered macrolides because all of the drugs induce the methylase enzyme. Strains of MAC with decreased susceptibility or resistance to clarithromycin have been reported in patients who received the drug for treatment or prevention of MAC infection. MAC isolates resistant to clarithromycin are cross-resistant to azithromycin. [#] ]]>
[#]

Pseudomembranous colitis has been reported with clarithromycin use. [#]

Headache is a common adverse effect of clarithromycin therapy. [#]

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic dysfunction is usually reversible, but fatalities with clarithromycin use have been reported. [#]

Increased prothrombin time and thrombocytopenia have also been reported with the use of clarithromycin. [#] ]]>
[#]

Clarithromycin should be used with caution in patients taking carbamazepine and other medications metabolized by the cytochrome P450 (CYP) enzyme system. Because clarithromycin has been shown to significantly increase the plasma concentrations of these medications, serum concentration should be monitored when coadministered with clarithromycin. Concurrent use of clarithromycin and astemizole is not recommended, as QTc-interval prolongation and torsades de pointes have been reported with concurrent use of astemizole and erythromycin. Cisapride, pimozide, and terfenadine, when used concurrently with clarithromycin, have been associated with cardiac arrhythmias, including QTc-interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes. These arrhythmias may be fatal, and concurrent use of clarithromycin with these medications is contraindicated. [#]

Concomitant administration of clarithromycin and antiretroviral agents may alter the pharmacokinetics of both clarithromycin and the antiretroviral agent. Administration of clarithromycin and delavirdine results in a 100% increase in the AUC of clarithromycin but has no effect on delavirdine's pharmacokinetics. Similarly, clarithromycin has no apparent effect on the pharmacokinetics of didanosine. Concurrent use of clarithromycin does increase the Cmax of ritonavir by 12% to 15%; clarithromycin's AUC and Cmax increase by 77% and 31%, respectively. Limited studies have shown that clarithromycin decreases the steady-state AUC of zidovudine by a mean 12% and decreases the Cmax by approximately 41%. This effect is partially offset if the two drugs are given 2 to 4 hours apart. The manufacturer of clarithromycin states that dosage modification is not necessary for concurrent clarithromycin and HAART in patients with normal renal function. However, the clarithromycin dose should be reduced by 50% in patients with creatinine clearance (CrCl) of 30 to 60 ml/min and by 75% in patients with CrCl below 30 ml/min when administered with HAART. [#]

Concurrent use of clarithromycin and rifabutin or rifampin increases the metabolism of clarithromycin. A study of patients with advanced HIV infection demonstrated inhibition of rifabutin metabolism by clarithromycin and induction of clarithromycin metabolism by rifabutin. The AUC of clarithromycin decreased by an average 44% while the AUC of rifabutin increased by an average 99%. [#]

Concurrent administration of warfarin and clarithromycin has been shown to potentiate the effects of warfarin. Prothrombin time should be monitored closely in patients receiving anticoagulants and clarithromycin concurrently. [#]

Serum concentrations of digoxin increase when digoxin is used concurrently with clarithromycin; serum digoxin concentrations should be monitored.

Clarithromycin increases the AUC of theophylline by 17%, and monitoring of theophylline serum concentration is recommended, especially for patients with theophylline concentrations in the upper therapeutic range. [#] ]]>
[#]

Clarithromycin should be used with caution in patients with impaired renal function, because the elimination of clarithromycin is significantly reduced, especially in patients with CrCl less than 30 ml/min. The dose of clarithromycin should be halved or the dosing interval should be doubled in these patients. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Biaxin Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Bermudex LE, Yamazaki Y. Effects of macrolides and ketolides on mycobacterial infections. Curr Pharm Des. 2004;10(26):3221-8.
Jacobson MA, Nicolau DP, Sutherland C, Smith A, Aweeka F. Pharmacokinetics of clarithromycin extended-release (ER) tablets in patients with AIDS. HIV Clin Trials. 2005 Sep-Oct;6(5):246-53.
Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis. 2004 Sep;4(9):557-65. Review.
Waller EA, Roy A, Brumble L, Khoor A, Johnson MM, Garland JL. The expanding spectrum of Mycobacterium avium complex-associated pulmonary disease. Chest. 2006 Oct;130(4):1234-41.]]>
Abbott Park, IL 60064-3500
Phone: 800-633-9110]]>
Abbott Park, IL 60064-3500
Phone: 800-633-9110]]>
<![CDATA[Doxorubicin (liposomal)]]>[#] ]]>[#] ]]>[#] [#] The conventional, nonencapsulated formulations of the drug have also been used in the palliative treatment of AIDS-related KS. [#] ]]>[#] [#] Liposomal doxorubicin HCl in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have not received at least one prior therapy. [#] ]]>[#] ]]>[#]

For patients with AIDS-related Kaposi's sarcoma, doxorubicin HCl liposome injection should be administered intravenously at a dose of 20 mg/m2. An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. The dose should be repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment. [#]

Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. Therefore do not substitute one drug for the other. [#]

Do not administer as a bolus injection or an undiluted solution. [#]

Dosage of the infusion should be reduced in patients with impaired hepatic function. Based on experience with doxorubicin HCl, it is recommended that the liposomal doxorubicin dosage be reduced if the bilirubin is elevated. [#] ]]>
[#] When shipped, vials of doxorubicin HCl for injection are packaged with a gel refrigerant (blue ice) to maintain a temperature between 2 C to 8 C (36 F to 46 F). [#] ]]>
[#]

Doxorubicin is extremely irritating to tissues and therefore must be administered by intravenous (IV) infusion. Following IV infusion of a single 10- or 20-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, average peak plasma doxorubicin (mostly bound to liposomes) concentrations are 4.33 mcg/mL or 10.1 mcg/mL, respectively; following a 15-minute infusion they are 4.12 mcg/mL; and following a 30-minute infusion, they are 8.34 mcg/mL. Following IV infusion over 15 minutes of a 40-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, peak plasma concentrations averaged 20.1 mcg/mL. [#]

Encapsulation in PEG-stabilized liposomes substantially slows the rate of distribution into the extravascular space. As a result, the liposomally encapsulated drug distributes mainly in intravascular fluid, whereas nonencapsulated drug distributes widely into the extravascular fluids and tissues. Doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in cerebrospinal fluid. Trace amounts of doxorubicin have been found in fetal mice whose mothers received the drug during pregnancy, and there are limited data to indicate that nonencapsulated doxorubicin crosses the human placenta. Nonencapsulated drug is distributed into milk, and it achieves concentrations that often exceed those in plasma; doxorubicinol (the major metabolite) also distributes into milk. [#]

Liposomal doxorubicin HCl is in FDA Pregnancy Category D. Liposomal doxorubicin can cause fetal harm when administered to a pregnant woman. Adequate and well-controlled studies have not been done in pregnant women to assess doxorubicin's effects on fertility and pregnancy. Use of the drug is not recommended during pregnancy. Women of childbearing age should be advised to avoid pregnancy during treatment and, in general, use of contraception is recommended during any cytotoxic drug therapy. If liposomal doxorubicin is to be used during pregnancy or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with liposomal doxorubicin, the prolonged half-life of the drug must be considered. Studies to evaluate the carcinogenic potential of liposomal doxorubicin injection have not been performed; however, the active ingredient doxorubicin is carcinogenic and mutagenic in experimental models. Limited in vitro and in vivo assays have shown that the liposome component of liposomal doxorubicin is not mutagenic. [#] [#]

It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from liposomal doxorubicin, mothers should discontinue nursing prior to taking this drug. [#]

Protein binding of liposomal doxorubicin has not been determined. [#] Plasma concentrations of liposomally encapsulated doxorubicin HCl appear to decline in a biphasic manner. Following IV administration of a single 10- to 40-mg/m2 dose of doxorubicin HCl as a liposomal injection in patients with AIDS-related KS, the initial plasma half-life of doxorubicin averaged 3.76 to 5.2 hours, whereas the terminal elimination half-life averaged 39.1 to 55 hours. Plasma clearance of liposomal doxorubicin HCl appears to be substantially slower than that of nonencapsulated doxorubicin. [#] ]]>
[#]

The FDA has issued a boxed warning for doxorubicin HCl liposome injection for adverse infusion reactions, myelosuppresion, cardiotoxicity, liver impairment, and accidental substitution. [#]

Irreversible myocardial toxicity leading to congestive heart failure, often unresponsive to cardiac supportive therapy, may be encountered as the total dosage of doxorubicin HCl approaches 550 mg/m2. Prior use of other anthracyclines or anthracenediones will reduce the total cumulative dose of doxorubicin HCl that can be given without cardiac toxicity. Cardiac toxicity also may occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy. In a clinical trial of 250 patients on cumulative liposomal doxorubicin HCl doses of 450 to 550 mg/m2, the risk of cardiac toxicity was 11%. Doxorubicin HCl should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk to the patient. [#]

Acute infusion-related reactions, including flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and hypotension, have occurred in up to 7.1% of patients treated with liposomal doxorubicin HCl. The initial infusion rate should be 1 mg/min to minimize the risk of infusion reactions. [#]

Severe myelosuppression may occur, most commonly as leukopenia in patients with AIDS-related KS. Myelosuppression appears to be dose-limiting at the recommended 20 mg/m2 dosage in this population. [#]

Accidental substitution of doxorubicin HCl liposome injection for doxorubicin HCl has resulted in severe side effects.The liposomal form should not be substituted for nonencapsulated doxorubicin HCl on a mg-per-mg basis. Liposomal doxorubicin HCl should be administered only under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. [#] ]]>
[#]

Doxorubicin may potentiate the toxicity of other antineoplastic therapies and vice versa. Combined therapy with other myelosuppresive agents may increase the severity of hematologic toxicity. Evidence suggests that concomitant use of cyclosporine and doxorubicin may result in more severe and prolonged hematologic toxicity, and seizures or coma may occur. [#]

Doxorubicin-induced cardiotoxicity may be potentiated by concomitant use of calcium channel blocking agents. Phenobarbital has increased the elimination of doxorubicin. Doxorubicin has decreased serum phenytoin concentrations. Streptozocin may inhibit hepatic metabolism of doxorubicin. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] Translucent, red, liposmal dispersion upon dilution. [#] ]]>[#] ]]>[#] ]]>Doxil Prescribing Information from the FDA Web site. A more current version may be available on the manufacturer's Web site.
Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007 Jan;12(1):114-23.
Di Lorenzo G, Di Trolio R, Montesarchio V, Palmieri G, Nappa P, Delfino M, De Placido S, Dezube BJ. Pegylated liposomal doxorubicin as second-line therapy in the treatment of patients with advanced classic Kaposi sarcoma: a retrospective study. Cancer. 2008 Mar 1;112(5):1147-52.
Di Trolio R, Di Lorenzo G, Delfino M, De Placido S. Role of pegylated lyposomal doxorubicin (PLD) in systemic Kaposi's sarcoma: a systematic review. Int J Immunopathol Pharmacol. 2006 Apr-Jun;19(2):253-63. Review.
Little RF, Aleman K, Kumar P, Wyvill KM, Pluda JM, Read-Connole E, Wang V, Pittaluga S, Catanzaro AT, Steinberg SM, Yarchoan R. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood. 2007 Dec 15;110(13):4165-71. Epub 2007 Sep 10.
Udhrain A, Skubitz KM, Northfelt DW. Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma. Int J Nanomedicine. 2007;2(3):345-52. Review.]]>
430 Rt. 22 East
Bridgewater, NJ 08807-0914
Phone: 800-682-6532
Fax: 800-682-6532]]>
<![CDATA[Dronabinol]]>[#] ]]>[#] ]]>[#] [#] ]]>[#] ]]>[#] ]]>[#]

The pharmacologic effects of dronabinol capsules are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of dronabinol treatment. [#]

The recommended adult dose of dronabinol capsules for appetite stimulation is initially, 2.5 mg administered orally twice daily, before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of dronabinol capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol capsules because of the increased frequency of dose-related adverse experiences at higher dosages. [#] ]]>
[#] ]]>
[#]

Although dronabinol is 90% to 95% absorbed after administration of single oral doses, only 10% to 20% reaches systemic circulation due to first-pass hepatic metabolism and high lipid solubility. Peak concentration is reached 2 to 4 hours after oral administration. Psychoactive effects last 4 to 6 hours; appetite-stimulating effects last at least 24 hours. [#]

Dronabinol binds very highly (97%) to plasma proteins and has a large (approximately 10 l/kg) apparent volume of distribution. Dronabinol is eliminated in a biphasic manner, with an initial half-life of 4 hours and a terminal half-life of 25 to 36 hours. Extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yields both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. [#]

Dronabinol is in FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Reproduction studies in mice and rats at doses up to 30 times and 20 times the maximum recommended human dose in AIDS patients, respectively, have revealed no evidence of teratogenicity. However, increased fetal mortality, early resorptions, and dose-dependent decreases in weight gain and number of viable pups were observed. Dronabinol is distributed into and concentrated in human breast milk. [#]

Elimination is primarily biliary, with approximately 50% of an oral dose appearing in the feces in 72 hours (less than 5% as unchanged drug); 10% to 15% of the parent drug and metabolites appear in the urine within 72 hours. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. Prolonged, low-level elimination of dronabinol and its metabolites is attributed to the drug's large and complex volume of distribution. [#] [#] ]]>
[#] [#] ]]>[#]

Because dronabinol is highly plasma protein bound, it may displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. [#] ]]>
[#] [#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Marinol Prescribing Information from the FDA Web site. A more current version may be available on the manufacturer's Web site.
Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B, Morales JO, Murphy R, Powderly W, Plasse TF, Mosdell KW, Shepard KV. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage. 1997 Jul;14(1):7-14.
Cannabis-In-Cachexia-Study-Group; Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006 Jul 20;24(21):3394-400.
Nemechek PM, Polsky B, Gottlieb MS. Treatment guidelines for HIV-associated wasting. Mayo Clin Proc. 2000 Apr;75(4):386-94. Review.
Walsh D, Nelson KA, Mahmoud FA. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer. 2003 Mar;11(3):137-43. Epub 2002 Aug 21. Review.]]>
Deerfield, IL 60015
Phone: 847-282-5400
Fax: 847-374-8480]]>
Deerfield, IL 60015
Phone: 847-282-5400
Fax: 847-374-8480]]>
<![CDATA[Entecavir]]>[#] ]]>[#] ]]>[#] Limited clinical data have determined that entecavir partially, but potently, inhibits HIV replication in a patient coinfected with HIV and HBV and taking entecavir monotherapy. Entecavir is not recommended for individuals with HBV/HIV coinfection who are not also on an effective highly active antiretroviral therapy (HAART) regimen. [#] [#] [#] ]]>[#]

The FDA based its approval of entecavir on the results of three studies that compared entecavir to lamivudine, another drug used for the treatment of HBV. In all three studies, patients treated with entecavir showed significant improvement in the liver inflammation caused by HBV and an improvement in the degree of liver fibrosis (scarring). In addition, a higher percentage of patients treated with entecavir showed significant overall improvement compared to lamivudine. [#] ]]>
[#] ]]>[#]

Oral solution containing entecavir 0.05 mg/ml in a 260-ml bottle. [#]

The recommended dose of entecavir for adults is 0.5 mg once daily. Entecavir dosage regimens should be adjusted according to renal function in adult patients with creatinine clearance (CrCl) less than 50 ml/min as follows: 0.25 mg once daily or 0.5 mg every 48 hours for CrCl 30 to 49 mL/min, 0.15 mg once daily or 0.5 mg every 72 hours for CrCl 10 to 29 mL/min, and 0.05 mg once daily or 0.5 mg every 7 days for CrCl less than 10 mL/min. [#] ]]>
[#]

Store entecavir oral solution in its outer carton at 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F and 86 F). [#] ]]>
[#]

Entecavir has not been fully evaluated in human trials. In 1 randomized, double-blind, placebo-controlled study, entecavir was compared to placebo in 68 patients coinfected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing HAART regimen. Patients continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either entecavir 1 mg once daily (51 patients) or placebo (17 patients) for 24 weeks, followed by an open-label phase for an additional 24 weeks, in which all patients received entecavir. At baseline, patients had a mean serum HBV DNA level by PCR of 9.13 log10 copies/ml. The median HIV RNA level remained stable at approximately 100 copies/ml through 24 weeks of blinded therapy. There are no data in patients with HIV/HBV coinfection who have not received prior lamivudine therapy. Clinical experience suggests that resistance to HIV nucleoside reverse transcriptase inhibitors can develop in HIV infected individuals who are on entecavir but are not on an active HAART regimen. These individuals should not be prescribed entecavir. [#]

Following oral administration in healthy volunteers, entecavir peak plasma concentrations (Cmax) occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately twofold accumulation. For a 0.5-mg oral dose, Cmax at steady state was 4.2 ng/ml and trough plasma concentration (Cmin) was 0.3 ng/ml. For a 1-mg oral dose, Cmax was 8.2 ng/ml and Cmin was 0.5 ng/ml. In healthy volunteers, tablet bioavailability was 100% relative to the oral solution; the oral solution and tablet may be used interchangeably. [#]

Oral administration of entecavir 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in delayed absorption (1.0 to 1.5 hour fed vs. 0.75 hours fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%. [#]

Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues. [#]

Entecavir is in FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits at orally administered doses of 200 and 16 mg/kg/day and showed no embryotoxicity or maternal toxicity in rat and rabbit at doses producing systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose of 1 mg/day in humans. In rats, maternal toxicity, embryo-fetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3,100 times those in humans. In rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peripostnatal study, no adverse effects on offspring were seen with entecavir administered orally to rats at exposures greater than 94 times those in humans. Because animal reproduction studies are not always predictive of human response, entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits. To monitor fetal outcomes of pregnant women exposed to entecavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. [#]

Entecavir is excreted into the milk of rats. It is not known whether this drug is excreted in human milk. Mothers should be instructed not to breastfeed if they are taking entecavir. There are no studies in pregnant women and no data on the effect of entecavir on the transmission of HBV from mother to infant. Appropriate interventions should be used to prevent neonatal acquisition of HBV. [#]

Binding of entecavir to human serum proteins in vitro is approximately 13%.(8) After reaching peak concentration, entecavir plasma concentrations decrease in a biexponential manner, with a terminal elimination half-life of approximately 128 to 149 hours. The observed drug accumulation index is approximately twofold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours. [#]

Following administration of carbon-14-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP) enzyme system. [#]

Entecavir is predominately eliminated by the kidney, with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 ml/min, suggesting that entecavir undergoes both glomerular filtration and net tubular secretion. [#]

The pharmacokinetics of entecavir following a single 1-mg dose were studied in patients without chronic hepatitis B infection with selected degrees of renal impairment, including patients whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Dosage adjustment is recommended for patients with a creatinine clearance of less than 50 ml/min, including patients on hemodialysis or CAPD. Following a single 1-mg dose of entecavir administered 2 hours before hemodialysis, approximately 13% of the entecavir dose was removed by hemodialysis over 4 hours. Entecavir should be administered after hemodialysis. CAPD removed approximately 0.3% of the dose over 7 days. [#]

Entecavir has not been evaluated in HIV/HBV coinfected patients not simultaneously receiving effective HIV treatment. Clincal experience reported HIV/HBV coinfected patients not simultaneously receiving HAART as having developed the M184V resistance substitution while on entecavir. Two other patients have been reported to have had a 1-log reduction in HIV viral loads while on entecavir. When considering therapy with entecavir in an HIV/HBV coinfected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information. Entecavir is not recommended in this setting. [#] [#] [#]

The coadministration of HIV nucleoside reverse transcriptase inhibitors (NRTIs) with entecavir is unlikely to reduce the antiviral efficacy of entecavir against HBV or of any of these agents against HIV. In HBV combination assays in vitro, abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir was not antagonistic to the in vitro anti-HIV activity of these NRTIs at greater than four times the Cmax of entecavir. [#]

Cross resistance has been observed among HBV nucleoside analogues. In cell-based assays entecavir had 8- to 30-fold less inhibition of replication of HBV that contained lamivudine and telbivudine resistance mutations rtL180M and rtM204V/I than of wild-type virus. Recombinant HBV genomes encoding adefovir resistance substitutions at either rtN236T or rtA181V remained susceptible in vitro to adefovir but retained resistance to lamivudine. [#] ]]>
[#]

A large post-marketing study of entecavir will be conducted by the manufacturer to evaluate the risks of cancer and liver-related complications. [#] ]]>
[#]

Because entecavir is primarily eliminated by the kidneys, coadministration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. The effects of coadministration of entecavir with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse effects when entecavir is coadministered with such drugs. [#]

Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. [#] [#] ]]>
[#]

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued antihepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue antihepatitis B therapy. If appropriate, reinitiation of anti-hepatitis B therapy may be warranted. [#]

Limited clinical experience suggests that resistance to HIV nucleoside reverse transcriptase inhibitors can develop if entecavir is used to treat HBV in HIV infected individuals who are not on HAART. Entecavir is not recommended for individuals coinfected with HBV and HIV who are not also on an active HAART regimen. [#] [#] ]]>
[#] ]]>[#] ]]>Baraclude Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Honkoop P, De Man RA. Entecavir: a potent new antiviral drug for hepatitis B. Expert Opin Investig Drugs. 2003 Apr;12(4):683-8.
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004 Mar;11(2):97-107.
Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B. Expert Rev Anti Infect Ther. 2004 Dec;2(6):853-71.
Sims KA, Woodland AM. Entecavir: a new nucleoside analog for the treatment of chronic hepatitus B infection. Pharmacotherapy. 2006 Dec;26(12):1745-57. Review.]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Epoetin alfa]]>[#] ]]>[#] ]]>[#] ]]>
Epoetin alfa is also indicated for the treatment of anemia in patients with nonmyeloid malignancies in which anemia is due to concomitantly administered chemotherapy. Epoetin alfa can be used to correct anemia in patients who are scheduled to undergo elective, noncardiac nonvascular surgery, reducing the need for allogeneic blood transfusions. Epoetin alfa is not a substitute for blood transfusions; however, with chronic use, epoetin alfa reduces the need for repeated maintenance blood transfusions. [#] ]]>
[#]

Subcutaneous injection. [#] ]]>
[#] ]]>[#] ]]>
[#]

Epoetin alfa corrects the erythropoietin deficiency in patients with CRF. Epoetin alfa also stimulates red blood cell production in patients who do not have a documented erythropoietin deficiency. However, it may not be effective in patients who are anemic despite having significantly elevated concentrations of erythropoietin. [#]

Because of its protein nature, epoetin alfa is degraded in the gastrointestinal tract and must be administered parenterally. Serum concentrations peak significantly sooner and are substantially higher with IV administration as compared to subcutaneous injection; however, the concentrations of epoetin alfa are less sustained with IV administration. After a single IV dose, serum concentration peaks at 15 minutes; after a single subcutaneous dose, serum concentration peaks between 5 to 24 hours. However, with subcutaneous dosing, peak concentrations may be maintained for 12 to 16 hours, and detectable quantities are present for at least 24 hours after administration. [#]

Epoetin alfa's distribution in the human body is unknown. Epoetin alfa appears to distribute into a single compartment with an apparent volume of distribution that approximates or slightly exceeds plasma volume (about 4% to 5% of body weight); thus, extravascular distribution of epoetin alfa and endogenous hormone appears to be minimal. [#]

Epoetin alfa is in Pregnancy Category C. There have been no adequate and well-controlled studies of epoetin alfa in pregnant women. Adverse effects have been seen in rats given five times the human dose of epoetin alfa. [#] It is not known whether epoetin alfa is excreted into human breast milk; however, in animal studies, administration of up to 500 units per kg of body weight to female rats during lactation produced no adverse effects in their pups. Epoetin alfa should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. [#] [#]

IV-administered epoetin alfa is eliminated at a rate consistent with first-order kinetics. The half-life in healthy volunteers is approximately 20% shorter than the half-life of epoetin in CRF patients. The elimination half-life of epoetin averages 4 to 13 hours following IV or subcutaneous administration and is generally higher after the first few doses than after 2 or more weeks of treatment. [#]

Increase in reticulocyte count is appreciable within 7 to 10 days of administration. Clinically significant increases in red blood cell count, hemoglobin, and hematocrit generally occur in 2 to 6 weeks. The rate and extent of the response are dependent on dosage and availability of iron stores. In a series of clinical trials enrolling anemic cancer patients who received epoetin alfa three times weekly, the response over a 2-week period was as follows: administration of 50 units per kg of body weight three times weekly increases the hematocrit by an average of 1.5 points; administration of 100 units per kg of body weight three times weekly increases the hematocrit by an average of 2.5 points; and administration of 150 units per kg of body weight three times weekly increases the hematocrit by an average of 3.5 points. [#] ]]>
[#]

Unlike in patients with CRF, epoetin alfa therapy has not been linked to the exacerbation of hypertension, seizures, and thrombotic events in HIV infected patients. [#]

As with all therapeutic proteins, there is the potential for immunogenicity. [#] Seizures and pure red cell aplasia (PRCA), in association with neutralizing antibodies to native erythropoietin, have occurred in patients with CRF while taking epoetin. [#] During hemodialysis, patients treated with epoetin may require anticoagulation with heparin to prevent clotting of the artificial kidney. [#] ]]>
[#]

Androgens increase the sensitivity of erythroid progenitors; they have been used as an adjunct to epoetin alfa to decrease the total amount of epoetin alfa therapy needed to ameliorate anemia. However, controlled studies are needed to establish potential benefits and risks of such combination therapies. Concurrent therapy with epoetin alfa and desmopressin has resulted in an additive effect on reduction of bleeding time in a patient with end-stage renal disease who was receiving epoetin for correction of uremia-induced increased bleeding time and epistaxis. Probenecid has been shown to inhibit the renal tubular secretion of endogenous erythropoietin in animals. While the relevance to humans of this interaction is not known, it should be considered when these two substances are given concomitantly. [#]

Iron requirements may be raised as existing iron stores are used for erythropoiesis. Iron supplementation may be necessary for some patients, especially those who undergo frequent blood transfusions. In some patients, oral iron supplementation may be insufficient and IV iron dextran may be required. [#] ]]>
[#]

Risk-benefit should be considered in patients with aluminum intoxication, Vitamin B12 or folic acid deficiency, hemolysis, infection, inflammation, iron deficiency (virtually all patients will eventually require supplemental iron therapy), malignancy (the possibility that epoetin can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded), osteitis fibrosa cystica, occult blood loss, controlled hypertension, hypercoagulable disorders, myelodysplastic syndromes, sickle cell anemia, peripheral vascular disease, porphyria, and history of seizure disorders. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>Prescribing Information is available on the FDA Web site. More current versions may be available on the manufacturer's Web site.
Belperio PS, Rhew DC. Prevalence and outcomes of anemia in individuals with human immunodeficiency virus: a systematic review of the literature. Am J Med. 2004 Apr 5;116 Suppl 7A:27S-43S. Review.
Buskin SE, Sullivan PS. Anemia and its treatment and outcomes in persons infected with human immunodeficiency virus. Transfusion. 2004 Jun;44(6):826-32.
Pau AK, McLaughlin MM, Hu Z, Agyemang AF, Polis MA, Kottilil S. Predictors for hematopoietic growth factors use in HIV/HCV-coinfected patients treated with peginterferon alfa 2b and ribavirin. AIDS Patient Care STDS. 2006 Sep;20(9):612-9.
Sherman M, Cohen L, Cooper MA, Elkashab M, Feinman V, Fletcher D, Girgrah N, Heathcote J, Levstik M, McNaull WB, Wong D, Wong F, Yim C. Clinical recommendations for the use of recombinant human erythropoietin in patients with hepatitis C virus being treated with ribavirin. Can J Gastroenterol. 2006 Jul;20(7):479-85. Review.
Volberding PA, Levine AM, Dieterich D, Mildvan D, Mitsuyasu R, Saag M; Anemia in HIV Working Group. Anemia in HIV infection: clinical impact and evidence-based management strategies. Clin Infect Dis. 2004 May 15;38(10):1454-63. Epub 2004 Apr 27.]]>
430 Rt. 22 East
Bridgewater, NJ 08807-0914
Phone: 800-682-6532
Fax: 800-682-6532]]>
Thousand Oaks, CA 91320-1799
Phone: 800-772-6436
Fax: 805-447-1010]]>
430 Rt. 22 East
Bridgewater, NJ 08807-0914
Phone: 800-682-6532
Fax: 800-682-6532]]>
<![CDATA[Etoposide]]>[#] ]]>[#] ]]>[#] [#] [#] [#] Etoposide is also used to treat AIDS-related Kaposi's sarcoma. [#] ]]>[#] ]]>[#]

Intravenous. [#] ]]>
[#]

Etoposide phosphate: 100 mg vials to be reconstituted at concentrations of 10 mg/ml and 20 mg/ml. [#] ]]>
[#]

Store etoposide phosphate unopened vials under refrigeration between 2 C and 8 C (36 F to 46 F) and keep in the original package to protect it from light. [#] ]]>
[#]

Etoposide is variously absorbed following oral administration, depending on dosage formulation. The absolute bioavailability of etoposide in liquid-filled soft gelatin capsules averages 50%, with a range of 25% to 75%. With this formulation, peak plasma concentrations (Cmax) of etoposide are achieved within 1 to 1.5 hours. Cmax and area under the plasma concentration-time curve (AUC) for this formulation vary but are consistently within the same range as those following an IV dose half as large. Following oral administration of 160 or 200 mg/m2 soft gelatin capsules, peak plasma etoposide concentrations of 9 mcg/ml and 9.6 mcg/ml, respectively, were attained. [#]

Following IV administration of etoposide phosphate, the drug is rapidly absorbed and completely converted to etoposide in plasma. Clinical studies directly comparing the pharmacokinetic parameters of etoposide and etoposide phosphate showed no statistically-significant difference in the etoposide plasma Cmax or AUC of the two formulations. [#]

As with oral formulations, absorption of IV etoposide varies markedly among patients. Over a dose range of 100 to 600 mg/m2, plasma Cmax and AUC increase linearly with dose. In adults with normal renal and hepatic function, an 80 mg/m2 IV dose given over 1 hour averaged an etoposide plasma Cmax of 14.9 mcg/ml. Following 500 mg/h IV infusions of 400, 500, or 600 mg/m2, etoposide plasma peak concentrations of 26 to 53, 27 to 73, and 42 to 114 mcg/ml, respectively, were attained. With continuous IV infusion of 100 mg/m2 daily for 72 hours, plasma drug concentrations of 2 to 5 mcg/ml were reached 2 to 3 hours after the start of infusion and were maintained until the end of infusion. In children 3 months to 16 years of age with normal renal and hepatic function, IV infusions of 200 to 250 mg/m2 given over 0.5 to 2.25 hours resulted in peak serum etoposide concentrations ranging from 17 to 88 mcg/ml. [#]

Following IV administration, etoposide undergoes rapid distribution. Apparent steady-state volume averages 20% to 28% of body weight 18 to 29 l or 7 to 17 l/m2 in adults and 5 to 10 l/m2 in children. IV etoposide is distributed minimally into pleural fluid and has been detected in saliva, liver, spleen, kidney, myometrium, healthy brain tissue, and brain tumor tissue. Etoposide and its metabolites do not readily penetrate the central nervous system. Concentrations of etoposide in cerebrospinal fluid range from undetectable to less than 5% of concurrent plasma concentrations during the initial 24 hours after IV administration, even with high doses. In vitro, etoposide is approximately 94% bound to serum proteins at a concentration of 10 mcg/ml. [#]

Etoposide is in FDA Pregnancy Category D; it can cause fetal harm when administered to pregnant women. The drug has been shown to have severe teratogenic effects in laboratory animals and is therefore likely to be teratogenic in humans. If etoposide is used during pregnancy, the patient should be warned of potential harm to the fetus. Women of childbearing age should be advised to avoid pregnancy while receiving etoposide therapy. It is not known whether etoposide is excreted in human milk; however, because of the potential for HIV transmission and for serious adverse effects to the breastfed infant if the drug is distributed into milk, women should be instructed not to breastfeed while receiving etoposide therapy. [#]

The metabolic fate of etoposide has not been fully determined. The major urinary metabolite of etoposide is the hydroxy acid 4'-demethylepipodophyllic acid-9-(4,6-0-(R)-ethylidene- beta-D-glucopyranoside). It is also present in human plasma, presumably as the trans isomer. Glucuronide and sulfate conjugates of etoposide are excreted in human urine and represent 5% to 22% of the dose. O-demethylation of the dimethoxyphenol ring occurs through the cytochrome P (CYP) 3A4 isoenzyme pathway to produce the corresponding catechol. [#]

Metabolism and excretion of etoposide appear to be similar following oral or IV administration. Etoposide and its metabolites are excreted principally in urine; fecal excretion of the drug is variable. Following IV infusion in patients with normal renal and hepatic function, approximately 40% to 60% of a dose is excreted in urine as unchanged drug and metabolites within 48 to 72 hours; less than 2% to 16% is excreted in feces within 72 hours; about 20% to 30% of the dose is excreted in urine unchanged within 24 hours and 30% to 45% within 48 hours. Following oral administration, about 5% to 25% of the dose is excreted in urine within 24 to 48 hours. [#]

Following IV infusion, etoposide disposition has been described as biphasic, although some data indicate triphasic elimination with a prolonged terminal phase. In adults with normal renal and hepatic function, etoposide half-life averages from about 0.6 to 2.0 hours in the initial phase and from 5.3 to 10.8 hours in the terminal phase. In children with normal renal and hepatic function, etoposide half-life averages from 0.6 to 1.4 hours in the initial phase and from 3 to 5.8 hours in the terminal phase. [#]

Because patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC, and lower volume of distribution at steady state, initial dose modification should be considered based on measured creatinine clearance. [#] Reduced plasma clearance and elimination of etoposide has been reported in some patients with impaired hepatic function. [#] ]]>
[#] With leukopenia, the nadir of granulocyte count occurs 7 to 14 days after administration. Recovery is usually complete by the 20th day after administration; cumulative myelosuppression has not been reported. [#]

Other frequently reported but less serious adverse effects include abdominal pain, reversible alopecia, asthenia, anorexia, chills and/or fever, constipation, diarrhea, dizziness, extravasation, malaise, mucositis, nausea and vomiting, phlebitis, pruritus, rash, taste perversion, and urticaria. [#] Localized herpes zoster infections have occurred in a few HIV infected patients being treated with etoposide. [#]

In rare cases, anaphylactic reactions have occurred in patients receiving etoposide. These reactions have been characterized by one or more of the following symptoms: bronchospasm, chills, diaphoresis, dyspnea, fever, pruritus, hypertension or hypotension, loss of consciousness, nausea, rigors, tachycardia, and vomiting. Anaphylactic reactions occurring during initial infusion of etoposide have included back pain, laryngospasm, loss of consciousness, swelling of the face and tongue, and tightness in the throat. [#] ]]>
[#]

Caution should be used when administering etoposide phosphate with drugs that inhibit phosphatase activities, such as levamisole hydrochloride. [#]

Concurrent use of etoposide with bone marrow depressants or radiation therapy may cause additive bone marrow depression. [#]

Normal immune mechanisms may be suppressed during etoposide therapy, causing a patient's antibody response to a killed virus vaccine to be decreased. In addition, concurrent use of etoposide with a live virus vaccine may enable virus replication, increase adverse effects of the vaccine, or decrease a patient's antibody response to the vaccine. Patients receiving etoposide therapy should therefore avoid any vaccination until etoposide therapy has been discontinued for 3 months to 1 year. [#] ]]>
[#] Risk-benefit of etoposide therapy should be considered in individuals who have bone marrow depression, existing or recent chickenpox, herpes zoster, hepatic function impairment, infection, renal function impairment, or previous cytotoxic drug therapy or radiation therapy. [#] ]]>[#] Etoposide: 4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside] [#] ]]>[#] Etoposide: 33419-42-0 [#] ]]>[#]

Unopened vials of etoposide phosphate for injection are stable until the date indicated on the label if stored under refrigeration between 2 C to 8 C (36 F to 46 F); at controlled room temperature between 20 C to 25 C (68 F to 77 F) following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature between 20 C to 25 C for 48 hours following reconstitution with Sterile Bacteriostatic Water for Injection with Benzyl Alcohol, USP, or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol, USP. Further diluted solutions of etoposide phosphate can be stored under refrigeration between 2 C to 8 C or at controlled room temperature between 20 C to 25 C for 24 hours. [#] ]]>
[#]

Etoposide phosphate: Soluble in water and practically insoluble in organic solvents. [#] ]]>
Prescribing Information is available on the FDA web site. More current versions may be available on the manufacturer's web site.
Aldenhoven M, Barlo NP, Sanders CJ. Therapeutic strategies for epidemic Kaposi's sarcoma. Int J STD AIDS. 2006 Sep;17(9):571-8. Review.
Combs S, Neil N, Aboulafia DM. Liposomal doxorubicin, cyclophosphamide, and etoposide and antiretroviral therapy for patients with AIDS-related lymphoma: a pilot study. Oncologist. 2006 Jun;11(6):666-73.
Fardet L, Blum L, Kerob D, Agbalika F, Galicier L, Dupuy A, Lafaurie M, Meignin V, Morel P, Lebbe C. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients. Clin Infect Dis. 2003 Jul 15;37(2):285-91. Epub 2003 Jul 01.
Re A, Cattaneo C, Michieli M, Casari S, Spina M, Rupolo M, Allione B, Nosari A, Schiantarelli C, Vigano M, Izzi I, Ferremi P, Lanfranchi A, Mazzuccato M, Carosi G, Tirelli U, Rossi G, Mazzuccato M. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol. 2003 Dec 1;21(23):4423-7. Epub 2003 Oct 27. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. Mazzuccato Maurizio [corrected to Mazzuccato Mauro].
Sparano JA, Lee S, Chen MG, Nazeer T, Einzig A, Ambinder RF, Henry DH, Manalo J, Li T, Von Roenn JH. Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol. 2004 Apr 15;22(8):1491-500.]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Fluconazole]]>[#] ]]>[#] ]]>[#] Fluconazole may also be used for primary prophylaxis and for long-term suppressive or chronic maintenance therapy to prevent recurrence or relapse of serious fungal infections in patients considered at high risk for developing such infections, such as those with AIDS. These infections include coccidioidomycosis, cryptococcosis, histoplasmosis, and mucocutaneous candidiasis. [#]

Fluconazole is also indicated for the treatment and suppression of cryptococcal meningitis as a less toxic (albeit less efficacious) course of treatment than amphotericin B with flucytosine in AIDS patients. Although amphotericin B (with or without flucytosine) has been considered the initial treatment of choice for cryptococcal meningitis, fluconazole is an alternative for these infections in patients whose disease is not severe, because it is well tolerated and is distributed into cerebrospinal fluid at high concentrations. In maintenance therapy, fluconazole is usually better tolerated than amphotericin B alone. [#] ]]>
[#] [#]

Fluconazole is approved by the FDA for the treatment of systemic candidal infections and is an appropriate, less toxic alternative to amphotericin B. [#] ]]>
[#] ]]>[#]

Oral suspension containing fluconazole 10 mg/ml in 35-ml bottles. [#]

Injection for IV infusion containing fluconazole 200 mg/100 ml (2 mg/ml) or 400 mg/200 ml (2 mg/ml) in 5.6% dextrose diluent in Viaflex Plus plastic containers. [#]

Injection for IV infusion containing fluconazole 200 mg/100 ml (2 mg/ml) or 400 mg/200 ml (2 mg/ml) in 0.9% sodium chloride in glass bottles or Viaflex Plus plastic containers. [#] ]]>
[#]

Protect fluconazole injection in glass bottles from freezing and store between 5 C to 30 C (41 F to 86 F). Protect fluconazole injection in Viaflex Plus plastic containers from freezing and store between 5 C to 25 C (41 F to 77 F). Brief exposures to temperatures up to 40 C (104 F) will not adversely affect the product. [#] [#] ]]>
[#]

Fluconazole is rapidly and almost completely absorbed from the gastrointestinal (GI) tract. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug are generally attained within 1 to 2 hours after oral administration. Limited studies indicated that bioavailability for adults with HIV appears similar to that seen in healthy adults. Unlike other antifungal agents (e.g., itraconazole, ketoconazole), GI absorption of fluconazole does not appear to be affected by gastric pH. [#]

Following oral or IV administration, fluconazole is widely distributed throughout the body, with good penetration of cerebrospinal fluid (ranging from 50% to 94% of concurrent plasma concentrations in patients with fungal meningitis), the eye, and peritoneal fluid. The apparent volume of distribution of fluconazole approximates that of total body water and has been reported to be 0.7 l/kg to 1 l/kg. It is not known if fluconazole crosses the placenta, but fluconazole is distributed into human milk in concentrations similar to those attained in plasma. [#]

Fluconazole is in FDA Pregnancy C. Fluconazole was administered orally to pregnant rabbits during organogenesis in 2 studies, at 5, 10, and 20 mg/kg, and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at 75 mg/kg (20 to 60 times the recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs or renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20 to 60 times the recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition. [#]

There are no adequate and well-controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole therapy for coccidioidomycosis (an off-label use). The relationship between fluconazole use and these events is unclear. Fluconazole should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus. [#]

Unlike itraconazole and ketoconazole, fluconazole exhibits very low binding to proteins (11% to 12%). Metabolism of fluconazole is primarily hepatic. The plasma elimination half-life of fluconazole in healthy adults is approximately 30 hours (ranging from 20 hours to 50 hours). In patients with impaired renal function, plasma concentrations of fluconazole are higher and the half-life is prolonged; elimination half-life of the drug is inversely proportional to the patient's creatinine clearance. [#] [#]

Fluconazole is largely excreted in urine, and fluconazole elimination is principally renal. Renal clearance of the drug averages 0.27 ml/min per kg in adults with normal renal function. Approximately 60% to 80% of a single oral or IV dose of fluconazole is excreted in urine unchanged, and about 11% is excreted in urine as metabolites. Small amounts of the drug are excreted in feces. Fluconazole is removed by hemodialysis and peritoneal dialysis. A 3-hour hemodialysis session decreases plasma levels by approximately 50%. [#] [#]

Resistance to fluconazole can be produced in vitro by serial passage of Candida albicans in the presence of increasing concentrations of the drug. Some Candida species (e.g., C. krusei) are intrinsically resistant to fluconazole, and many strains of C. glabrata are resistant to the drug. Prolonged or intermittent use of oral fluconazole in immunocompromised patients has been suggested as a major contributing factor to the emergence of fluconazole resistance in candidal infections. Fluconazole-resistant fungi may also be cross resistant to other azole antifungal agents (e.g., itraconazole, ketoconazole). Although the clinical importance is unclear, fluconazole-resistant strains of C. albicans that were cross resistant to amphotericin B have been isolated from a few immunocompromised individuals, including patients with leukemia and HIV. [#] ]]>
[#]

The most common adverse events to fluconazole in pharmacologic testing have been headache, nausea, and abdominal pain. Clinical adverse effects were reported more frequently in HIV infected patients than in HIV uninfected patients. [#] With the use of fluconazole, there is an increased risk of agranulocytosis, thrombocytopenia, and exfoliative skin disorders, such as Stevens-Johnson syndrome. [#] ]]>
[#]

In addition to those drugs contraindicated with its use, many drugs may produce interactions if taken concurrently with fluconazole. Concurrent use of fluconazole with oral antidiabetic agents, such as tolbutamide, chlorpropamide, glyburide, or glipizide, has increased the plasma concentrations of these sulfonylurea agents. Hypoglycemia has been noted with these agents, and blood glucose concentrations should be monitored, as the dose of oral hypoglycemia agent may need to be reduced. The anticoagulant effects of warfarin may be increased when warfarin is used concurrently with any azole antifungal, resulting in an increase of prothrombin time; patients on such a regimen should be monitored carefully. Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin) may decrease fluconazole plasma concentrations, leading to treatment failure or clinical relapse. Use of immunosuppressive drugs such as cyclosporine, methylprednisolone, sirolimus, and tacrolimus or the antiasthmatic theophylline with concurrent fluconazole should be monitored carefully because fluconazole may inhibit their metabolism, increasing the plasma concentration of these drugs to toxic levels. Use of fluconazole with astemizole and other drugs metabolized by the CYP450 system may be associated with elevations in serum levels of these drugs. Rifampin and rifabutin may increase the metabolism of fluconazole and other azoles, lowering the plasma concentration, which may lead to clinical failure or relapse. [#] [#]

Amphotericin B may have an antagonistic relationship with fluconazole, but it is unclear if such antagonism actually occurs in vivo. Flucytosine may have a synergistic, additive, or indifferent effect when used with fluconazole, possibly because fluconazole damages the fungal cell membrane, allowing greater intercellular penetration of flucytosine. Central nervous system toxicity has been reported when amitriptyline, a tricyclic antidepressant, is used concurrently with fluconazole; increased serum concentrations of amitriptyline have been observed and are presumably related to fluconazole interfering with amitriptyline metabolism. Concurrent use of thiazide diuretics with fluconazole may increase peak fluconazole plasma concentrations, presumably because the diuretic decreases renal clearance of fluconazole by as much as 20%. [#]

Concomitant administration of fluconazole with HIV protease inhibitors may have clinically important effects; use with indinavir may result in a decrease in serum concentrations of indinavir, whereas use with ritonavir may result in an increase in serum concentrations of ritonavir. Fluconazole may interfere with zidovudine metabolism and increase serum concentrations of this nucleoside reverse transcriptase inhibitor. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] Slightly soluble in saline. [#] ]]>Diflucan Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Bicanic T, Harrison T, Niepieklo A, Dyakopu N, Meintjes G. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis. 2006 Oct 15;43(8):1069-73.
Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, Harrison T.Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25. Erratum in: Clin Infect Dis. 2007 Aug 15;45(4):526.
Pienaar ED, Young T, Holmes H. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst Rev. 2006 Jul 19;3:CD003940.
Yamada H, Kotaki H, Takahashi T. Recommendations for the treatment of fungal pneumonias. Expert Opin Pharmacother. 2003 Aug;4(8):1241-58.]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
New York, NY 10017-5755
Phone: 800-438-1985]]>
<![CDATA[Ganciclovir]]>[#] Compared to acyclovir, ganciclovir differs structurally such that it has substantially increased antiviral activity against cytomegalovirus (CMV) and less selectivity for viral DNA. [#] ]]>[#] Compared to acyclovir, ganciclovir differs structurally such that it has substantially increased antiviral activity against cytomegalovirus (CMV) and less selectivity for viral DNA. [#] ]]>[#]

The ganciclovir intravitreal implant was approved by the FDA on March 5, 1996, for the intraocular treatment of CMV retinitis in patients with AIDS. [#] ]]>
[#] [#] [#] ]]>[#] ; intravitreal. [#] ]]>[#]

Ganciclovir sodium for injection in 10 ml sterile vials, each containing the equivalent of ganciclovir 500 mg. [#]

Intravitreal implant containing ganciclovir 4.5 mg, with magnesium stearate 0.25% and polyvinyl alcohol and ethylene vinyl acetate polymers. [#] ]]>
[#] [#] Store ganciclovir sodium vials for injection below 40 C (104 F) and protect from freezing. [#] Store ganciclovir intravitreal implants between 15 C and 30 C (59 F and 86 F) and protect from freezing and excessive heat and light. [#] ]]>
[#] [#] Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase. Chain elongation resumes when ganciclovir is removed. In CMV-infected cells, ganciclovir is thought to be phosphorylated much more rapidly than in uninfected cells; however, uninfected cells can also produce low levels of ganciclovir triphosphate. [#] Concentrations of ganciclovir triphosphate may be as much as 100-fold greater in CMV-infected than in uninfected cells and may persist for days in the CMV-infected cell. [#]

Ganciclovir is poorly absorbed from the gastrointestinal (GI) tract. The absolute bioavailability of oral ganciclovir under fasting conditions is about 5%, and about 6% to 9% when administered with food. [#] [#] In HIV infected individuals receiving 1 g of oral ganciclovir every 8 hours with food, the steady-state area under the concentration-time curve (AUC) increased by about 22%, peak serum concentrations (Cmax) increased from 0.85 to 0.96 mcg/ml, and the time to peak concentration (Tmax) increased from 1.8 to 3 hours as compared to fasting administration. [#]

Ganciclovir is widely distributed to all tissues and crosses the placenta; however, there is no marked accumulation in any one type of tissue. [#] Although the distribution of ganciclovir into human tissue and fluid is not fully understood, autopsy findings show that IV-administered ganciclovir concentrates in the kidneys, with lower concentrations in the lung, liver, brain, and testes. One study in individuals with normal renal function showed that steady-state distribution of the drug averaged 32.8 to 44.5 l/1.73 m2 following IV administration. In individuals with renal impairment, distribution appears to be reduced. Ganciclovir crosses the blood-brain barrier; cerebrospinal fluid concentration of ganciclovir following IV administration averaged 41%. [#] The volume of distribution in adults and neonates is approximately 0.74 l/kg. [#]

Limited data show that ganciclovir has good intraocular distribution. Following IV administration, one adult had subretinal concentrations of ganciclovir of 0.87 and 2 times concurrent plasma concentrations at 5.5 and 8 hours, respectively. Concentrations of ganciclovir in the aqueous humor and the vitreous humor of another adult were 0.4 and 0.6 higher, respectively, than concurrent plasma concentrations at 2.5 hours following IV administration. [#]

Ganciclovir is in FDA Pregnancy Category C. There are no adequate or controlled studies in pregnant women; however, ganciclovir has been shown to be teratogenic in rabbits and embryotoxic in rabbits and mice. Based on this evidence, ganciclovir may be teratogenic and embryotoxic in humans when given at usual therapeutic dosages. It is not known whether ganciclovir is distributed into milk in humans; however, it is distributed into milk in laboratory animals and causes significant adverse effects in their offspring. [#] [#]

Ganciclovir is 1% to 2% bound to plasma proteins at drug concentrations of 0.5 to 51 mcg/ml. Other than intracellular phosphorylation, ganciclovir is not metabolized appreciably in humans. Serum half-life in individuals with normal renal function is 2.5 to 3.6 hours following IV administration and 3.1 to 5.5 hours following oral administration. In individuals with renal impairment, serum half-life is 9 to 30 hours following IV administration and 15.7 to 18.2 hours following oral administration. Approximately 90% to 99% of the drug is excreted unchanged in urine. Renal excretion of ganciclovir occurs mainly via glomerular filtration, although limited tubular secretion may also occur. Doses and frequency of administration of the drug should be modified according to creatinine clearance. Hemodialysis reduces plasma concentrations of ganciclovir by about 50%. [#] [#]

Resistance to ganciclovir is defined as CMV with an in vitro median inhibitory concentration (IC50) greater than 3.0 mcg/ml (12.0 mcM). Viral resistance has been observed in patients receiving prolonged IV treatment for CMV retinitis. CMV resistance to ganciclovir has also been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 protein of CMV, which controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir. [#]

The ganciclovir intravitreal implant is designed to release ganciclovir over a period of 5 to 8 months. In one clinical trial, the median time to progression of CMV retinitis after insertion of the implant was 210 days. With the comparison treatment (recommended induction and maintenance doses of intravenous ganciclovir), the median time to progression of CMV retinitis was 120 days. [#] ]]>
[#]

Retinal detachment can develop as a result of ganciclovir-induced resolution of retinitis and has been reported in up to 30% of ganciclovir-treated patients with CMV retinitis. This complication appears to occur more frequently in AIDS patients than in other immunosuppressed patients and may be related to the inability of AIDS patients to form firm scar tissue, secondary to impaired inflammatory responses, as the retina heals. [#] Other side effects observed with use of the ganciclovir intravitreal implant include bacterial endophthalmitis, mild conjunctival scarring, foreign body sensation, retinal detachment, scleral induration, and subconjunctival hemorrhage. [#] Blurred or decreased vision has been known to occur following insertion of the intravitreal implant and may last 2 to 4 weeks after insertion of the implant. For the first 2 months after surgery, patients may see flashes or sparks of light, floating spots before the eyes, or a veil or curtain appearing across part of their vision. They may also have eye pain or tearing, red or bloodshot eyes, or sensitivity to light. Patients are encouraged to seek medical attention if they experience any side effects. [#]

In animal studies, ganciclovir was carcinogenic and teratogenic and caused aspermatogenesis. Usual doses of ganciclovir are likely to cause temporary or permanent inhibition of spermatogenesis in men and may suppress fertility in women. Because of ganciclovir's high toxicity and mutagenic and teratogenic potential, use in pregnant women should be avoided. In addition, women of childbearing age should use effective contraception while taking ganciclovir. Men should use barrier contraception during treatment and for at least 90 days following treatment. [#]

Because solutions of ganciclovir are alkaline (pH 11), direct contact of capsule powder or parenteral solution with skin or with mucous membranes can cause irritation or burning. [#] ]]>
[#]

Blood dyscrasia-causing medications, bone marrow depressants, and radiation therapy should not be taken concurrently with ganciclovir. Concurrent use of these medications may increase the bone marrow depressant effects of these medications and radiation therapy. [#]

Nephrotoxic medications should not be used with ganciclovir. Concurrent use of these medications with ganciclovir may increase serum creatinine. Taking ganciclovir with certain nephrotoxic medications, such as cyclosporine or amphotericin B, may increase the chance of renal function impairment, which could subsequently decrease ganciclovir elimination and increase the risk of toxicity. [#]

Concurrent use of ganciclovir and zidovudine has been associated with severe hematologic toxicity in some patients, even when the zidovudine dose was reduced to 300 mg/day. If ganciclovir and zidovudine are administered together, the AUC of zidovudine increases by 14% to 19%. In vitro studies have found concurrent use of these two drugs to be synergistically cytotoxic, so concurrent administration should be approached with caution. [#]

Ganciclovir has exhibited additive or synergistic antiviral activity with foscarnet against CMV and herpes simplex virus type 2 (HSV-2). Combined therapy may be effective in treatment of CMV infection that is resistant to either drug alone. [#] ]]>
[#]

Patients with contraindications for intraocular surgery, such as external infection or severe thrombocytopenia, should not receive ganciclovir intravitreal implants. [#] ]]>
[#] Ganciclovir: 6H-Purin-6-one,2- amino-1,9-dihydro-9-((2-hydroxy-1- (hydroxymethyl)ethoxy)methyl)- [#] ]]>[#] Ganciclovir: 82410-32-0 [#] ]]>[#] ]]>[#] ]]>
Ganciclovir and ganciclovir sodium: freely soluble in water at high pH and less soluble at more neutral pH, although crystallization may occur in concentrated solutions of the drug exceeding 10 mg/ml. [#] ]]>
Ganciclovir Prescribing Information from the FDA Web site. More current versions may be available on the manufacturer's Web site.
De Clercq E. Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33. Review.
Drew WL. Cytomegalovirus Disease in the Highly Active Antiretroviral Therapy Era. Curr Infect Dis Rep. 2003 Jun;5(3):257-265.
Dunn JP, Van Natta M, Foster G, Kuppermann BD, Martin DF, Zong A, Jabs DA; Studies of Ocular Complications of AIDS Research Group. Complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial. Retina. 2004 Feb;24(1):41-50.
Griffiths P. Cytomegalovirus infection of the central nervous system. Herpes. 2004 Jun;11 Suppl 2:95A-104A. Review.
Jabs DA, Martin BK, Forman MS, Hubbard L, Dunn JP, Kempen JH, Davis JL, Weinberg DV; Cytomegalovirus Retinitis and Viral Resistance Study Group. Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol 2003 Jan;135(1):26-34.
Kappel PJ, Charonis AC, Holland GN, Narayanan R, Kulkarni AD, Yu F, Boyer DS, Engstrom RE Jr, Kuppermann BD; Southern California HIV/Eye Consortium. Outcomes associated with ganciclovir implants in patients with AIDS-related cytomegalovirus retinitis. Ophthalmology. 2006 Apr;113(4):683.e1-8.]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
Claremont, CA 91711
Phone: 800-531-2020
Fax: 909-399-1525]]>
<![CDATA[Immune globulin]]>[#] ]]>[#] ]]>[#] IVIG was approved by the FDA on December 27, 1993, for use in HIV infected children to reduce the risk of serious bacterial infections. [#] However, there is no evidence to suggest that IVIG confers incremental benefit to antiretroviral therapy and prophylactic antibiotics administered according to current standards of practice. In children with advanced HIV disease who are receiving zidovudine, IVIG decreases the risk of serious bacterial infections. However, this benefit is apparent only in children who are not receiving sulfamethoxazole-trimethoprim as prophylaxis and for children with a CD4 count of greater than 200 to 400 cells/mm3. [#] ]]>[#] IVIG can replace or boost IgG in individuals with antibody-deficiency syndromes resulting from defective antibody synthesis, such as congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyperimmunoglobulin M, severe combined immunodeficiency, and Wiskott-Aldrich syndrome. IVIG is indicated for the treatment of idiopathic thrombocytopenic purpura when a rapid rise in the platelet count is required, such as prior to surgery, to control excessive bleeding, or to defer or avoid splenectomy. [#]

In conjunction with aspirin, IVIG is used in the treatment of Kawasaki's disease. Use of this combination within the first 10 days of illness significantly reduces the prevalence of coronary artery abnormalities associated with this condition, and IVIG has been shown to decrease the prevalence of giant coronary artery aneurysms associated with the highest morbidity and mortality rates in Kawasaki's disease. [#]

IVIG is used as a treatment adjunct for the prevention of recurrent bacterial infections in patients with hypogammaglobulinemia associated with B cell chronic lymphocytic leukemia. IVIG is also used to prevent the risk of acute graft-versus-host disease, associated interstitial pneumonia, and infections (e.g., cytomegalovirus infection, varicella-zoster infection, recurrent bacterial infection) after bone marrow transplantation in patients 20 years of age or older. [#] ]]>
[#] ]]>[#]

By protein mass per volume in solution form: 50 mg per ml, 100 mg per ml. [#] ]]>
[#] ]]>
[#] [#]

The mechanism by which IVIG increases platelet counts in the treatment of idiopathic thrombocytopenic purpura has not been fully elucidated. It has been suggested that IVIG may saturate Fc receptors on cells of the reticuloendothelial system, resulting in a decrease in Fc-mediated phagocytosis of antibody-coated cells. This Fc receptor blockade on macrophages may occur in bone marrow, spleen, and other parts of the reticuloendothelial system and also may occur through competition for Fc receptors by increased serum concentrations of IgG or by circulating immune complexes. Altered Fc-receptor affinity for IgG or suppression of antiplatelet antibody production may also be involved. [#]

The long-term effects of IVIG can be attributed to the immunomodulatory effects of IVIG on T cells and macrophages, particularly on cytokine synthesis, and B cell immune function and its regulatory action on the membrane-damaging components of the complement system. In contrast, the effects of IVIG on Kawasaki's disease and perhaps other diseases may be caused by the presence of specific antibodies in IVIG that are capable of neutralizing bacterial or even viral toxins that can affect the host's immune and inflammatory systems. It is likely that no single mechanism accounts for all of the immune modulating effects of IVIG in inflammatory and autoimmune processes. [#]

Following IV administration of IVIG, IgG is detectable in serum immediately; serum concentrations of IgG attained with IVIG appear to be directly dose related. IVIG reportedly has a half-life of about 21 to 29 days following IV administration; however, interindividual variation in the half-life has been reported, especially in patients with immunodeficiencies. [#] After an IV infusion of IVIG 2 g/kg of body weight, the serum IgG levels increase fivefold and then decline by 50% in 72 hours before returning to pretreatment level in 21 to 28 days. The marked initial decrease reflects extravascular redistribution. The IgG in the infusion easily enters the cerebrospinal fluid (CSF). During the first 48 hours of the infusion, when the serum IgG level is high, the concentration of IgG in the CSF increases as much as twofold but returns to normal within a week. [#]

Immune globulin is in FDA Pregnancy Category C. Adequate and well-controlled studies have not been done in pregnant women. It is not known whether immune globulin can cause fetal harm or affect reproduction capacity. [#] [#] IVIG should be given to a pregnant woman only if clearly needed. Intact immune globulin crosses the placenta from maternal circulation increasingly after 30 weeks gestation. In cases of maternal idiopathic thrombocytopenia purpura in which IVIG was administered to the mother prior to delivery, the platelet response and clinical effect were similar in the mother and neonate. [#] [#] It is not known if IVIG is distributed into breast milk; however, problems in humans have not been documented. [#]

During their circulating life span, IgG antibodies repeatedly exit and enter the vascular compartment. Most antibodies never encounter their specific target antigen and are eventually removed from the circulation and degraded at an unknown site. The rate of IVIG degradation is determined by the Fc region and by the IVIG concentration; degradation is accelerated in hypergammaglobulinema and reduced in hypogammaglobulinemia. The half-life of most IVIG preparations is 18 to 32 days, similar to that of native IgG. The half-life of IVIG in neonates is similar to that in adults. There is, however, considerable individual variability, which reflects several factors, including the immunoglobulin level before infusion, the peak immunoglobulin level after infusion, the presence of infection or burns, the reliability in determining immunoglobulin levels, and other factors. [#] ]]>
[#]

The reported incidence of adverse effects associated with the administration of IVIG ranges from 1% to 15%, but usually is less than 5%. Most of these reactions are mild and self-limited. Severe reactions occur very infrequently and usually do not contraindicate further IVIG therapy. [#] Most adverse reactions to IVIG appear to be related to the rate of administration rather than the dose and may be relieved by decreasing the rate of administration or by temporarily stopping the infusion. [#]

Adverse effects seen with immune globulin use include dyspnea; tachycardia; burning sensation in the head; cyanosis; faintness or lightheadedness; fatigue; wheezing; arthralgia; backache or pain; headache; malaise; myalgia; nausea or vomiting; chest or hip pain; leg cramps; redness, rash, or pain at the injection site; and urticaria. [#] ]]>
[#] ]]>[#]

IVIG is contraindicated in individuals who have had anaphylactic or severe systemic reaction to immune globulin or any ingredients in the formulations (e.g., sorbitol). Epinephrine should be available for immediate treatment of an anaphylactic reaction if it occurs. Most IVIG preparations are contraindicated in individuals with selective IgA deficiencies because these individuals may have serum antibodies to IgA or may develop antibodies following administration of immune globulin and anaphylaxis could result following administration. IVIG occasionally causes a precipitous fall in blood pressure and the clinical manifestations of anaphylaxis; these appear to be related to the rate of administration of the drug and therefore the recommended rate of infusion should not be exceeded. Patients with agammaglobulinemia or extreme hypogammaglobulinemia who have not previously received IVIG or who not have received this drug within the preceding 8 weeks are at particular risk of developing these reactions. [#]

IVIG should be administered with extreme caution in patients with a history of cardiovascular disease or thrombotic episodes. Patients with thrombotic risk factors, including advanced age, hypertension, cerebrovascular disease, coronary artery disease, diabetes mellitus, high serum levels of monoclonal protein, a history of prolonged immobilization, and/or a history of thrombotic episodes should be carefully evaluated before IVIG administration and such patients should only receive infusion solutions of IVIG with a protein concentration of 5% or less.

Consideration should be given to the effect of the additional acid load of IVIG preparations that have a pH of 4 to 4.5 if the drug is used in patients with limited or compromised acid-base compensatory mechanisms. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>Prescribing Information from the FDA Web site. More current versions may be available on the manufacturer's Web site.
Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Transfus Clin Biol. 2003 Jun;10(3):165-9. Review.
Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006 May;46(5):741-53. Review.
Green JA, Martin EM, Mullen BT, Lum T, Pitrak D, Green DS, Fletcher T. Immune-specific immunoglobulin G-mediated enhancement of human immunodeficiency virus-induced IFN-alpha production. J Interferon Cytokine Res. 2002 Dec;22(12):1201-8.
Johnson RM, Barbarini G, Barbaro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV-infected patients. AIDS. 2003 Apr;17 Suppl 1:S77-82. Review.
Metlas R, Srdic T, Veljkovic V. Anti-IgG antibodies from sera of healthy individuals neutralize HIV-1 primary isolates. Curr HIV Res. 2007 Apr;5(2):261-5.
Mouthon L, Lortholary O. Intravenous immunoglobulins in infectious diseases: where do we stand? Clin Microbiol Infect. 2003 May;9(5):333-8.]]>
West Haven, CT 06516-4175
Phone: 800-288-8371]]>
550 North Brand Blvd
Glendale, CA 91203
Phone: 800-423-2090]]>
West Haven, CT 06516-4175
Phone: 800-288-8371]]>
1616 Ft. Myer Drive 17th Floor
Arlington, VA 22209-8746
Phone: 800-446-8883
Fax: 703-312-8746]]>
<![CDATA[Interferon alfa-2]]>[#] Naturally occurring interferon alfa is a protein with antiviral, antiproliferative, and immunomodulating activity. Interferons alfa-2a and -2b are of recombinant DNA origin and exist as single interferon subtype preparations. They are commercially available as peginterferons alfa-2a and -2b, which contain the drugs covalently bound to polyethylene glycol (PEG) monomethoxy ether. [#]

Interferon alfa-2a and -2b are synthetic interferons manufactured by recombinant DNA technology using a genetically engineered Escherichia coli bacterium. [#] [#] Interferons alfa-2a and -2b are biosynthetic forms of interferon alfa that consist of 165 amino acids. Interferons alfa-2a and -2b differ at amino acid position 23; alfa-2a has a lysine in that position, while -2b has an arginine at that position. Compared to other interferon alfa subtypes, interferons alfa-2a and -2b both have a deletion at position 44 in the amino acid sequence. [#]

Interferon alfa-2b is commonly prescribed in a kit with ribavirin. [#] ]]>
[#] Naturally occurring interferon alfa is a protein with antiviral, antiproliferative, and immunomodulating activity. Interferons alfa-2a and -2b are of recombinant DNA origin and exist as single interferon subtype preparations. They are commercially available as peginterferons alfa-2a and -2b, which contain the drugs covalently bound to polyethylene glycol (PEG) monomethoxy ether. [#]

Interferon alfa-2a and -2b are synthetic interferons manufactured by recombinant DNA technology using a genetically engineered Escherichia coli bacterium. [#] [#] Interferons alfa-2a and -2b are biosynthetic forms of interferon alfa that consist of 165 amino acids. Interferons alfa-2a and -2b differ at amino acid position 23; alfa-2a has a lysine in that position, while -2b has an arginine at that position. Compared to other interferon alfa subtypes, interferons alfa-2a and -2b both have a deletion at position 44 in the amino acid sequence. [#]

Interferon alfa-2b is commonly prescribed in a kit with ribavirin. [#] ]]>
[#] Interferons alfa-2a and -2b were approved by the FDA on November 21, 1988 [#] , and are indicated for the treatment of AIDS-associated Kaposi's sarcoma in adults. [#] ]]>[#] [#] ; hairy cell leukemia; AIDS-related Kaposi's sarcoma; chronic myelogenous leukemia; non-Hodgkin and cutaneous T-cell lymphomas; renal cell carcinoma; bladder, ovarian, and cervical cancers; basal cell carcinoma; metastatic melanoma; multiple myeloma; various angiomatous (angiogenic) disorders; and metastatic small intestinal carcinoid tumors. [#]

Interferon alfa-2b is additionally indicated for treatment of condyloma acuminatum (genital warts) and mycosis fungoides. [#] ]]>
[#] [#]

Interferon alfa-2b: intralesional, intramuscular, intravenous, and subcutaneous injection. [#] [#] ]]>

Single use injectable solution (subcutaneous or intramuscular administration): 36 million IU in 1 ml vials. [#]

Single use prefilled syringes (subcutaneous administration only): 3, 6, or 9 million IU in 0.5 ml vials. [#]

Multidose injectable solution (subcutaneous or intramuscular administration): 18 million IU in 1 ml vials. [#]

Interferon alfa-2b:

Powder for reconstitution with diluent, for injection: 5 million IU in 1 ml vials, 10 million IU in 2 ml vials, 18 million IU in 1 ml vials, 25 million IU in 5 ml vials, and 50 million IU in 1 ml vials. [#]

Solution for injection: 3, 5, or 10 million IU single dose vials; 18 or 25 million IU multidose vials. [#]

Multidose injection pens (subcutaneous only): six doses of 3 or 10 million IU in a single pen. [#]

Multidose injectable solution: six 3, 5, or 10 million IU vials. [#]

Available packaged in a kit with ribavirin. [#] ]]>
[#]

Interferon alfa-2a injectable solution and prefilled syringes should not be frozen or shaken. [#]

When dispensing for self-administration by the patient, physicians should make sure that patient instructions are included and that the patient understands how to prepare and administer the injections, including proper use of disposable syringes. [#] ]]>
[#] Antiviral and antiproliferative actions are thought to be related to alterations in the synthesis of RNA, DNA, and cellular proteins, including oncogenes. The exact mechanism of antineoplastic activity is unknown but could be related to interferon alfa's antiviral (inhibiting virus replication in virus-infected cells), antiproliferative (suppressing cell proliferation), and immunomodulatory (enhancing phagocytic activity of macrophages and augmenting specific cytotoxicity of lymphocytes for target cells) effects. [#] Because of their relative species-specific activity, interferons intended for human use are of human origin (e.g., prepared using donor-provided human cells such as leukocytes, using cultured human cell lines such as lymphoblastoid cells, or using recombinant techniques that employ human genes). [#]

The importance, if any, of the single amino acid difference between interferons alfa-2a and -2b has not yet been established. While both the amino and carboxy terminal regions of the molecules may be involved in eliciting antiviral activity, studies to determine which regions of the molecules confer various degrees of activity have yielded conflicting results. Some evidence indicates that different regions may be involved in eliciting various activities of the drug. [#]

Absorption of interferons alfa-2a and -2b is high (greater than 80%) when administered intramuscularly or subcutaneously. When given intralesionally, plasma concentrations of interferon alfa-2 are below detectable levels, but systemic effects have been reported, indicating some systemic absorption. [#] For systemic effects, interferon alfa is administered parenterally because the drug is susceptible to degradation by proteolytic enzymes of the gastrointestinal tract. Interferon alfa-2 is well absorbed following intramuscular (IM) or subcutaneous (SC) injection. Peak serum interferon alfa-2 concentrations following intravenous (IV) administration of the drug generally occur within 15 to 60 minutes and are substantially greater than those attained after IM or SC administration. However, serum interferon alfa concentrations following IM or SC administration are generally maintained longer than those produced by rapid injection or rapid (e.g., 40 minutes or less) IV infusion. Depending on the dose, serum interferon concentrations generally are detectable for approximately 4 hours to 8 hours after rapid IV injection or infusion or for approximately 16 hours to 30 hours after IM or SC injection. [#] Time to peak concentration is 3.8 hours for a single IM dose of interferon alfa-2a, and 7.3 hours for an SC dose. [#] Time to peak concentration of a single IM or SC dose of interferon alfa-2b is usually 3 hours to 12 hours. [#]

Limited data suggest that mixtures of naturally occurring human or animal interferons are widely and rapidly distributed into body tissues after parenteral administration, with the highest concentrations occurring in spleen, kidney, liver, and lung. Limited evidence also indicates interferon uptake and/or binding by other kinds of tissue or tumors. Although a similar pattern of tissue distribution was noted in animals given certain recombinant DNA-derived interferons (human interferon alfa-2c), animal studies in which recombinant interferon alfa-2a or -2b were used suggest that these interferons are not concentrated in any organ or that only the kidney, which appears to be the principal site of interferon metabolism, demonstrates substantial uptake of the drugs. The volume of distribution of interferon alfa in humans reportedly approximates 20% to 60% of body weight. Interferon alfa does not readily distribute into cerebrospinal fluid (CSF) following systemic administration of mixtures of naturally occurring human or recombinant interferons in animals or humans, although low concentrations have been detected in CSF following administration of large systemic doses. It is not known whether interferon crosses the placenta or is distributed into breast milk in humans, but studies in mice indicate that murine interferon is distributed into milk. [#]

Both interferons alfa-2a and -2b are in FDA Pregnancy Category C. Adequate and well-controlled studies have not been done in pregnant women. For interferon alfa-2a, studies in rhesus monkeys at doses approximately 20 to 500 times the therapeutic human dose found a significant increase in abortifacient activity but no evidence of teratogenic activity. For interferon alfa-2b, studies in rhesus monkeys at does of 90 to 180 times the IM or SC dose of 2 million IUs per square meter of body surface area found an abortifacient effect. When given in high doses via daily IM injection in rhesus monkeys, interferon alfa has been shown to cause menstrual cycle changes, with normal menstrual rhythm returning after interferon alfa was withdrawn. Use of recombinant interferon alfa-2a has been associated with reversible menstrual irregularities, including prolonged or shortened menstrual period and erratic bleeding with anovulation in rhesus monkeys given 5 million and 25 million IUs per kg of body weight per day. It is not known if interferon alfa distributes into milk in humans; mouse interferons do distribute into mouse milk. Avoidance of breastfeeding in nursing mothers should be considered while alpha interferon is being administered because of the potential of serious adverse effects in nursing infants. [#]

Interferon alfa-2/ribavirin combination therapy is in FDA Pregnancy Category X. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Use of interferon alfa with ribavirin is contraindicated in women who are pregnant or in the male partners of women who are pregnant. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [#]

Elimination of interferon alfa is rapid from plasma following IV injection or IV infusion in animals or humans, while more prolonged concentrations are observed following IM or SC administration. In healthy individuals with normal renal function, plasma concentrations of interferon alfa appear to decline in a biphasic manner. Limited data from studies in humans receiving interferon alfa-2a or alfa-2b suggest that variability in the reported elimination half-life of interferon alfa may be related to route or method of administration, interindividual variability in drug disposition, and/or presence of disease. [#] The IM half-life of interferon alfa-2a is 6 hours to 8 hours; the half-life for IV infusion is 3.7 hours to 8.5 hours (mean 5.1 hours). The IV or SC half-life of interferon alfa-2b is 2 hours to 3 hours. [#]

Tumor cells may be resistant to the antiproliferative effects of interferon alfa despite the presence of functional, specific high-affinity interferon receptors on their cell surfaces. Resistance to the antiproliferative effects of interferon alfa usually occurs at the cellular level; however, the precise mechanism responsible for resistance to the drugs may differ among cell populations. An association has been observed between the presence of neutralizing anti-interferon antibodies and clinical resistance to interferon alfa in some patients with hairy cell leukemia, suggesting that resistance may not always arise at the intracellular level. However, a causal relationship between the presence of antibodies and disease progression and/or resistance to interferon alfa therapy was not established, and some patients who developed neutralizing antibodies to interferon continued to respond to the drug. Therefore, the development of antibodies should not necessarily be interpreted as an indication of drug resistance. [#] ]]>
[#]

Interferon alfa-2 may cause serious adverse effects such as anemia; autoimmune diseases, including vasculitis, arthritis, hemolytic anemia, and erythematosus syndrome; cardiotoxicity; hepatotoxicity; hyperthyroidism or hypothyroidism; transient ischemic attacks; leukopenia; neurotoxicity; peripheral neuropathy; and thrombocytopenia. Some lesser side effects that may not need medical attention include blurred vision, change in taste or metallic taste, cold sores or stomatitis, diarrhea, dizziness, dry mouth, dry skin or itching, flu-like syndrome, increased sweating, leg cramps, loss of appetite, nausea or vomiting, skin rash, unusual tiredness, weight loss, and partial loss of hair. [#] [#] ]]>
[#]

Interferon alfa-2 should be used with caution in patients receiving drugs that are potentially myelosuppressive. The antineoplastic activity of interferon alfa and certain cytoxic agents (e.g., cisplatin, cyclophosphamide, doxorubicin, eflornithine, fluorouracil, mechlorethamine, melphalan, methotrexate, mitomycin, nitrosureas, vinblastine, vincristine) may be additive or synergistic in vitro and in vivo against some tumors. Further studies are needed to determine the potential interactions between interferon alfa and antineoplastic agents and to establish the optimum regimens, including dosages and sequencing. Limited data indicate that the antineoplastic activity of interferon alfa and vinblastine does not appear to be additive against renal cell carcinoma or AIDS-related Kaposi's sarcoma. However, vinblastine may potentiate the toxicity of interferon alfa when these drugs are used concomitantly. Neurotoxicity (e.g., paresthesia, peripheral neuropathy) in patients receiving interferon alfa usually occurs more frequently in those who have previously received or are concomitantly receiving vinca alkaloids (e.g., vinblastine, vincristine). [#]

Response rates in patients with AIDS-related Kaposi's sarcoma receiving combination chemotherapy with interferon alfa and etoposide suggest that the combination has no synergistic antineoplastic activity against this malignancy, and the incidence of toxicity (e.g., hematologic effects) is higher with the combination than with either drug alone. Combination therapy of high-dose aldesleukin with antineoplastic agents, specifically interferon alfa, has caused hypersensitivity reactions consisting of erythema, pruritus, and hypotension. Aldesleukin in combination with interferon alfa-2 has been associated with the development or exacerbation of autoimmune disease and inflammatory disorders. [#]

Interferon alfa-2 has been reported to reduce the clearance of theophylline, possibly via the hepatic cytochrome P450 (CYP) enzyme system. It is not known whether interferon alfa itself interacts with CYP enzymes or if the drug exerts this effect through an interaction with the immune system. Interferon alfa may also inhibit metabolism of barbiturates. Further studies and experience are needed to establish the clinical importance of this potential drug interaction and to determine whether interferon alfa interacts with other drugs that are metabolized by the hepatic CYP enzyme system. [#]

It has been reported that interferon alfa-2 also inhibits the metabolism of antipyrine. [#]

Interferon alfa-2 has been used as an adjunct to radiation therapy in patients with various neoplasms; however, severe toxicity has been reported in some patients receiving such combined therapy. Patients receiving interferon alfa with radiation therapy should be closely monitored. [#] ]]>
[#]

Interferon alfa-2 is contraindicated in patients hypersensitive to interferon alfa or any component of the product formulations, patients with autoimmune hepatitis, or those with hepatic decompensation. Combination therapy with ribavirin is contraindicated in women who are pregnant or in men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of patients taking combination interferon alfa/ribavirin therapy. [#]

Risk-benefit should be considered if patients have a history of autoimmune disease; severe cardiac disease, including recent myocardial infarction; diabetes mellitus (if the patient is prone to ketoacidosis), ischemic disorders, or pulmonary disease; existing or recent chicken pox, including recent exposure or herpes zoster; compromised central nervous system function, severe or history of psychiatric or seizure disorders; infectious disorders that interferon alfa may aggravate or cause fatal or life-threatening effects; or thyroid function impairment. [#] [#] ]]>
[#] Interferon alfa-2b [#] ]]>[#] 99210-65-8 (2b) [#] ]]>[#]

Interferon alfa-2b: clear and colorless to light yellow solution. [#] ]]>
[#] When stored as directed, the commercially available injection has an expiration date of 12 months following the date of manufacture. Exposure of the injection to room temperature should not exceed 24 hours. [#]

Interferon alfa-2b for intravenous administration should be prepared by mixing with 0.9% sodium chloride immediately prior to use. Interferon alfa-2b powder for injection is stable up to a temperature of 45 C (113 F) for up to 7 days. The reconstituted solution with bacteriostatic diluent is stable for 1 month between 2 C and 8 C (36 F to 46 F); when prepared with sterile water for injection, solutions are stable for 24 hours when stored between 2 C and 8 C (36 F to 46 F). [#] [#] When stored as directed, the commercially available powder for injection has an expiration date of 24 months following the date of manufacture. Any remaining reconstituted solution should be discarded after the period noted previously. When refrigeration is unavailable (e.g., while traveling), interferon alfa-2b powder and reconstituted solutions are stable for short periods (1 to 2 days) at ambient temperatures up to 104 F. However, for longer periods without refrigeration, vials should be placed in a suitable container (e.g., plastic bag) and kept cold (2 C to 8 C; 36 F to 46 F) in a cooler or thermos. Interferon alfa-2b is stable over a pH range of 6.5 to 8. [#] ]]>
Intron A Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Roferon-A Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Prescribing Information is available on the FDA Web site. More current versions may be available on the manufacturer's Web site.
Aversa SM, Cattelan AM, Salvagno L, Crivellari G, Banna G, Trevenzoli M, Chiarion-Sileni V, Monfardini S. Treatments of AIDS-related Kaposi's sarcoma. Crit Rev Oncol Hematol. 2005 Mar;53(3):253-65.
Crespo M, Esteban JI, Ribera E, Falco V, Sauleda S, Buti M, Esteban R, Guardia J, Ocana I, Pahissa A. Utility of week-4 viral response to tailor treatment duration in hepatitis C virus genotype 3/HIV co-infected patients. AIDS. 2007 Feb 19;21(4):477-481.
Haydon GH, Mutimer DJ. Hepatitis B and C virus infections in the immune compromised. Curr Opin Infect Dis. 2003 Oct;16(5):473-9. PMID: 14502001
Medina J, Garcia-Buey L, Moreno-Monteagudo JA, Trapero-Marugan M, Moreno-Otero R. Combined antiviral options for the treatment of chronic hepatitis C. Antiviral Res. 2003 Oct;60(2):135-43. Review.
Neau D, Trimoulet P, Winnock M, Rullier A, Le Bail B, Lacoste D, Ragnaud JM, Bioulac-Sage P, Lafon ME, Chene G, Dupon M; ROCO Study Group. Comparison of 2 regimens that include interferon-alpha-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients. Clin Infect Dis. 2003 Jun 15;36(12):1564-71. Epub 2003 Jun 03.
Puoti M, Zanini B, Quinzan GP, Ravasio L, Paraninfo G, Santantonio T, Rollo A, Artioli S, Maggiolo F, Zaltron S, Raise E, Mignani E, Resta F, Verucchi G, Pastore G, Suter F, Carosi G; MASTER HIV/HCV Co-Infection Study Group. A randomized, controlled trial of triple antiviral therapy as initial treatment of chronic hepatitis C in HIV-infected patients. J Hepatol. 2004 Aug;41(2):312-8.]]>
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100 USA
Phone: 908-423-1000

]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100 USA
Phone: 908-423-1000

]]>
Nutley, NJ 07110
Phone: 973-235-5000]]>
<![CDATA[Isoniazid]]>[#] ]]>[#] ]]>[#] ]]>[#]

Isoniazid is also indicated in combination with other antitubercular agents in the treatment of all forms of tuberculosis, including tuberculous meningitis. [#] ]]>
[#]

Intramuscular. [#] ]]>

Syrup containing isoniazid 50 mg/5 ml in 70% sorbitol. [#]

Injection for intramuscular administration containing isoniazid 100 mg/ml with preservative. [#]

Fixed combination capsules with rifampin (isoniazid 150 mg and rifampin 300 mg per capsule). [#]

Fixed combination tablets with rifampin and pyrazinamide (isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet). [#] ]]>
[#] ]]>
[#] The exact mechanism of isoniazid's antitubercular action is unknown, but it may involve inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms. [#] Isoniazid may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The drug is active against susceptible bacteria only during bacterial cell division. [#]

Isoniazid is readily absorbed from the gastrointestinal (GI) tract after oral administration and from intramuscular injection sites. [#] Both absorption and bioavailability are reduced when isoniazid is administered with food. [#] Following oral administration, peak plasma concentrations occur within 1 to 2 hours. [#]

Isoniazid distributes readily into all body fluids and tissues, including cerebrospinal fluid (CSF), pleural and ascitic fluids, skin, sputum, saliva, lungs, muscle, and caseous tissue. [#] CSF concentrations are reported to be 90% to 100% of concurrent plasma concentrations. [#]

The plasma half-life of isoniazid ranges from 1 to 4 hours, depending on rate of metabolism in a given individual. Impaired hepatic function or severe renal impairment will prolong the plasma half-life. Isoniazid may undergo significant first-pass hepatic metabolism following oral administration. Isoniazid is inactivated in the liver by acetylation and dehydrazination; inactive metabolites may also undergo hydroxylation by the cytochrome P450 oxidase system. The rate of isoniazid acetylation is genetically determined and is subject to individual variation; however, it is usually constant for each person. The rate of acetylation does not appear to alter efficacy when the drug is administered daily or 2 to 3 times weekly, but it has been noted that rapid inactivation relates to poor therapeutic response in once-weekly intermittent regimens. Isoniazid is excreted as unchanged drug and metabolites primarily by the kidneys (75% to 96%) within 24 hours of administration. It can be removed by hemodialysis or peritoneal dialysis. [#]

Isoniazid is in FDA Pregnancy Category C. Isoniazid crosses the placenta, resulting in fetal plasma concentrations approximately equal to or exceeding maternal plasma concentrations. It is also distributed in milk, possibly resulting in infant plasma concentrations similar to maternal concentrations. Isoniazid has not been shown to be teratogenic in mice, rats, or rabbits. [#] No isoniazid-related congenital abnormalities have been observed in mammalian reproductive studies, but it has been reported that isoniazid may exert an embryocidal effect when the drug is administered orally in pregnant rats and rabbits. Although safe use of the drug during pregnancy has not been definitely established, isoniazid (combined with rifampin and/or ethambutol) has been used to treat clinical tuberculosis in pregnant women. The potential benefits of isoniazid therapy for latent tuberculosis infection during pregnancy should be weighed against the possible risks to the fetus. Neonates and breastfed infants of isoniazid-treated mothers should be carefully observed for evidence of adverse effects. [#]

Natural and acquired resistance to isoniazid has been demonstrated in vitro and in vivo in strains of M. tuberculosis. The mechanism of resistance may be related to the failure of the drug to penetrate or be taken up by the resistant bacteria. Resistant strains develop rapidly if isoniazid is used alone in the treatment of clinical tuberculosis; however, development of resistance does not appear to be a major problem when the drug is used alone in preventive therapy. Further, when isoniazid is combined with other antitubercular agents in the treatment of clinical tuberculosis, emergence of resistant strains may be delayed or prevented. [#] ]]>
[#]

Isoniazid has been reported to cause mild and transient elevations in serum AST (SGOT), ALT (SGPT), and bilirubin concentrations in 10% to 20% of patients, usually during the first 4 to 6 months of therapy. Laboratory values usually return to pretreatment levels with continued use of the drug; however, progressive liver damage, bilirubinemia, jaundice, and severe and sometimes fatal hepatitis have occurred rarely. Hepatitis and hepatitis prodromal symptoms (e.g., persistent fatigue, weakness, or fever exceeding 3 days; malaise; nausea; vomiting; or unexplained anorexia) have been observed with the use of isoniazid. The incidence of isoniazid-associated hepatitis is lowest in those younger than 20 years of age and highest in daily users of alcohol and in patients 35 years of age or older. Liver function tests should be performed periodically, and patients should be carefully observed for any of the prodromal symptoms of hepatitis. [#]

Hypersensitivity reactions, including fever, skin eruptions, lymphadenopathy, vasculitis, and hypotension, have occurred rarely with isoniazid, generally 3 to 7 weeks after the start of treatment. Other adverse effects requiring medical attention include optic neuritis, characterized by a sometimes painful blurring or loss of vision, and hematologic abnormalities, such as agranulocytosis, eosinophilia, thrombocytopenia, methemoglobinemia, and hemolytic, sideroblastic, or aplastic anemia. [#]

GI disturbances (abdominal pain, diarrhea, nausea, and vomiting), dryness of the mouth, hyperglycemia, pyridoxine deficiency, pellagra, metabolic acidosis, urinary retention, and gynecomastia in males have also been reported with isoniazid use. Irritation at the site of injection has occurred during intramuscular administration of isoniazid. [#] ]]>
[#] Fixed-dose combination products containing isoniazid should be administered either 1 hour before or 2 hours after a meal. [#]

Concurrent use of alcohol, disulfiram, and other hepatotoxic medications with isoniazid may increase the potential for hepatotoxicity and should be avoided. Concurrent use of rifampin with isoniazid also may increase the potential for hepatotoxicity, requiring additional monitoring of liver enzymes and clinical symptoms. [#] Some evidence suggests that adverse nervous system effects may be additive if antitubercular agents are taken concurrently; isoniazid should be used with caution in patients receiving cycloserine and ethionamide. Isoniazid inhibits the multiplication of bacille Calmette-Guerin (BCG); the BCG vaccine may not be effective if adminstered during isoniazid therapy. [#]

Concurrent administration of isoniazid with carbamazepine has resulted in increased serum concentrations of the anticonvulsant and caused symptoms of carbamazepine toxicity, including ataxia, headache, vomiting, blurred vision, drowsiness, and confusion. This interaction is believed to occur because isoniazid inhibits hepatic metabolism of carbamazepine; the symptoms of toxicity subside when carbamazepine dosage is decreased or when the antitubercular agent is discontinued. Isoniazid also inhibits the hepatic metabolism of phenytoin, resulting in increased plasma phenytoin concentrations and toxicity in some patients. Patients should be closely monitored for any evidence of toxicity, and anticonvulsant doses should be reduced accordingly. [#]

Isoniazid may have MAO-inhibiting activity, so there is a slight risk of serotonin syndrome when isoniazid is given in combination with selective serotonin-reuptake inhibitors (SSRIs) or other serotonergic medications. Aluminum hydroxide-containing antacids decrease GI absorption of isoniazid, so isoniazid should be administered at least 1 hour before the antacid. [#] ]]>
[#]

Isoniazid is also contraindicated in patients with acute liver disease or a history of previous isoniazid-associated hepatic injury. [#] ]]>
[#] ]]>[#] ]]>[#]

Injection isoniazid: Clear, colorless to faintly greenish-yellow liquid. [#] ]]>
[#] ]]>[#] At a temperature of 40 C (104 F), isoniazid is approximately 26% soluble in water and approximately 10% soluble in boiling alcohol. [#] ]]>
Prescribing Information from the FDA Web site. More current versions may be available on the manufacturer's Web site.
Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003 May 12;163(9):1009-21. Review.
Currie CS, Williams BG, Cheng RC, Dye C. Tuberculosis epidemics driven by HIV: is prevention better than cure? AIDS. 2003 Nov 21;17(17):2501-8.
Lim HJ, Okwera A, Mayanja-Kizza H, Ellner JJ, Mugerwa RD, Whalen CC. Effect of tuberculosis preventive therapy on HIV disease progression and survival in HIV-infected adults. HIV Clin Trials. 2006 Jul-Aug;7(4):172-83.
Rolla VC, da Silva Vieira MA, Pereira Pinto D, Lourenco MC, de Jesus Cda S, Goncalves Morgado M, Ferreira Filho M, Werneck-Barroso E. Safety, efficacy and pharmacokinetics of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin combined therapy in HIV patients with tuberculosis. Clin Drug Investig. 2006;26(8):469-79.
Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B, Silva-Trigo C, Zhao Z, Hodge T; Tuberculosis Trials Consortium. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis. 2005 May 15;40(10):1481-91. Epub 2005 Apr 14.
Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science. 2003 Sep 12;301(5639):1535-7. Epub 2003 Aug 14.]]>
Nutley, NJ 07110-1199
Phone: 800-821-8590]]>
Suite 400
Princeton, NJ 08540
Phone: 609-627-8500
Fax: 609-627-8659]]>
<![CDATA[Itraconazole]]>[#] ]]>[#] ]]>[#] Itraconazole is also used orally for the prevention of serious fungal infections (e.g., coccidiodomycosis, cryptococcosis, histoplasmosis, mucocutaneous candidiasis) in patients with HIV infection. [#] ]]>[#] ]]>[#] ]]>[#]

Oral solution containing itraconazole 10 mg/ml. [#]

Injection for intravenous infusion in one 25 ml colorless glass ampule containing itraconazole 10 mg/ml in pyrogen-free solution. [#] ]]>
[#]

Store oral solution at or below 25 C (77 F) and protect from freezing. [#]

Store injection at or below 25 C (77 F) and protect from light and freezing. [#] ]]>
[#]

Gastrointestinal (GI) absorption of itraconazole is affected by achlorhydria or hypochlorhydria (no or low acid levels in the stomach); because cases of HIV infected individuals with these conditions have been reported, physicians should consider this in their decision to use itraconazole. [#] Bioavailability of itraconazole when given in capsule form is 40% to 55% in the fasting state and 90% to 100% when taken with food. The bioavailability of the oral solution form is 90% to 100% in the fasting state and 55% when taken with food. The time to peak serum concentration may be from 2.5 hours to 4.4 hours, depending on formulation and whether the drug was taken with food. [#]

Itraconazole is highly lipophilic and is extensively distributed to tissues, concentrating in fatty tissues, omentum (lining of the bowel wall), liver, and kidneys. Aqueous fluids, such as the cerebrospinal fluid, aqueous humor, and saliva, contain negligible concentrations of itraconazole. Itraconazole does not distribute into peritoneal dialysate effluent. Exudates such as pus may have up to 3.5 times the simultaneous plasma concentration of the drug, while tissues that are prone to fungal invasion, such as the skin, lung tissue, and the female genital tract, have several times the plasma concentration. [#]

Itraconazole is in FDA Pregnancy Category C. Adequate and well-controlled studies have not been done in pregnant women. Based on the teratogenic and embyrotoxic effects shown in animal studies, itraconazole should only be used during pregnancy or nursing when the potential benefits justify the possible risks to the fetus or nursing infant. Animal studies indicate that itraconazole causes a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity. In rats, these consist of major skeletal defects at doses approximately 5 to 20 times the maximum recommended human dose (MRHD); in mice, these consist of encephaloceles and/or macroglossia at doses 10 times the MRHD. Itraconazole did not affect the fertility of male or female rats treated with oral doses of up to 5 times the MRHD, although parental toxicity was present at this dosage level. Itraconazole is distributed into breast milk. [#]

Itraconazole binding to proteins is very high (99%). Metabolism of itraconazole is primarily hepatic. Biliary excretion of the capsule form is estimated to be 3% to 18%. [#] Adjustment of oral itraconazole dosage in patients with renal impairment appears unnecessary; itraconazole injection should not be given to patients with creatinine clearance less than 30 ml/min, because severe renal impairment reduces clearance of hydroxypropyl beta-cyclodextrin (an excipient contained in itraconazole injection). While the effect of hepatic impairment on itraconazole pharmacokinetics currently remains unclear, plasma concentrations of the drug should be monitored carefully in patients with such impairment. [#]

Itraconazole capsules and oral solution should not be used interchangeably. Drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. [#] ]]>
[#]

The most common adverse events to itraconazole injection in pharmacologic testing have been nausea, hypokalemia, bilirubinemia, diarrhea, and vomiting. The injection is associated with increased levels of hepatic enzymes, abnormal hepatic function, and jaundice, which may be indicative of possible liver disease. If patients develop clinical signs and symptoms consistent with liver disease, the administration of IV itraconazole should be discontinued. The oral solution is safe and generally well tolerated; the most common adverse effects are nausea, diarrhea, and fever. [#] The most common side effects seen with itraconazole capsule use in the treatment of systemic fungal infections have been nausea and skin rash. [#] ]]>
[#] Patients with achlorhydria or hypochlorhydria (no or low acid levels in the stomach) will have decreased absorption of itraconazole. Itraconazole capsules should be taken with a full meal to ensure maximal absorption of the medication; itraconazole oral solution should be taken on an empty stomach to increase absorption of the medication. [#]

Concurrent use of itraconazole with oral antidiabetic agents such as tolbutamide, chlorpropamide, glyburide, or glipizide has increased the plasma concentrations of these sulfonylurea agents, leading to hypoglycemia; blood glucose concentrations should be monitored, as the dose of oral hypoglycemic agent may need to be reduced. Itraconazole may inhibit the metabolism of the antineoplastics busulfan, docetaxel, and vinca alkaloids. Use of itraconazole with calcium channel blockers (e.g., felodipine, nifedipine, verapamil) may result in edema; dosage adjustment may be needed. Caution should be used as itraconazole may inhibit calcium channel blockers' metabolism and these drugs can have a negative inotropic effect that may be additive to those of itraconazole. [#] Concurrent use of itraconazole with benzodiazepines (e.g., alprazolam, diazepam, midazolam, triazolam) elevates the plasma concentration of the benzodiazepines, which may potentiate and prolong their hypnotic and sedative effects. [#]

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin) may decrease itraconazole plasma concentrations, leading to treatment failure or clinical relapse. Use of immunosuppressive drugs such as cyclosporine, methylprednisolone, sirolimus, or tacrolimus with itraconazole should be monitored carefully because itraconazole may inhibit their metabolism, increasing the plasma concentration of these drugs to toxic levels. Itraconazole may increase serum digoxin or alfentanil concentrations, leading to toxicity. Rifampin and rifabutin may increase the metabolism of itraconazole and other azoles, thus lowering the plasma concentration, which may lead to clinical failure or relapse. Macrolide antibiotics (e.g., clarithromycin, erythromycin) are known inhibitors of CYP3A4 and may increase plasma concentrations of itraconazole. [#] The anticoagulant effects of warfarin may be increased when warfarin is used concurrently with any azole antifungal, resulting in an increase of prothrombin time; patients on a concurrent regimen should be monitored carefully. [#]

Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes, such as amphotericin B. Itraconazole may increase plasma concentrations of protease inhibitors (e.g., indinavir, ritonavir, saquinavir); conversely, indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Nevirapine (and potentially other nucleoside reverse transcriptase inhibitors) may induce the metabolism of itraconazole and has been shown to reduce the bioavailability of ketoconazole, another azole antifungal. [#]

People allergic to fluconazole or ketoconazole may also be allergic to itraconazole, another antifungal in this drug family. [#] ]]>
[#] Negative inotropic effects were seen when itraconazole was administered intravenously to healthy human volunteers. If signs or symptoms of CHF occur during the administration of itraconazole injection, continued itraconazole use should be reassessed. [#]

Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (lemomethadyl) with itraconazole capsules, injection, or oral solution is contraindicated. Itraconazole, a potent cytochrome CYP3A4 inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, or sudden death, have occurred in patients using cisapride, pimozide, levomethadyl, or quinidine concomitantly with itraconazole or other CYP3A4 inhibitors. [#]

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms consistent with liver disease develop, treatment should be discontinued and liver function testing performed. Continued itraconazole use or reinstitution of treatment is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. [#]

Itraconazole is contraindicated in patients who have shown hypersensitivity to itraconazole and should be prescribed with caution to patients with hypersensitivity to other azoles. [#] Concurrent use of itraconazole with astemizole, terfenadine, atorvastatin, cerivastatin, lovastatin, or simvastatin is contraindicated. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#]

A dedicated infusion line should be used for administration of itraconazole injection; do not introduce concomitant medication in the same bag or same line as itraconazole injection. [#]

Correct preparation and administration of itraconazole injection are necessary to ensure maximal efficacy and safety. A precise mixing ratio is required in order to obtain a stable admixture. It is critical to maintain a 3.33 mg/ml itraconazole:diluent ratio. Failure to maintain this concentration will lead to the formation of a precipitate. [#] ]]>
[#] Very slightly soluble in alcohols and freely soluble in dichloromethane, and it has a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. [#] ]]>
Sporanox Capsules Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Sporanox Injection Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Sporanox Oral Solution Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS. 2007 Jan 30;21(3):365-7.
Marty F, Mylonakis E. Antifungal use in HIV infection. Expert Opin Pharmacother. 2002 Feb;3(2):91-102. Review.
Ostrosky-Zeichner L. Novel approaches to antifungal prophylaxis. Expert Opin Investig Drugs. 2004 Jun;13(6):665-72. Review.
Ruhnke M. Mucosal and systemic fungal infections in patients with AIDS: prophylaxis and treatment. Drugs. 2004;64(11):1163-80. Review.
Wu JJ, Pang KR, Huang DB, Tyring SK. Therapy of systemic fungal infections. Dermatol Ther. 2004;17(6):532-8. Review.]]>
Titusville, NJ 08560-0200
Phone: 800-526-7736
Fax: 609-730-2461]]>
430 Rt. 22 East
Bridgewater, NJ 08807-0914
Phone: 800-682-6532
Fax: 800-682-6532]]>
<![CDATA[Megestrol acetate]]>[#] ]]>[#] ]]>[#]

In clinical trials, megestrol acetate in 800 mg daily doses experienced appetite and weight gain, despite caloric intakes similar to those of control groups. Weight gain was associated with nonwater body weight. HIV patients also reported subjective improvement in their sense of well-being during megestrol therapy. [#] ]]>
[#] ]]>[#] ]]>[#]

Concentrated oral suspension containing megestrol acetate 125 mg/ml. [#] ]]>
[#]

Store oral suspension in tight containers at 25 C (77 F) or less. [#]

Store concentrated oral suspension between 15 C and 25 C (59 F to 77 F), dispense in a tight container, and protect from heat. [#] ]]>
[#]

The exact mechanism of the antineoplastic action of megestrol acetate has not been determined. The antineoplastic effect may result from suppression of luteinizing hormone by inhibition of pituitary function. Results of one clinical study suggested that megestrol acetate produced a local effect on the cancerous cell by converting the actively growing stroma into decidua. [#]

The drug is well absorbed from the gastrointestinal (GI) tract; peak plasma concentrations (Cmax) of the drug were obtained in 1 to 5 hours. Following daily single 800 mg doses of megestrol acetate to cachectic AIDS patients, steady-state Cmax on day 21 occurred 5 hours after administration and averaged 753 ng/ml. [#]

Megestrol acetate oral suspension is in FDA Pregnancy Category X; the tablet form is in Category D. The drug may cause fetal harm when administered to a pregnant woman. Although there have been no adequate or well-controlled studies in pregnant women, results from studies in pregnant rats given high doses of megestrol acetate showed decreased fetal birth weight, fewer live births, and reversible feminization of some male fetuses. [#] [#]

Progestins, including megestrol acetate, are distributed into breast milk. [#] Because of the potential for transmission of HIV from the mother and for serious adverse effects from megestrol acetate to the breast-fed infant, women should be instructed not to breast-feed while taking megestrol acetate. [#]

The drug is completely metabolized in the liver to free steroids and glucuronides of steroidal metabolites. The major route of elimination appears to be urinary excretion. Following oral administration of radiolabeled megestrol acetate, about 66% of the dose was excreted in urine and about 20% was excreted as feces within 10 days. [#] ]]>
[#]

Megestrol acetate is usually well tolerated. Adverse reactions occurring in more than 5% of patients include diarrhea, flatulence, nausea, vomiting, impotence, decreased libido, rash, and hypertension. Hypertension has been reported to resolve following initiation of diuretic therapy or adjustment of patient's pre-existing antihypertensive regimen. [#]

Postmarketing reports associate megestrol acetate with thrombophlebitis, pulmonary embolism, glucose intolerance, and diabetes mellitus. [#]

Pneumonia has been reported in 2% of patients receiving megestrol acetate for AIDS-related cachexia. Nervous system effects reported in patients receiving megestrol acetate for AIDS-related cachexia include insomnia, headache, asthenia, paresthesia, confusion, seizure, depression, neuropathy, hypesthesia, and abnormal thinking. Other adverse effects reported among patients being treated for AIDS-related cachexia include fever, anemia, leukopenia, hepatomegaly, abdominal pain, infections, candidiasis, herpes, pruritus, vesiculobullous rash, sweating, skin disorders, amblyopia, increase in LDH, and sarcoma. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Megace Tablets - FDA Oncology Tools Product Label [html]. A more current version may be available on the manufacturer's Web site.
Megace ES Oral Suspension Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Batterham MJ, Garsia R. A comparison of megestrol acetate, nandrolone decanoate and dietary counseling for HIV associated weight loss. Int J Androl 2001 Aug;24(4):232-40.
Mwamburi DM, Gerrior J, Wilson IB, Chang H, Scully E, Saboori S, Miller L, Forfia J, Albrecht M, Wanke CA. Combination megestrol acetate, oxandrolone, and dietary advice restores weight in human immunodeficiency virus. Nutr Clin Pract. 2004 Aug;19(4):395-402.
Mwamburi DM, Gerrior J, Wilson IB, Chang H, Scully E, Saboori S, Miller L, Forfia J, Albrecht M, Wanke CA. Comparing megestrol acetate therapy with oxandrolone therapy for HIV-related weight loss: similar results in 2 months. Clin Infect Dis. 2004 Mar 15;38(6):895-902. Epub 2004 Mar 01.
Pascual Lopez A, Roque i Figuls M, Urrutia Cuchi G, Berenstein EG, Almenar Pasies B, Balcells Alegre M, Herdman M. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage. 2004 Apr;27(4):360-9. Review.]]>
Spring Valley, NY 10977
Phone: 800-828-9393]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Spring Valley, NY 10977
Phone: 800-828-9393]]>
<![CDATA[Paclitaxel]]>[#] ]]>[#] ]]>[#]

Use of a liposomal anthracycline (doxorubicin or daunorubicin) is currently the first-line therapy of choice for advanced AIDS-related KS. Although the comparative efficacy of paclitaxel versus other treatments for advanced AIDS-related KS has not been established, paclitaxel has shown substantial activity in patients with advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease). Objective responses to paclitaxel therapy have been reported in patients with poor prognostic factors, including low baseline helper/inducer T-cell counts, visceral involvement, or history of opportunistic infection as well as in patients who have received prior systemic chemotherapy. However, the depressed immunologic status of these patients limits the therapeutic benefit of systemic chemotherapy, and there currently are no data showing unequivocal evidence of improved survival with any treatment for AIDS-related KS. [#] ]]>
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Paclitaxel is also used for the treatment of small cell lung, esophageal, bladder, head and neck, cervical, endometrial, gastric, and relapsed or refractory testicular cancer. [#] ]]>
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For patients with advanced HIV infection, paclitaxel therapy should only be initiated or continued if the neutrophil count is above 1,000 cells/mm3. [#]

For patients with AIDS-related KS that has failed to respond to first-line or subsequent chemotherapy, there are two recommended paclitaxel regimens. One recommended regimen is paclitaxel 135 mg/m2 administered by 3-hour IV infusion once every 3 weeks; another recommended regimen is paclitaxel 100 mg/m2 administered by 3-hour IV infusion once every 2 weeks. [#] ]]>
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[#] Evidence suggests that paclitaxel may also induce cell death by triggering apoptosis. Paclitaxel also enhances the cytotoxic effects of ionizing radiation. [#]

Peak plasma concentrations of paclitaxel following IV administration exhibit marked interindividual variation. Plasma concentrations of paclitaxel increase during continuous IV administration of the drug and decline immediately following completion of infusion. Following 24-hour IV infusion of paclitaxel at doses of 135 to 175 mg/m2 in patients with advanced ovarian cancer, peak plasma concentrations (Cmax) averaged 195 or 365 ng/ml, respectively. The increase in dose (30%) was associated with a disproportionately greater increase in peak plasma concentration (68%) and area under the concentration-time curve (89%). [#]

Paclitaxel is widely distributed into body fluids and tissues after IV administration. Paclitaxel has a large volume of distribution that appears to be affected by dose and duration of infusion. Following administration of paclitaxel doses of 135 to 175 mg/m2 by IV infusion over 24 hours in patients with advanced ovarian cancer, the mean apparent volume of distribution at steady state ranged from 227 to 688 l/m2. Paclitaxel does not appear to readily penetrate the central nervous system, but paclitaxel has been detected in ascitic fluid following IV infusion. It is not known if paclitaxel distributes into human milk, but in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug. [#]

Paclitaxel is in FDA Pregnancy Category D. Adequate and well-controlled studies have not been done in pregnant women. Studies in rats at doses of 1 mg per kg of body weight found that paclitaxel reduced fertility. It is usually recommended that the use of antineoplastics, especially combination chemotherapy, be avoided whenever possible in pregnant women, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered. Hazards to the fetus include adverse reactions seen in adults. Paclitaxel was found to cause maternal and embryo-fetal toxicity in rabbits at intravenous doses of 3 mg/kg given during organogenesis. In rats and rabbits, paclitaxel was found to cause abortions, decreased corpora lutea, a decrease in implantations and live fetuses, and increased resorptions and embryo-fetal deaths. No gross external, soft tissue, or skeletal alterations have been observed. [#]

At plasma concentrations ranging from 0.1 to 50 mcg/ml, 88% to 98% of paclitaxel is bound to plasma proteins. Following IV infusion of paclitaxel over periods ranging from 6 to 24 hours in adults with malignancy, plasma concentrations of paclitaxel appear to decline in a biphasic manner in some studies, with an average distribution half-life of 0.34 hours and an average elimination half-life of 5.8 hours. However, additional studies, particularly those in which paclitaxel is administered over a shorter period of infusion, show that the drug exhibits nonlinear pharmacokinetic behavior. In patients receiving paclitaxel 175 mg/m2 administered by 3-hour IV infusion, the distribution half-life averages 0.27 hours and the elimination half-life averages 2.33 hours. [#]

Paclitaxel is extensively metabolized in the liver by the isoenzymes cytochrome P450 (CYP) 2C8 and CYP3A4. Paclitaxel and its metabolites are principally excreted in the feces via biliary elimination with minimal urinary excretion; unchanged drug in urine typically accounts for less than 10% of an administered dose. Hemodialysis only minimally removes paclitaxel. Administration of cisplatin followed by paclitaxel decreases paclitaxel clearance by 25% to 33%. When cisplatin and paclitaxel must be administered sequentially, the sequence of paclitaxel followed by cisplatin is recommended. [#] ]]>
[#] Adverse effects observed with the use of paclitaxel include anemia; hypersensitivity reaction; leukopenia or neutropenia, with or without infection; thrombocytopenia; cardiovascular effects, including bradycardia, hypotension, or abnormal electrocardiogram (ECG); elevated serum hepatic enzymes; arthralgias or myalgias; diarrhea; nausea or vomiting; peripheral neuropathy, including mild paresthesia; and alopecia. [#] ]]>[#]

Concurrent use of bone marrow depressants and radiation therapy with paclitaxel may cause additive bone marrow depression. Dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively. Severity of paclitaxel-induced neutropenia may be related to the extent of prior myelotoxic therapy. [#] Sequence-dependent drug interactions have been reported to occur when paclitaxel is administered with other antineoplastic agents, including cisplatin, doxorubicin, and cyclophosphamide. [#]

Because normal defense mechanisms may be suppressed by paclitaxel therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, or may decrease the patient's antibody response to the vaccine. Immunization of patients taking paclitaxel should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the paclitaxel therapy. [#] ]]>
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Risk-benefit assessment should be considered in patients with bone marrow depression; cardiac function impairment, including angina and cardiac conduction abnormalities; history of congestive heart failure or myocardial infarction within the past 6 months; existing or recent onset or exposure to chickenpox or herpes zoster; infection; or previous cytotoxic drug therapy or radiation therapy. It is recommended that paclitaxel not be administered to patients with AIDS-related KS when baseline neutrophil counts are lower than 1,000 cells/mm3 because use of paclitaxel will further bone marrow depression. [#] ]]>
[#] ]]>[#] ]]>[#] ]]>[#] ]]>[#] ]]>Taxol Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Aldenhoven M, Barlo NP, Sanders CJ. Therapeutic strategies for epidemic Kaposi's sarcoma. Int J STD AIDS. 2006 Sep;17(9):571-8. Review.
Aversa SM, Cattelan AM, Salvagno L, Crivellari G, Banna G, Trevenzoli M, Chiarion-Sileni V, Monfardini S. Treatments of AIDS-related Kaposi's sarcoma. Crit Rev Oncol Hematol. 2005 Mar;53(3):253-65. Review.
Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: emerging challenges in the era of highly active antiretroviral therapy. Oncologist. 2005 Jun-Jul;10(6):412-26.
Dhillon T, Stebbing J, Bower M. Paclitaxel for AIDS-associated Kaposi's sarcoma. Expert Rev Anticancer Ther. 2005 Apr;5(2):215-9. Review.]]>
Irvine, CA 92618-1902
Phone: 800-729-9991
Fax: 949-855-8210]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
Princeton, NJ 08543-4500
Phone: 800-321-1335]]>
<![CDATA[Peginterferon alfa-2]]>[#]

Peginterferon alfa-2a is a covalent conjugate of recombinant alfa-2a interferon with a single branched bis-monomethoxy polyethlyene glycol (PEG) chain. The PEG moiety is linked at a single site via a stable amide bond to lysine. Peginterferon alfa-2b is a covalent conjugate of recombinant alfa-2b interferon with PEG. Interferons alfa-2a and -2b are produced using recombinant DNA technology, through which a human leukocyte interferon gene is inserted into and expressed in Escherichia coli. [#]

The PEG conjugate improves the pharmacokinetic profile of interferon alfa; pegylated interferon alfa clearance is lower than that of nonpegylated interferon alfa. [#] ]]>
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Peginterferon alfa-2a is a covalent conjugate of recombinant alfa-2a interferon with a single branched bis-monomethoxy polyethlyene glycol (PEG) chain. The PEG moiety is linked at a single site via a stable amide bond to lysine. Peginterferon alfa-2b is a covalent conjugate of recombinant alfa-2b interferon with PEG. Interferons alfa-2a and -2b are produced using recombinant DNA technology, through which a human leukocyte interferon gene is inserted into and expressed in Escherichia coli. [#]

The PEG conjugate improves the pharmacokinetic profile of interferon alfa; pegylated interferon alfa clearance is lower than that of nonpegylated interferon alfa. [#] ]]>
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Peginterferon alfa-2b: powder for injection in 0.5-ml vials, containing the equivalent of peginterferon alfa-2b 50, 80, 120, and 150 mcg. [#] [#] ]]>
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Store peginterferon alfa-2b powder for injection at 25 C (77 F), with excursions permitted between 15 C and 30 C (59 F to 86 F). Peginterferon alfa-2b should not be frozen. [#] ]]>
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After subcutaneous (SQ) administration of peginterferon alfa-2a, maximal serum concentrations (Cmax) occur between 72 to 96 hours post dose. The Cmax and area under the plasma concentration-time curve (AUC) measurements increase in a dose-related manner. Week 48 mean trough concentrations at 168 hours post dose are approximately twofold higher than Week 1 mean trough concentrations (16 ng/ml versus 8 ng/ml, respectively). Steady state serum levels are reached within 5 to 8 weeks of once weekly dosing. The mean systemic clearance of peginterferon alfa-2a in healthy subjects was 94 ml/h, which is approximately 100-fold lower than that for nonpegylated interferon alfa-2a. The mean terminal half-life after SQ dosing in patients with chronic HCV was 80 hours (range 50 to 140 hours). In comparison, the mean terminal half-life of the nonpegylated interferon alfa-2a was 5.1 hours (range 3.7 to 8.5 hours). [#]

The absorption half-life for peginterferon alfa-2b is 4.6 hours. [#] After SQ administration of peginterferon alfa-2b, Cmax occurs between 15 to 44 hours postdose and is sustained for up to 48 to 72 hours. Cmax and AUC values increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability. Week 48 mean trough concentrations are approximately 3 times higher than Week 4 mean trough concentrations. The mean peginterferon alfa-2b elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. Renal elimination accounts for 30 percent of the clearance, and impaired renal function (creatinine clearance less than 50 ml/minute) leads to a significant reduction in drug clearance. [#]

Peginterferon alfa (used alone) is in FDA Pregnancy Category C. There have been no adequate or well-controlled studies of peginterferon alfa-2 in pregnant women. Although no teratogenic effects occurred in laboratory animals whose offspring were delivered at term, there was a significant increase in spontaneous abortions seen with use of both peginterferons alfa-2a and -2b. Peginterferon alfa should be assumed to have abortifacient potential and should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. [#] [#]

Peginterferon alfa-2/ribavirin combination therapy is in FDA Pregnancy Category X. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Use of peginterferon alfa with ribavirin is contraindicated in women who are pregnant or in the male partners of women who are pregnant. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. [#] [#]

It is not known whether peginterferons alfa-2a and -2b are excreted into breast milk, but because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the treatment, taking into account the importance of the product to the mother. [#] [#]

In patients with end-stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in peginterferon alfa-2a clearance, resulting in correspondingly higher exposure to the drug. Patients should be monitored for symptoms of interferon toxicity and may require dose reduction. [#] Renal elimination of peginterferon alfa-2b is approximately 30%, with clearance possibly reduced by one-half in patients with renal function impairment. [#] Both peginterferons alfa-2a and -2b should be used with caution in patients with creatinine clearances less than 50 ml/min. [#] [#] ]]>
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Nearly all study patients in clinical trials involving peginterferon alfa-2a or -2b experienced one or more adverse events. [#] Peginterferon use may cause or aggravate life-threatening or fatal neuropsychiatric, autoimmune, ischemic, and infectious reactions. Patients should be monitored closely with periodic clinical and laboratory evalulations. Patients with persistent severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after peginterferon alfa therapy is discontinued. Use of peginterferon alfa with ribavirin may cause a broad variety of serious adverse reactions, including birth defects and/or death of the fetus. Ribavirin also causes hemolytic anemia. [#] [#]

The most common reasons for dose modification or withdrawal from studies were hematologic abnormalities (e.g., anemia, neutropenia). Incidences of adverse hematologic effects appear to be greater in patients receiving concomitant therapy with peginterferon alfa and oral ribavirin than in those receiving peginterferon alfa monotherapy. [#] ]]>
[#] [#] Coadministration of peginterferon alfa with theophylline, which is metabolized by CYP450 enzymes, resulted in a 25% increase of theophylline serum concentrations. Routine monitoring of plasma theophylline concentrations and appropriate dosage adjustments are recommended. Coadministration of ribavirin (as a common adjunct to peginterferon alfa) and didanosine is not recommended. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, have been reported in clinical trials. Ribavirin also antagonizes the in vitro antiviral activity of stavudine and zidovudine, so concomitant use of treatments containing ribavirin with either of these drugs should be avoided. [#] ]]>[#] [#] [#]

Risk-benefit should be considered in patients with autoimmune diseases (e.g., interstitial nephritis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, thrombocytopenia, thyroiditis); cardiovascular diseases; diabetes mellitus, hyperglycemia, hyperthyroidism, or hypothyroidism; psychiatric disorders; pulmonary function impairment or pulmonary infiltrates; or renal function impairment. [#]

Additionally, peginterferon alfa-2a formulations contain benzyl alcohol and are therefore contraindicated in neonates and infants. Benzyl alcohol is associated with an increased incidence of sometimes fatal neurologic and other complications in neonates and infants. [#] [#] ]]>
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Peginterferon alfa-2b: White to off-white lyophilized powder. [#] Reconstituted solutions of peginterferon alfa-2b are clear, colorless, and contain no preservative. [#] ]]>
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After reconstitution of the powder with the supplied diluent, peginterferon alfa-2b solution should be used immediately, but may be stored up to 24 hours between 2 C and 8 C (36 F to 46 F). The reconstituted solution contains no preservative. [#] ]]>
Pegasys Prescribing Information from the FDA Web site [HTML]. A more current version may be available on the manufacturer's Web site.
PEG-Intron Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, Morand P, Goujard C, Pialoux G, Piroth L, Salmon-Ceron D, Degott C, Cacoub P, Perronne C; ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004 Dec 15;292(23):2839-48.
Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, Peters MG, Koziel MJ, Bhan AK, Alston B, Colquhoun D, Nevin T, Harb G, van der Horst C; AIDS Clinical Trials Group A5071 Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451-9.
Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, Caumes E, Pialoux G, Benhamou Y, Thibault V, Katlama C. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. AIDS. 2006 May 12;20(8):1157-61.
Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez-Tapias JM, Bargallo X, Garcia-Criado A, de Lazzari E, Larrousse M, Leon A, Lonca M, Milinkovic A, Gatell JM, Mallolas J. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004 Sep 3;18(13):F27-36.
Matthews G. The management of HIV and hepatitis B coinfection. Curr Opin Infect Dis. 2007 Feb;20(1):16-21.
Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin Liver Dis. 2004;24 Suppl 2:61-8. Review.
Vogel M, Nattermann J, Baumgarten A, Klausen G, Bieniek B, Schewe K, Jessen H, Boeseckeg C, Rausch M, Lutz T, Fenske S, Schranzo D, Kummerle T, Schuler C, Theisen A, Mayr C, Seidel T, Rockstroh JK. Pegylated interferon-alpha for the