Viracept nelfinavir mesylate 250 mg Tablet, Film Coated, 300-count — NDC 63010-010-30 (Billing 63010-0010-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Nelfinavir is an inhibitor of the HIV-1 protease [see Microbiology (12.4) ] .

12.2Pharmacodynamics Effects on Electrocardiogram The effect of Viracept at the recommended dose of 1250 mg twice daily on the QTcF interval administered with a low fat meal (20% fat) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled, crossover study in 66 healthy subjects. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Viracept 3125 mg was administered following a 3-day administration of Viracept 1250 mg twice daily.

The exposure at 3125 mg was 1.4-fold that at 1250 mg. The dose of 3125 mg in this study did not achieve the anticipated exposures in patients taking a high fat meal (50% fat) or with concomitant administration of drugs that could increase nelfinavir exposure [see Pharmacokinetics (12.3) ] . No subject in any group had an increase in QTcF of ≥60 milliseconds from baseline.

No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 milliseconds.

12.3Pharmacokinetics The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups. Absorption Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC 24 ], peak plasma concentrations [C max ], morning and evening trough concentrations [C trough ]) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 7.

Table 7: Summary of a Pharmacokinetic Study in HIV-positive Patients With Multiple Dosing of 1250 mg (Five 250 mg Tablets) BID for 28 Days and 750 mg (Three 250 mg Tablets) TID for 28 Days Regimen AUC 24 mg∙h/L C max mg/L C trough Morning mg/L C trough Afternoon or Evening mg/L Data are mean ± SD 1250 mg BID 52.8±15.7 4.0±0.8 2.2±1.3 0.7±0.4 750 mg TID 43.6±17.8 3.0±1.6 1.4±0.6 1.0±0.5 The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.

In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and C max were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the C max was comparable for both formulations.

In HIV-1 infected subjects (N=21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (C max and AUC). Table 8 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 × 625 mg tablets) to HIV-infected patients (N=21) for 14 days. Table 8: Summary of the Steady State Pharmacokinetic Parameters (Mean ± SD) of Nelfinavir After Multiple Dose Administration of 1250 mg BID (2 × 625 mg Tablets) to HIV-infected Patients (N=21) for 14 Days.

Regimen AUC 12 mg∙h/L C max mg/L C min mg/L AUC 12 : Steady state AUC C max : Maximum plasma concentration at steady state C min : Minimum plasma concentration at steady state 1250 mg BID 35.3 (16.4) 4.7 (1.9) 1.5 (1.0) In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of th… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Nelfinavir is an inhibitor of the HIV-1 protease [see Microbiology (12.4) ] .

12.3Pharmacokinetics The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups. Absorption Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC 24 ], peak plasma concentrations [C max ], morning and evening trough concentrations [C trough ]) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 7.

Table 7: Summary of a Pharmacokinetic Study in HIV-positive Patients With Multiple Dosing of 1250 mg (Five 250 mg Tablets) BID for 28 Days and 750 mg (Three 250 mg Tablets) TID for 28 Days Regimen AUC 24 mg∙h/L C max mg/L C trough Morning mg/L C trough Afternoon or Evening mg/L Data are mean ± SD 1250 mg BID 52.8±15.7 4.0±0.8 2.2±1.3 0.7±0.4 750 mg TID 43.6±17.8 3.0±1.6 1.4±0.6 1.0±0.5 The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.

In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and C max were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the C max was comparable for both formulations.

In HIV-1 infected subjects (N=21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (C max and AUC). Table 8 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 × 625 mg tablets) to HIV-infected patients (N=21) for 14 days. Table 8: Summary of the Steady State Pharmacokinetic Parameters (Mean ± SD) of Nelfinavir After Multiple Dose Administration of 1250 mg BID (2 × 625 mg Tablets) to HIV-infected Patients (N=21) for 14 Days.

Regimen AUC 12 mg∙h/L C max mg/L C min mg/L AUC 12 : Steady state AUC C max : Maximum plasma concentration at steady state C min : Minimum plasma concentration at steady state 1250 mg BID 35.3 (16.4) 4.7 (1.9) 1.5 (1.0) In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of the 250 mg tablet and oral powder. Effect of Food on Oral Absorption Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state.

In one study, healthy volunteers received a single dose of 1250 mg of VIRACEPT 250 mg tablets (5 tablets) under fasted or fed conditions (three different meals). In a second study, healthy volunteers received single doses of 1250 mg VIRACEPT (5 × 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 9 and Table 10, respectively.

Table 9: Increase in AUC, C max and T max for Nelfinavir in Fed State Relative to Fasted State Following 1250 mg VIRACEPT (5 × 250 mg Tablets) Number of Kcal % Fat Number of subjects AUC fold increase C max fold increase Increase in T max (hr) 125 20 n=21 2.2 2.0 1.00 500 20 n=22 3.1 2.3 2.00 1000 50 n=23 5.2 3.3

2.00Table 10: Increase in Nelfinavir AUC, C max and T max in Fed Low Fat (20%) versus High Fat (50%) State Relative to Fasted State Following 1250 mg VIRACEPT (5 × 250 mg Tablets) Number of Kcal % Fat Number of subjects AUC fold increase C max fold increase Increase in T max (hr) 500 20 n=22 3.1 2.5 1.8 500 50 n=22 5.1 3.8

2.1Nelfinavir exposure can be increased by incr… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects on Electrocardiogram The effect of Viracept at the recommended dose of 1250 mg twice daily on the QTcF interval administered with a low fat meal (20% fat) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled, crossover study in 66 healthy subjects. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Viracept 3125 mg was administered following a 3-day administration of Viracept 1250 mg twice daily.

The exposure at 3125 mg was 1.4-fold that at 1250 mg. The dose of 3125 mg in this study did not achieve the anticipated exposures in patients taking a high fat meal (50% fat) or with concomitant administration of drugs that could increase nelfinavir exposure [see Pharmacokinetics (12.3) ] . No subject in any group had an increase in QTcF of ≥60 milliseconds from baseline.

No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 milliseconds.

14 CLINICAL STUDIES Description of Clinical Studies The efficacy of VIRACEPT is based on analyses of multiple clinical studies in HIV-1 infected antiretroviral treatment-naïve and experienced adult patients. In the adult clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA <400 copies/mL (Studies 511 and 542), <500 copies/mL (Study ACTG 364), or <50 copies/mL (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the study's definition of virologic failure.

14.1Studies in Antiretroviral Treatment Naïve Adult Patients Study 511: VIRACEPT + zidovudine + lamivudine versus zidovudine + lamivudine Study 511 is a double-blind, randomized, placebo-controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of VIRACEPT (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naïve HIV-1 infected patients. The median age was 35 years [range 21 to 63]; 89% were male and 78% were Caucasian.

Mean baseline CD4 cell count was 288 cells/mm 3 and mean baseline plasma HIV RNA was 5.21 log 10 copies/mL (160,394 copies/mL). The proportion of patients with plasma HIV RNA <400 copies/mL at Week 48 was 86%, as summarized in Figure 1. The mean change in CD4 cell count at Week 48 was 207.6 cells/mm 3 .

Figure 1 Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL Figure 1 Study 542: VIRACEPT BID + stavudine + lamivudine compared to VIRACEPT TID + stavudine + lamivudine Study 542 is a, randomized, open-label trial comparing the HIV RNA suppression achieved by VIRACEPT 1250 mg BID versus VIRACEPT 750 mg TID in patients also receiving stavudine (d4T; 30–40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naïve to protease inhibitors.

Mean baseline CD4 cell count was 296 cells/mm 3 and mean baseline plasma HIV RNA was 5.0 log 10 copies/mL (100,706 copies/mL). Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm 3 at 24 weeks and approximately 200 cells/mm 3 at 48 weeks. The percent of patients with HIV RNA <400 copies/mL and the outcomes of patients through 48 weeks of treatment are summarized in Table 14.

Table 14: Outcomes of Randomized Treatment Through 48 Weeks Outcome VIRACEPT 1250 mg BID Regimen VIRACEPT 750 mg TID Regimen Number of patients evaluable Twelve patients in the BID arm and fourteen patients in the TID arm had not yet reached 48 weeks of therapy. 323 192 HIV-1 RNA <400 copies/mL 198 (61%) 111 (58%) HIV-1 RNA ≥400 copies/mL 46 (14%) 22 (11%) Discontinued due to VIRACEPT toxicity These rates only reflect dose-limiting toxicities that were counted as the initial reason for treatment failure in the analysis [see Adverse Reactions (6) ] .

9 (3%) 2 (1%) Discontinued due to other antiretroviral agents' toxicity 3 (1%) 3 (2%) Others Consent withdrawn, lost to follow-up, intercurrent illness, noncompliance or missing data; all assumed as failures. 67 (21%) 54 (28%) Study Avanti 3: VIRACEPT TID + zidovudine + lamivudine compared to zidovudine + lamivudine Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of VIRACEPT (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo i… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies in mice and rats were conducted with nelfinavir at oral doses up to 1000 mg/kg/day. No evidence of a tumorigenic effect was noted in mice at systemic exposures (C max ) up to 9-fold those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). In rats, thyroid follicular cell adenomas and carcinomas were increased in males at 300 mg/kg/day and higher and in females at 1000 mg/kg/day.

Systemic exposures (C max ) at 300 and 1000 mg/kg/day were 1- to 3-fold, respectively, those measured in humans at the recommended therapeutic dose. Repeated administration of nelfinavir to rats produced effects consistent with hepatic microsomal enzyme induction and increased thyroid hormone deposition; these effects predispose rats, but not humans, to thyroid follicular cell neoplasms. Nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays.

These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay. Nelfinavir produced no effects on either male or female mating and fertility or embryo survival in rats at systemic exposures comparable to the human therapeutic exposure.