Drugs

Ritonavir

Brand Name: Norvir Other Names: RTV Drug Class: Protease Inhibitors

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Chemical Image:

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ritonavir

ritonavir

Molecular Weight: 720.9552

Drug Description


NORVIR (ritonavir) is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

NORVIR tablets are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80.

NORVIR oral solution is available for oral administration as 80 mg/mL of ritonavir in a peppermint and caramel flavored vehicle. Each 8-ounce bottle contains 19.2 grams of ritonavir. NORVIR oral solution also contains ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6.

NORVIR soft gelatin capsules are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.


HIV/AIDS-Related Uses


NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on the results from a study in patients with advanced HIV disease that showed a reduction in both mortality and AIDS-defining clinical events for patients who received NORVIR either alone or in combination with nucleoside analogues. Median duration of follow-up in this study was 13.5 months.


Dosing Information


Mode of Delivery

Oral.

Dosage Form

  • Soft gelatin capsules containing ritonavir 100 mg.
     
  • Tablets containing ritonavir 100 mg.
     
  • Oral solution containing ritonavir 600 mg ritonavir per 7.5 mL (80 mg/mL).

DOSAGE AND ADMINISTRATION

NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure®, or Advera® within one hour of dosing.

General Dosing Guidelines
Patients who take the 600 mg twice daily soft gel capsule NORVIR dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (Cmax) achieved with the tablet formulation relative to the soft gel capsule. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

Patients initiating combination regimens with NORVIR and reverse transcriptase inhibitors may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding reverse transcriptase inhibitors before completing two weeks of NORVIR monotherapy.

Dose Modification for NORVIR
Dose reduction of NORVIR is necessary when used with other protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.
Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir.

Adult Patients
Recommended Dosage for Treatment of HIV-1.

The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

Pediatric Patients
Ritonavir should be used in combination with other antiretroviral agents. The recommended dosage of ritonavir in children > 1 month is 350 to 400 mg/m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and increased at 2 to 3 day intervals by 50 mg/m2 twice daily. If patients do not tolerate 400 mg/m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. When possible, dose should be administered using a calibrated dosing syringe.

Pediatric Dosage Guidelines

Body Surface Area (m2): 0.20
• Twice Daily Dose 250 mg/m2: 0.6 mL (50 mg)
• Twice Daily Dose 300 mg/m2: 0.75 mL (60 mg)
• Twice Daily Dose 350 mg/m2: 0.9 mL (70 mg)
• Twice Daily Dose 400 mg/m2: 1.0 mL (80 mg)

Body Surface Area (m2): 0.25
• Twice Daily Dose 250 mg/m2: 0.8 mL (62.5 mg)
• Twice Daily Dose 300 mg/m2: 0.9 mL (75 mg)
• Twice Daily Dose 350 mg/m2: 1.1 mL (87.5 mg)
• Twice Daily Dose 400 mg/m2: 1.25 mL (100 mg)

Body Surface Area (m2): 0.50
• Twice Daily Dose 250 mg/m2: 1.6 mL (125 mg)
• Twice Daily Dose 300 mg/m2: 1.9 mL (150 mg)
• Twice Daily Dose 350 mg/m2: 2.2 mL (175 mg)
• Twice Daily Dose 400 mg/m2: 2.5 mL (200 mg)

Body Surface Area (m2): 0.75
• Twice Daily Dose 250 mg/m2: 2.3 mL (187.5 mg)
• Twice Daily Dose 300 mg/m2: 2.8 mL (225 mg)
• Twice Daily Dose 350 mg/m2: 3.3 mL (262.5 mg)
• Twice Daily Dose 400 mg/m2: 3.75 mL (300 mg)

Body Surface Area (m2): 1.00
• Twice Daily Dose 250 mg/m2: 3.1 mL (250 mg)
• Twice Daily Dose 300 mg/m2: 3.75 mL (300 mg)
• Twice Daily Dose 350 mg/m2: 4.4 mL (350 mg)
• Twice Daily Dose 400 mg/m2: 5 mL (400 mg)

Body Surface Area (m2): 1.25
• Twice Daily Dose 250 mg/m2: 3.9 mL (312.5 mg)
• Twice Daily Dose 300 mg/m2: 4.7 mL (375 mg)
• Twice Daily Dose 350 mg/m2: 5.5 mL (437.5 mg)
• Twice Daily Dose 400 mg/m2: 6.25 mL (500 mg)

Body Surface Area (m2): 1.50
• Twice Daily Dose 250 mg/m2: 4.7 mL (375 mg)
• Twice Daily Dose 300 mg/m2: 5.6 mL (450 mg)
• Twice Daily Dose 350 mg/m2: 6.6 mL (525 mg)
• Twice Daily Dose 400 mg/m2: 7.5 mL (600 mg)

Body surface area (BSA) can be calculated as follows:
BSA (m2) = sq rt [Ht(cm)xWt(kg)/3600]

Storage

Store soft gelatin capsules in the refrigerator between 2°-8°C (36°-46°F) until dispensed. Refrigeration of NORVIR soft gelatin capsules by the patient is recommended, but not required if used within 30 days and stored below 25°C (77°F). Protect from light. Avoid exposure to excessive heat.
 
Store NORVIR film-coated tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP controlled room temperature]. Dispense in original container or USP equivalent tight container (60 mL or less). For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended.

Store NORVIR oral solution at room temperature 20°-25°C (68°-77°F). Do not refrigerate. Shake well before each use. Use by product expiration date. Product should be stored and dispensed in the original container. Avoid exposure to excessive heat. Keep cap tightly closed.


Pharmacology


Mechanism of Action
Ritonavir is an antiviral drug

Pharmacokinetics
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 ≥50 cells/μL). See below for ritonavir pharmacokinetic characteristics.

Absorption
The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.

NORVIR tablets are not bioequivalent to NORVIR capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg NORVIR dose was administered as a tablet compared with a capsule, AUC(0- ∞) met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: ↑15 -↑39%).

No information is available comparing NORVIR tablets to NORVIR capsules under fasting conditions.

Effect of Food on Oral Absorption
When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera® or Ensure® did not significantly affect the extent and rate of ritonavir absorption. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mg•h/mL.

A food effect is observed for NORVIR tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of NORVIR was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC(0-∞) [90% confidence intervals: ↓30%-↓15%], and a 23% decrease in mean Cmax [90% confidence intervals: ↓34%-↓11%]) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) [90% confidence intervals: ↓28%-↓13%], and a 22% decrease in mean Cmax [90% confidence intervals: ↓33%-↓9%]) was observed relative to fasting conditions.

However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals.

Metabolism
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.

Elimination
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Ritonavir Pharmacokinetic Characteristics

Parameter (N): Values (Mean ± SD)
• Cmax SS (10): 11.2 ± 3.6 μg/mL
• Ctrough SS (10): 3.7 ± 2.6 μg/mL
• Vβ/F (91): 0.41 ± 0.25 L/kg
• t½: 3 - 5 h
• CL/F SS (10): 8.8 ± 3.2 L/h
• CL/F (91): 4.6 ± 1.6 L/h
• CLR (62): < 0.1 L/h
• RBC/Plasma Ratio: 0.14
• Percent Bound*: 98 to 99%

† SS = steady state; patients taking ritonavir 600 mg q12h.
‡ Single ritonavir 600 mg dose.
* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 μg/mL.

Effects on Electrocardiogram
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir.

Special Populations

Gender, Race and Age
No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.

Pediatric Patients
Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg/m2 twice-daily to 400 mg/m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg/m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m2 twice-daily in pediatric patients > 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg/m2 twice-daily in children < 2 years of age. Higher ritonavir exposures were not evident with 450 mg/m2 twice-daily compared to the 350 mg/m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg/m2 twice-daily in children < 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.

Renal Impairment
Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic Impairment
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
(For additional information, consult the Norvir complete prescribing information).

Microbiology

Mechanism of Action
Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of noninfectious immature HIV particles.

Antiviral Activity in Cell Culture
The activity of ritonavir was assessed in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 value for low passage clinical isolates was 22 nM (n = 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either didanosine (ddI) or zidovudine (ZDV). Studies which measured cytotoxicity of ritonavir on several cell lines showed that > 20 μM was required to inhibit cellular growth by 50% resulting in a cell culture therapeutic index of at least 1000.

Resistance
HIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene leading to amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n = 18) and genotypic (n = 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Substitutions associated with the HIV–1 viral protease in isolates obtained from 43 patients appeared to occur in a stepwise and ordered fashion at positions V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional 5 specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in cell culture from baseline.

Cross-Resistance to Other Antiretrovirals
Among protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in cell culture but did not demonstrate a concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 3 patients had a decrease in susceptibility to nelfinavir (6- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV-1 isolate tested in cell culture retained full susceptibility to ritonavir.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category B

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

No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.

Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to NORVIR, 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-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV
. It is not known whether ritonavir is secreted 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 breast-feed if they are receiving NORVIR.
(For additional information, consult the Norvir complete prescribing information).


Adverse Events/Toxicity


Hepatic Reactions
Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs. There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

Pancreatitis
Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

Allergic Reactions/Hypersensitivity
Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.

PR Interval Prolongation
Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.

Lipid Disorders
Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors

Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. 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 jiroveci pneumonia, 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.

Patients with Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-resistance
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Laboratory Tests
Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with reverse transcriptase inhibitors, physicians should refer to the complete product information for each of these drugs.

The most common treatment-emergent adverse reactions (> 5% and of moderate to severe intensity) occurring in adult patients were abdominal pain, asthenia, headache, malaise, anorexia, diarrhea, dyspepsia, nausea, vomiting, paresthesia, circumoral paresthesia, peripheral paresthesia, dizziness, and taste perversion. Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in ≥ 2% of pediatric patients enrolled in NORVIR clinical trials.


Drug and Food Interactions


When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera® or Ensure® did not significantly affect the extent and rate of ritonavir absorption. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mg•h/mL.

A food effect is observed for NORVIR tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of NORVIR was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC(0-∞) [90% confidence intervals: ↓30%-↓15%], and a 23% decrease in mean Cmax [90% confidence intervals: ↓34%-↓11%]) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) [90% confidence intervals: ↓28%-↓13%], and a 22% decrease in mean Cmax [90% confidence intervals: ↓33%-↓9%]) was observed relative to fasting conditions.

However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals.

WARNING: Coadministration of NORVIR with sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs.

Coadministration of NORVIR is contraindicated with the drugs listed below because ritonavir mediated CYP3A inhibition can result in serious and/or life-threatening reactions. Voriconazole and St. John’s Wort are exceptions in that coadministration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations.

Drugs that are Contraindicated with NORVIR

  • Alpha1adrenoreceptor antagonist: Alfuzosin HCL – Potential for hypotension.
  • Antiarrhythmics: Amiodarone, bepridil, flecainide, propafenone, quinidine – Potential for cardiac arrhythmias.
  • Antifungal: Voriconazole – Coadministration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response. Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater.
  • Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine – Potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
  • GI Motility Agent: Cisapride – Potential for cardiac arrhythmias.
  • Herbal Products: St. John's Wort (hypericum perforatum) – May lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
  • HMG-CoA Reductase Inhibitors: Lovastatin, simvastatin – Potential for myopathy including rhabdomyolysis.
  • PDE5 enzyme inhibitor: Sildenafil (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH) – A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
  • Sedative/hypnotics: Oral midazolam, triazolam – Prolonged or increased sedation or respiratory depression.

Drug Interactions
When coadministering NORVIR with other protease inhibitors (amprenavir, atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

Norvir is a CYP3A4 inhibitor.  Initiating treatment with Norvir in patients receiving medications metabolized by CYP3A4 or initiating medications metabolized by CYP3A4 in patients already maintained on Norvir may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with Norvir. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with Norvir.

Potential for NORVIR to Affect Other Drugs
Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co- administered with ritonavir. Thus, coadministration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown below.

Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

Established and Other Potentially Significant Drug Interactions
Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction

HIV-Antiviral Agents
• Atazanavir: Atazanavir plasma concentrations achieved with atazanavir 300 mg q.d. and ritonavir 100 mg q.d. are higher than those achieved with atazanavir 400 mg q.d. See the complete prescribing information for Reyataz® (atazanavir) for details on coadministration of atazanavir 300 mg q.d. with ritonavir 100 mg q.d.

• Darunavir: See the complete prescribing information for Prezista® (darunavir) for details on coadministration of darunavir 600 mg b.i.d. with ritonavir 100 mg b.i.d. or darunavir 800 mg q.d. with ritonavir 100 mg q.d.

• Fosamprenavir: See the complete prescribing information for Lexiva® (fosamprenavir) for details on coadministration of fosamprenavir 700 mg b.i.d. with ritonavir 100 mg b.i.d., fosamprenavir 1400 mg q.d. with ritonavir 200 mg q.d. or fosamprenavir 1400 mg q.d. with ritonavir 100 mg q.d.

• Indinavir: Alterations in concentrations are noted when reduced doses of indinavir are coadministered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established.

• Saquinavir: See the complete prescribing information for Invirase® (saquinavir) for details on coadministration of saquinavir 1000 mg b.i.d with ritonavir 100 mg b.i.d. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

• Tipranavir: See the complete prescribing information for Aptivus® (tipranavir) for details on coadministration of tipranavir 500 mg b.i.d. with ritonavir 200 mg b.i.d. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.

• Delavirdine: Appropriate doses of this combination with respect to safety and efficacy have not been established.

• Maraviroc: Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).

Other Agents
• Analgesics, Narcotic: tramadol, propoxyphene – A dose decrease may be needed for these drugs when coadministered with ritonavir.

• Anesthetic: meperidine – Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
 
• Antialcoholics: disulfiram/ metronidazole – Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when coadministered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

• Antiarrhythmics: disopyramide, lidocaine, mexiletine – Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with ritonavir, if available.

• Anticancer Agents: vincristine, vinblastine – Concentrations of vincristine or vinblastine may be increased when coadministered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. Consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.

• Anticancer Agents: dasatinib, nilotinib – A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring coadministration with strong CYP3A inhibitors such as Norvir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

• Anticoagulant: warfarin – Initial frequent monitoring of the INR during ritonavir and warfarin coadministration is indicated.

• Anticonvulsants: carbamazepine, clonazepam, ethosuximide – Use with caution. A dose decrease may be needed for these drugs when coadministered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

• Anticonvulsants: divalproex, lamotrigine, phenytoin – Use with caution. A dose increase may be needed for these drugs when coadministered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

• Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs), tricyclics – A dose decrease may be needed for these drugs when coadministered with ritonavir.

• Antidepressant: bupropion – Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

• Antidepressant: desipramine – Dosage reduction and concentration monitoring of desipramine is recommended.

• Antidepressant: trazodone – Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

• Antiemetic: dronabinol – A dose decrease of dronabinol may be needed when coadministered with ritonavir.
 
• Antifungal: ketoconazole itraconazole voriconazole – High doses of ketoconazole or itraconazole (> 200 mg/day) are not recommended. Coadministration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Coadministration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

• Anti-gout: colchicines – Patients with renal or hepatic impairment should not be given colchicine with ritonavir.

Treatment of gout flares-coadministration of colchicine in patients on ritonavir:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-coadministration of colchicine in patients on ritonavir:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-coadministration of colchicine in patients on ritonavir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

• Anti-infective: clarithromycin – For patients with renal impairment the following dosage adjustments should be considered:

  • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
  • No dose adjustment for patients with normal renal function is necessary.

• Antimycobacterial: rifabutin – Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.

• Antimycobacterial: rifampin – Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).

• Antiparasitic: atovaquone – Clinical significance is unknown; however, increase in atovaquone dose may be needed.

• Antiparasitic: quinine – A dose decrease of quinine may be needed when co-administered with ritonavir.

• β-Blockers: metoprolol, timolol – Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when coadministered with ritonavir.
 
• Bronchodilator: theophylline – Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
 
• Calcium channel blockers: diltiazem, nifedipine, verapamil – Caution is warranted and clinical monitoring of patients is recommended.A dose decrease may be needed for these drugs when coadministered with ritonavir.
 
• Digoxin – Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when coadministering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
 
• Endothelin receptor antagonists: bosentan

Coadministration of bosentan in patients on ritonavir:
In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Coadministration of ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.
After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

• HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin – Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.

• Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) – Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with ritonavir.
 
• Inhaled Steroid: fluticasone – Concomitant use of fluticasone propionate and NORVIR increases plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
 
• Long-acting betaadrenoceptor agonist: salmeterol – Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

• Narcotic Analgesic: methadone – Dosage increase of methadone may be considered.

• Narcotic Analgesic: fentanyl – Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with Norvir.

• Neuroleptics: perphenazine, risperidone, thioridazine – A dose decrease may be needed for these drugs when coadministered with ritonavir.

• Oral Contraceptives or Patch Contraceptives: ethinyl estradiol – A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 500 mg q. 12h. and a fixed-combination oral contraceptive resulted in reductions of the ethinyl estradiol mean Cmax and mean AUC by 32% and 40%, respectively. Alternate methods of contraception should be considered.

• PDE5 Inhibitors: sildenafil, tadalafil, vardenafil – Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see Contraindications].

The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir:

Coadministration of ADCIRCA in patients on ritonavir:
In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Coadministration of ritonavir in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:

  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours.

Use with increased monitoring for adverse events.

• Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem – A dose decrease may be needed for these drugs when co-administered with ritonavir.

• Sedative/hypnotics: Parenteral midazolam – Coadministration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

• Steroids: dexamethasone, fluticasone, prednisone – A dose decrease may be needed for these drugs when coadministered with ritonavir.

• Stimulant: methamphetamine – Use with caution. A dose decrease of methamphetamine may be needed when coadministered with ritonavir.


Contraindications


When coadministering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.

NORVIR is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis [TEN], Stevens-Johnson syndrome) to ritonavir or any of its ingredients.

Coadministration of NORVIR is contraindicated with the drugs listed below because ritonavir mediated CYP3A inhibition can result in serious and/or life-threatening reactions. Voriconazole and St. John’s Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations.

Drugs that are Contraindicated with NORVIR

  • Alpha1adrenoreceptor antagonist: Alfuzosin HCL – Potential for hypotension.
  • Antiarrhythmics: Amiodarone, bepridil, flecainide, propafenone, quinidine – Potential for cardiac arrhythmias.
  • Antifungal: Voriconazole – Coadministration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response. Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater.
  • Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine – Potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
  • GI Motility Agent: Cisapride – Potential for cardiac arrhythmias.
  • Herbal Products: St. John's Wort (hypericum perforatum) – May lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
  • HMG-CoA Reductase Inhibitors: Lovastatin, simvastatin – Potential for myopathy including rhabdomyolysis.
  • PDE5 enzyme inhibitor: Sildenafil (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH) – A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
  • Sedative/hypnotics: Oral midazolam, triazolam – Prolonged or increased sedation or respiratory depression.[1] [2] [3] [4] [5]
     


References

[1] FDA Norvir Prescribing Information (Capsule and Solution), April 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020945s028lbl.pdf. Accessed on: 09/13/2011.

[2] FDA Norvir Prescribing Information (Tablet and Solution), April 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020659s050,022417s001lbl.pdf. Accessed on: 09/13/2011.

[3] FDA – HIV and AIDS Activities. Safety revisions to Norvir (ritonavir) tablets, capsules and oral solution labeling, December 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm282943.htm. Accessed on 12/08/2011.

[4] FDA Norvir Prescribing Information (Tablet and Solution), February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020659s056,022417s007lbl.pdf. Accessed on: 03/04/2012.

[5] FDA Norvir Prescribing Information (Capsule and Solution), February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020945s034lbl.pdf. Accessed on: 03/04/2012.

Clinical Trials


Click here to search ClinicalTrials.gov for trials that use Ritonavir.


Chemistry


CAS Name


2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1-(2-(1- methylethyl)-4-thiazolyl)-3,6-dioxo-8,11- bis(phenylmethyl)-,5-thiazolylmethyl ester, (5S- (5R*,8R*,10R*,11R*))- [1]

CAS Number


155213-67-5 [2]

Molecular Weight

720.95 [3]

Physical Description

Ritonavir is a white to light tan powder with bitter metallic taste. [4]

Solubility

Freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. [5]


References

[1] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed on: 09/13/2011.

[2] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed on: 09/13/2011.

[3] FDA Norvir Prescribing Information (Tablet and Solution), April 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020659s050,022417s001lbl.pdf. Accessed on: 09/13/2011.

[4] FDA Norvir Prescribing Information (Tablet and Solution), April 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020659s050,022417s001lbl.pdf. Accessed on: 09/13/2011.

[5] FDA Norvir Prescribing Information (Tablet and Solution), April 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020659s050,022417s001lbl.pdf. Accessed on: 09/13/2011.

Further Reading


Norvir Prescribing Information from the FDA Web site [PDF] . A more current version may be available on the manufacturer's Web site.
Kashuba AD. Drug-drug interactions and the pharmacotherapy of HIV infection. Top HIV Med. 2005 Jun-Jul;13(2):64-9. Review.
Marcelin AG, Flandre P, Peytavin G, Calvez V. Predictors of virologic response to ritonavir-boosted protease inhibitors. AIDS Rev. 2005 Oct-Dec;7(4):225-32.
Molina JM, Cohen C, Katlama C, Grinsztejn B, Timerman A, Pedro RD, Vangeneugden T, Miralles D, De Meyer S, Parys W, Lefebvre E; on Behalf of the TMC 114-C208 and -C215 Study Groups. Safety and Efficacy of Darunavir (TMC114) With Low-Dose Ritonavir in Treatment-Experienced Patients: 24-Week Results of POWER 3. J Acquir Immune Defic Syndr. 2007 Sep 1; 46(1): 24-31.