Emtricitabine, Rilpivirine, Tenofovir Disoproxil Fumarate 200 mg; 25 mg; 300 mg Tablet, Film Coated, 30-count — NDC 0378-5440-93 (Billing 00378-5440-93)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4) ] .

12.2Pharmacodynamics Effects on Electrocardiogram The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).

When doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state C max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean C max observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.7) ] .

12.3Pharmacokinetics Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34). Single-dose administration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).

Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6. Table 5 Pharmacokinetic Properties of the Components of Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets NC = Not Calculated RPV FTC Tenofovir Absorption T max (h) 4-5 1-2 1 % Fasted oral bioavailability Median NC 93 25 Oral bioavailability of tenofovir from VIREAD.

Effect of a light meal (relative to fasting) Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets light meal = 390 kcal, 12 g fat; emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets standard meal = 540 kcal, 21 g fat. High fat meal not evaluated.

Increase = ↑; Decrease = ↓; No Effect = ↔ ↑9% ↔ ↑28% Effect of a standard meal (relative to fasting) ↑16% ↔ ↑38% Distribution % Bound to human plasma proteins ~99 <4 <0.7 Source of protein binding data In vitro In vitro In vitro Metabolism Metabolism CYP3A Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion CL renal Mean±SD (mL/min) NC 213±89 243±33 t 1/2 (h) t 1/2 values refer to median terminal plasma half-life. 50 10 17 % Of dose excreted in urine Dosing in mass balance studies: FTC (single dose administration of [ 14 C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [ 14 C] RPV); mass balance study not conducted for tenofovir.

6 86 70-80 % Of dose excreted in feces 8… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4) ] .

12.3Pharmacokinetics Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34). Single-dose administration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).

Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6. Table 5 Pharmacokinetic Properties of the Components of Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets NC = Not Calculated RPV FTC Tenofovir Absorption T max (h) 4-5 1-2 1 % Fasted oral bioavailability Median NC 93 25 Oral bioavailability of tenofovir from VIREAD.

Effect of a light meal (relative to fasting) Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets light meal = 390 kcal, 12 g fat; emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets standard meal = 540 kcal, 21 g fat. High fat meal not evaluated.

Increase = ↑; Decrease = ↓; No Effect = ↔ ↑9% ↔ ↑28% Effect of a standard meal (relative to fasting) ↑16% ↔ ↑38% Distribution % Bound to human plasma proteins ~99 <4 <0.7 Source of protein binding data In vitro In vitro In vitro Metabolism Metabolism CYP3A Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion CL renal Mean±SD (mL/min) NC 213±89 243±33 t 1/2 (h) t 1/2 values refer to median terminal plasma half-life. 50 10 17 % Of dose excreted in urine Dosing in mass balance studies: FTC (single dose administration of [ 14 C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [ 14 C] RPV); mass balance study not conducted for tenofovir.

6 86 70-80 % Of dose excreted in feces 85 ~14 NC Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults NA = Not Applicable; SD = Standard Deviation Parameter Mean ± SD RPV Population PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n = 679) FTC Multiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n = 20) Tenofovir Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state C max (μg/mL) NA 1.80±0.72 Data presented as steady state values 0.30±0.09 AUC tau (μg•hr/mL) 2.24±0.85 10.0±3.12 2.29±0.69 AUC 0-24h C 0h (μg/mL) 0.08±0.04 0.09±0.07 NA Specific Populations Geriatric Patients The pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5) ] .

Pediatric Patient Pediatric trials have not been conducted using emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Pediatric information is based on trials conducted with the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets [see Use in Specific Populations (8.4) ] . Emtricitabine: The pharmacokinetics of FTC at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral s… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects on Electrocardiogram The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).

When doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state C max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean C max observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.7) ] .

14 CLINICAL STUDIES

14.1Adult Subjects In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History The efficacy of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is based on the analyses of 48-and 96-week data from two randomized, double-blind, controlled studies (Study C209 [ECHO] and TRUVADA ® subset of Study C215 [THRIVE]) in treatment-naïve, HIV-1-infected subjects (N=1368). The studies are identical in design with the exception of the background regimen (BR). Subjects were randomized in a 1:1 ratio to receive either RPV 25 mg (N=686) once daily or EFV 600 mg (N=682) once daily in addition to a BR.

In Study C209 (N=690), the BR was FTC/TDF. In Study C215 (N=678), the BR consisted of 2 NRTIs: FTC/TDF (60%, n=406), lamivudine/zidovudine (30%, n=204), or abacavir + lamivudine (10%, n=68). For subjects who received FTC/TDF (N=1096) in studies C209 and C215, the mean age was 37 years (range 18–78), 78% were male, 62% were White, 24% were Black, and 11% were Asian.

The mean baseline CD4+ cell count was 265 cells/mm 3 (range 1–888) and 31% had CD4+ cell counts <200 cells/mm 3 . The median baseline plasma HIV-1 RNA was 5 log 10 copies/mL (range 2–7). Subjects were stratified by baseline HIV-1 RNA.

Fifty percent of subjects had baseline viral load ≤100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL, and 11% of subjects had baseline viral load >500,000 copies/mL. Treatment outcomes through 96 weeks for the subset of subjects receiving FTC/TDF in studies C209 and C215 (Table 16) are generally consistent with treatment outcomes for all participating subjects (presented in the prescribing information for Edurant). The incidence of virologic failure was higher in the RPV arm than the EFV arm at Week 96.

Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment. Table 16 Pooled Virologic Outcome of Randomized Treatment of Studies C209 and C215 at Week 96 in Adult Subjects With No Antiviral Treatment History in Combination with FTC/TDF) at Week 96 Analyses were based on the last observed viral load data within the Week 96 window (Week 90–103). RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 HIV-1 RNA <50 copies/mL Predicted difference (95% CI) of response rate is 0.5% (–4.5% to 5.5%) at Week 96.

77% 77% HIV-1 RNA ≥50 copies/mL Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral load value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. 14% 8% No Virologic Data at Week 96 Window Reasons Discontinued study due to adverse event or death Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.

4% 9% Discontinued study for other reasons Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA <50 copies/mL (or missing) 4% 6% Missing data during window but on study < 1% < 1% HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤100,000 83% 80% >100,000 71% 74% HIV-1 RNA ≥50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤100,000 7% 5% >100,000 22% 12% HIV-1 RNA <50 copies/mL by Baseline CD4+ Cell Count (cells/mm 3 ) <200 68% 72% ≥200 82% 79% HIV-1 RNA ≥ 50 copies/mL by Baseline CD4+ Cell Count (cells/mm 3 ) <200 27% 12% ≥200 8% 7% Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm 3 for RPV + FTC/TDF-treated subjects and 223 cells/mm 3 for EFV + FTC/TDF-treated subjects.

In Virologically Suppressed HIV-1-Infected Adult Subjects The… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the therapeutic dose). FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose. Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks.

Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females.

The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily). RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay.

RPV did not induce chromosomal damage in the in vivo micronucleus test in mice. In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.

Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice. There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation.

There was, however, an alteration of the estrous cycle in female rats.

13.2Animal Toxicology and/or Pharmacology Tenofovir DF: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir.

In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown. Evidence of renal toxicity was noted in 4 animal species.

Increases in serum creatinine, BUN, glycosuria, prote… [Excerpted — this section continues on DailyMed.]