Drug Description
ATRIPLA is a fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF). 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.
ATRIPLA tablets are for oral administration. Each 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. The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.
HIV/AIDS-Related Uses
ATRIPLA is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
Dosing Information
Mode of Delivery
Oral.
Dosage Form
ATRIPLA is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil).
DOSAGE AND ADMINISTRATION
Adults: The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.
Pediatrics: ATRIPLA is not recommended for use in patients less than 18 years of age.
Renal Impairment: Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL/min).
Storage
Store ATRIPLA tablets at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [See USP Controlled Room Temperature].
• Keep container tightly closed.
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing
Pharmacology
For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA and VIREAD prescribing information.
Mechanism of Action
ATRIPLA is a fixed-dose combination of antiviral drugs efavirenz, emtricitabine and tenofovir disoproxil fumarate.
Pharmacokinetics
ATRIPLA: One ATRIPLA tablet is bioequivalent to one SUSTIVA tablet (600 mg) plus one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).
Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14– 34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A 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 52–76 hours after single doses and 40–55 hours after multiple doses.
Emtricitabine: Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 μg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg/mL. The mean absolute bioavailability of emtricitabine was 93%. 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 with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate: Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted subjects is approximately 25%. 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 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 of tenofovir is approximately 17 hours.
Effects of Food on Oral Absorption
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.
Special Populations
Race
Efavirenz: The pharmacokinetics of efavirenz in HIV-1 infected subjects appear to be similar among the racial groups studied.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.
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 tenofovir DF.
Gender
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Efavirenz, emtricitabine, and tenofovir pharmacokinetics are similar in male and female subjects.
Pediatric and Geriatric Patients
Pharmacokinetic trials of tenofovir DF have not been performed in pediatric subjects (less than 18 years). Efavirenz has not been studied in pediatric subjects below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. ATRIPLA is not recommended for pediatric administration. Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (over 65 years).
Patients with Impaired Renal Function
Efavirenz: The pharmacokinetics of efavirenz have 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.
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/min, Cmax and AUC0-∞ of emtricitabine and tenofovir were increased.
Patients with Hepatic Impairment
Efavirenz: A multiple-dose trial showed no significant effect on efavirenz pharmacokinetics in subjects 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.
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.
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF 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.
Assessment of Drug Interactions
The drug interaction trials described were conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents; no drug interaction trials have been conducted using ATRIPLA.
Efavirenz: The steady-state pharmacokinetics of efavirenz and tenofovir were unaffected when efavirenz and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with efavirenz and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways.
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 (8.5−17 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 82–160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 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.
Drug interaction trials were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between efavirenz and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine.
Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on efavirenz exposures. The effects of coadministration of efavirenz on Cmax, AUC, and Cmin are summarized in Table 5 (effect of other drugs on efavirenz) and Table 6 (effect of efavirenz on other drugs). For information regarding clinical recommendations see Drug Interactions. [Consult the Atripla complete prescribing information to view Table 5 and Table 6].
Emtricitabine and Tenofovir Disoproxil Fumarate: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
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 emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir or tacrolimus in trials conducted in healthy volunteers.
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.
The effects of coadministered drugs on the Cmax, AUC, and Cmin of tenofovir are shown in Table 7. The effects of coadministration of tenofovir DF on Cmax, AUC, and Cmin of coadministered drugs are shown in Table 8 and Table 9. [Consult the Atripla full prescribing information to view Tables 7, 8, and 9].
Microbiology
Mechanism of Action
Efavirenz: Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
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.
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.
Antiviral Activity
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.
Efavirenz: The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC90-95) ranged from 1.7−25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2.
Emtricitabine: The antiviral activity in cell culture 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 NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and 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 in cell culture 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 NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and 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
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical trials. 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 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 trial of treatment-naive 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 HIV1 RT gene resulting in the K65R amino acid substitution.
Efavirenz: Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most frequently observed amino acid substitution in clinical trials with efavirenz is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in subjects failing treatment with efavirenz in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).
HIV-1 isolates with reduced susceptibility to efavirenz (greater than 380-fold increase in EC90 value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT.
Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical trials. 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.
Cross Resistance
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: 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.
Efavirenz: Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-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 efavirenz in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to efavirenz.
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, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.
Tenofovir Disoproxil Fumarate: The K65R substitution selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with the K65R substitution also showed 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 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 D [See Warnings and Precautions].
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 both efavirenz and tenofovir are secreted in milk. It is not known whether efavirenz, emtricitabine, or 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 ATRIPLA.
Pediatric Use
ATRIPLA is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, tenofovir DF, for which safety and efficacy have not been established in this age group.
Geriatric Use
Clinical trials of efavirenz, emtricitabine, or tenofovir DF 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 the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hepatic Impairment
ATRIPLA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data. Patients with mild hepatic impairment may be treated with ATRIPLA at the approved dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering ATRIPLA to these patients.
Renal Impairment
Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL/min).
Adverse Events/Toxicity
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA, in combination with other antiretrovirals.
- ATRIPLA is not approved for the treatment of chronic hepatitis B virus (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 have discontinued EMTRIVA or VIREAD, which are components of ATRIPLA. 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 ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted
WARNINGS AND PRECAUTIONS
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 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).
Patients Coinfected with HIV-1 and HBV
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.
ATRIPLA should not be administered with HEPSERA® (adefovir dipivoxil).
Drug Interactions
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A [See Contraindications, Drug Interactions].
Coadministration with Related Products
Related drugs not for coadministration with ATRIPLA include COMPLERA (emtricitabine/rilpivirine/tenofovir DF), EMTRIVA (emtricitabine), SUSTIVA (efavirenz), TRUVADA (emtricitabine/tenofovir DF), and VIREAD (tenofovir DF), 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).
Psychiatric Symptoms
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 trial 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 trial 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.
Nervous System Symptoms
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 2–4 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.
New Onset or Worsening Renal Impairment
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 below 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.
Reproductive Risk Potential
Pregnancy Category D: Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving ATRIPLA. Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives). 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.
There are no adequate and well-controlled trials of ATRIPLA in pregnant women. 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.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.
Efavirenz: 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.
Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20– 150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz. Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations. An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of efavirenz. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.
Rash
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 trials and expanded access was 0.1%. Rashes are usually mild-tomoderate 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.
Hepatotoxicity
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.
Decreases in Bone Mineral Density
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 trial of treatment-naive subjects receiving tenofovir DF, 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 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 24–48 weeks of the trial 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
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
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.
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.
Clinical Trials Experience
The most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir DF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
Drug and Food Interactions
See Contraindications for a listing of drugs that are contraindicated with ATRIPLA.
Coadministration with Related Products
Related drugs not for coadministration with ATRIPLA include COMPLERA (emtricitabine/rilpivirine/tenofovir DF), EMTRIVA (emtricitabine), SUSTIVA (efavirenz), TRUVADA (emtricitabine/tenofovir DF), and VIREAD (tenofovir DF), 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).
Efavirenz
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 (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Emtricitabine and Tenofovir Disoproxil Fumarate
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.
Coadministration of tenofovir DF 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 [for didanosine dosing adjustment recommendations, see below]. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir with ATRIPLA should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions [See below].
Coadministration of atazanavir with ATRIPLA is not recommended since coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. 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 [See below].
Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate
Other important drug interaction information for ATRIPLA is summarized below and in the Contraindications section. The drug interactions described are based on trials conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction trials have been conducted using ATRIPLA. The tables include potentially significant interactions, but are not all inclusive.
Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Antiretroviral agents
• Protease inhibitor: 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.
• Protease inhibitor: 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.
• Protease inhibitor: 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.
• Protease inhibitor: 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). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
• Protease inhibitor: 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.
• Protease inhibitor: saquinavir. Should not be used as sole protease inhibitor in combination with ATRIPLA.
• CCR5 co-receptor antagonist: maraviroc. Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
• NRTI: 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. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
• Anticoagulant: warfarin. Plasma concentrations and effects potentially increased or decreased by efavirenz.
• Anticonvulsants:
- 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.
• Antidepressant: sertraline. Increases in sertraline dose should be guided by clinical response.
• Antifungals:
- Itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered
- Ketoconazole. Drug interaction trials 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.
• Anti-infective: 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.
• Antimycobacterial: 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.
• Antimycobacterial: rifampin. Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
• Calcium channel blockers:
- 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.
- Others (e.g., felodipine, nicardipine, 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.
• Hormonal contraceptives:
- Oral: Ethinyl estradiol/Norgestimate. 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.
- Implant: Etonogestrel. 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.
• Narcotic analgesic: 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.
Efavirenz Assay Interference
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.
Contraindications
Hypersensitivity
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.
Contraindicated Drugs
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 with ATRIPLA are listed below.
Drugs That Are Contraindicated or Not Recommended for Use With ATRIPLA
• Antifungal: 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.
• 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 (NNRTIs). [1]
References
[1] FDA Atripla Prescribing Information, September 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021937s023lbl.pdf. Accessed 10/17/2011.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Efavirenz / Emtricitabina / Tenofovir DF.
Chemistry
CAS Name
Efavirenz: 2H-3,1-Benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4- dihydro-4-(trifluoromethyl)-, (4S)- [1] Emtricitabine: (2R-cis)-4-Amino-5-fluoro- 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] -2(1H)-pyrimidinone [2]Tenofovir DF: Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1) [3]
CAS Number
Efavirenz: 154598-52-4 [4]Emtricitabine: 143491-57-0 [5]Tenofovir DF: 147127-20-6 [6]
Molecular Formula
Efavirenz: C14-H9-Cl-F3-N-O2; Emtricitabine: C8-H10-F-N3-O3-S; Tenofovir DF: C19-H30-N5-O10-P.C4-H4-O4 [7]
Molecular Weight
Efavirenz: 315.68; Emtricitabine: 247.24; Tenofovir DF: 635.52 [8]
Physical Description
Efavirenz: White to slightly pink crystalline powder; Emtricitabine: White to off-white crystalline powder; Tenofovir DF: White to off-white crystalline powder. [9]
Solubility
Efavirenz: Practically insoluble in water (less than 10 μg/mL); Emtricitabine: Soluble in 25°C at 112 mg/mL; Tenofovir DF: Soluble in 25°C water at 13.4 mg/mL. [10]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[3] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[4] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[5] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[6] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/17/2011.
[7] FDA Atripla Prescribing Information, September 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021937s023lbl.pdf. Accessed 10/17/2011.
[8] FDA Atripla Prescribing Information, September 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021937s023lbl.pdf. Accessed 10/17/2011.
[9] FDA Atripla Prescribing Information, September 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021937s023lbl.pdf. Accessed 10/17/2011.
[10] FDA Atripla Prescribing Information, September 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021937s023lbl.pdf. Accessed 10/17/2011.
Further Reading
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.
Manufacturer Information
Atripla
Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335
Efavirenz / Emtricitabine / Tenofovir disoproxil fumarate
Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335
All Content Last Reviewed: October 17, 2011
Last Updated: October 17, 2011