Norvir Ritonavir 100 mg Powder, 30 packets — NDC 0074-3399-30 (Billing 00074-3399-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Ritonavir is an antiretroviral drug [see Microbiology ( 12.4 ) ] .

12.2Pharmacodynamics Cardiac Electrophysiology 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 [see Warnings and Precautions ( 5.6 )] .

12.3Pharmacokinetics The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD 4 greater than or equal to 50 cells per μL). See Table 4 for ritonavir pharmacokinetic characteristics. Absorption The absolute bioavailability of ritonavir has not been determined.

After a 100 mg tablet dose of NORVIR, peak concentrations of ritonavir were achieved approximately 3 hours and 4 hours after dosing under fasting conditions and moderate-fat (857 KCal; 31% fat, 13% protein, and 56% carbohydrate) meal, respectively. Effect of Food on Oral Absorption The bioavailability of NORVIR tablet and oral powder is decreased under fed conditions as compared to fasted conditions. Following the administration of a 100 mg tablet dose of NORVIR, C max and AUC inf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Following the administration of a 100 mg dose of NORVIR oral powder, C max and AUC inf of ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions. Metabolism Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14 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. Elimination In a study of five subjects receiving a 600 mg dose of 14 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. Table 4.

Ritonavir Pharmacokinetic Characteristics Parameter N Values (Mean ± SD) V β /F ‡ 91 0.41 ±

0.25L/kg t ½ 3 - 5 h CL/F SS † 10 8.8 ±

3.2L/h CL/F ‡ 91 4.6 ±

1.6 L/h CL R 62 <

0.1 L/h RBC/Plasma Ratio

0.14Percent 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. Special Populations Gender, Race and Age No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Ritonavir is an antiretroviral drug [see Microbiology ( 12.4 ) ] .

12.3Pharmacokinetics The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD 4 greater than or equal to 50 cells per μL). See Table 4 for ritonavir pharmacokinetic characteristics. Absorption The absolute bioavailability of ritonavir has not been determined.

After a 100 mg tablet dose of NORVIR, peak concentrations of ritonavir were achieved approximately 3 hours and 4 hours after dosing under fasting conditions and moderate-fat (857 KCal; 31% fat, 13% protein, and 56% carbohydrate) meal, respectively. Effect of Food on Oral Absorption The bioavailability of NORVIR tablet and oral powder is decreased under fed conditions as compared to fasted conditions. Following the administration of a 100 mg tablet dose of NORVIR, C max and AUC inf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Following the administration of a 100 mg dose of NORVIR oral powder, C max and AUC inf of ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions. Metabolism Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14 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. Elimination In a study of five subjects receiving a 600 mg dose of 14 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. Table 4.

Ritonavir Pharmacokinetic Characteristics Parameter N Values (Mean ± SD) V β /F ‡ 91 0.41 ±

0.25L/kg t ½ 3 - 5 h CL/F SS † 10 8.8 ±

3.2L/h CL/F ‡ 91 4.6 ±

1.6 L/h CL R 62 <

0.1 L/h RBC/Plasma Ratio

0.14Percent 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. 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 per m 2 twice-daily to 400 mg per m 2 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 per m 2 twice-daily in PACTG Study 345.

Across dose groups, ritonavir steady-state oral clearance (CL/F/m 2 ) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m 2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m 2 ) twice-daily. The following observ… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology 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 [see Warnings and Precautions ( 5.6 )] .

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

14.1Advanced Patients with Prior Antiretroviral Therapy 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 4 cell counts less than or equal to 100 cells per 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 1,090 patients, with mean baseline CD 4 cell count at study entry of 32 cells per 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. Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo.

This difference in rates was statistically significant. However, 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. During the double-blind phase of Study 247, CD 4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed.

From Week 4 and through Week 24, mean CD 4 cell counts for patients randomized to NORVIR appeared to plateau. In contrast, there was no apparent change in mean CD 4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

14.2Patients without Prior Antiretroviral Therapy In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD 4 = 364 cells per μL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs. During the double-blind phase of study 245, greater mean CD 4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms. Mean CD 4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD 4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily).

There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects.

In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. Mutagenesis However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli , the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.