NORVIR (ritonavir capsules) Soft Gelatin

WARNING

CO-ADMINISTRATION 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. SEE CONTRAINDICATIONS AND PRECAUTIONS SECTIONS.

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

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is CHNOS, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Ritonavir is a white-to-light-tan powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

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.

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.

Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

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

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions. 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 vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established.

Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 2 patients had a decrease in susceptibility to nelfinavir (12- 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 isolate tested in vitro retained full susceptibility to ritonavir.

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD ≥ 50 cells/µL). See Table 1 for ritonavir pharmacokinetic characteristics.

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.

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. After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) and oral solution (n = 18) formulations yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 121.7 ± 53.8 and 129.0 ± 39.3 µg•h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).

Nearly all of the plasma radioactivity after a single oral 600 mg dose of C-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.

In a study of five subjects receiving a 600 mg dose of C-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.

QTcF interval was eva luated 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 (See PRECAUTIONS – PR Interval Prolongation).

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.

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

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

Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic insufficiency (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.

See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS - Drug Interactions.

Table 2 and Table 3 summarize the effects on AUC and C, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see PRECAUTIONS - Drug Interactions.

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.

The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been eva luated in 1446 patients enrolled in two double-blind, randomized trials.

Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD cell counts ≤ 100 cells/µL. NORVIR 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1090 patients, with mean baseline CD cell count at study entry of 32 cells/µL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to NORVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 1).

The cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% for patients initially randomized to NORVIR compared to 26% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 2). Since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

Figure 3 and Figure 4 summarize the mean change from baseline for CD cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 247.

In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD = 364 cells/µL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs. Figure 5 and Figure 6 summarize the mean change from baseline for CD cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 245.

ALERT: Find out about medicines that should NOT be taken with NORVIR. This statement is included on the product's bottle label.

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including WARNINGS.

See CONTRAINDICATIONS- Table 4 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see PRECAUTIONS – Table 5 and Table 6 for drugs that should not be co-administered with NORVIR and for a listing of drugs with established and other significant drug interactions.

Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome have also been reported.

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 (see Table 8). 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 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 eva luated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

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.

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including PRECAUTIONS.

Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function (see WARNINGS and CLINICAL PHARMACOLOGY - Hepatic Insufficiency).

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see Microbiology).

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 has not been established.

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 eva luated. 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. See CLINICAL PHARMACOLOGY - Effects on Electrocardiogram.

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.

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. 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. See PRECAUTIONS - Table 5 and Table 6 for additional information on potential drug interactions with NORVIR and HMG CoA reductase inhibitors.

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 eva luation and treatment.

A statement to patients and health care providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with NORVIR. A Patient Package Insert (PPI) for Norvir is available for patient information.

Patients should be informed that NORVIR is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.

Patients should be told that the long-term effects of NORVIR are unknown at this time. They should be informed that NORVIR therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.

Patients should be advised to take NORVIR with food, if possible.

Patients should be informed to take NORVIR every day as prescribed. Patients should not alter the dose or discontinue NORVIR without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.

Patients receiving PDE5 inhibitors for erectile dysfunction (eg, sildenafil, tadalafil, or vardenafil) should be advised that they may be at an increased risk of associated adverse events including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. Concomitant use of sildenafil with NORVIR is contraindicated in patients with pulmonary arterial hypertension (PAH).

Patients receiving estrogen-based hormonal contraceptives should be instructed that additional or alternate contraceptive measures should be used during therapy with NORVIR.

Patients should be informed that NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm, or loss of consciousness.

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.

Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo (Table 3). 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. 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 as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in CONTRAINDICATIONS - Table 4 and under Drugs That Should Not Be Co-administered with NORVIR in Table 5.

Those drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY - Table 2 and Table 3. The clinical recommendations based on the results of these studies are listed in Table 6. Established and Other Potentially Significant Drug Interactions. A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir. There are a number of agents in which CYP3A or CYP2D6 partially contribute to the metabolism of the agent. In these cases, the magnitude of the interaction and therapeutic consequences cannot be predicted with any certainty.

When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors, some steroids, or other substrates of CYP3A; or most antidepressants, certain antiarrhythmics, and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction (> 50%); examples are listed in Table 6. Established and Other Potentially Significant Drug Interactions.

When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations (see Table 6. Established and Other Potentially Significant Drug Interactions).