Stribild elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate 150 mg; 150 mg; 200 mg; 300 mg Tablet, Film Coated, 30-count — NDC 61958-1201-1 (Billing 61958-1201-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action STRIBILD is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and TDF [see Microbiology (12.4) ] .

12.2Pharmacodynamics Effects on Electrocardiogram Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known. Elvitegravir: In a thorough QT/QTc study in 126 healthy subjects, elvitegravir (coadministered with 100 mg ritonavir) 125 mg and 250 mg (0.83 and 1.67 times the dose in STRIBILD) did not affect the QT/QTc interval and did not prolong the PR interval.

Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose.

Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation. Effects on Serum Creatinine The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an eGFR of at least 80 mL per minute (N=18) and with an eGFR of 50 to 79 mL per minute (N=12). A statistically significant change of eGFR CG from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an eGFR of at least 80 mL per minute (−9.9 ± 13.1 mL/min) and subjects with an eGFR of 50 to 79 mL per minute (−11.9 ± 7.0 mL per minute).

These decreases in eGFR CG were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an eGFR of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR CG , without affecting the actual glomerular filtration rate.

12.3Pharmacokinetics The pharmacokinetic properties of the components of STRIBILD are provided in Table 6. The multiple dose pharmacokinetic parameters of elvitegravir, cobicistat, emtricitabine, and tenofovir are provided in Table 7. Table 6 Pharmacokinetic Properties of the Components of STRIBILD Elvitegravir Cobicistat Emtricitabine Tenofovir NC=Not Calculated Absorption T max (h) 4 3 3 2 Effect of light meal (relative to fasting) Values refer to mean systemic exposure (90% confidence interval).

STRIBILD light meal=~373 kcal, 20% fat; STRIBILD high fat meal=~800 kcal, 50% fat. Increase = ↑; Decrease = ↓ ↑34% (↑19, ↑51) ↑3% (↓10, ↑17) ↓5% (↓9, 0) ↑24% (↑18, ↑30) Effect of high fat meal (relative to fasting) ↑87% (↑66, ↑110) ↓17% (↓27, ↓5) ↓4% (↓8, 0) ↑23% (↑17, ↑29) Distribution % Bound to human plasma proteins ~99 ~98 <4 <0.7 Source of protein binding data Ex vivo In vitro In vitro In vitro Blood-to-plasma ratio 0.73 0.5

0.6NC Metabolism Metabolism CYP3A (major) UGT1A1/3 (minor) CYP3A (major) CYP2D6 (minor) Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion T 1/2 (h) t 1/2 values refer to median terminal plasma half-life. 12.9 3.5 10 12–18 % Of dose excreted in urine Dosing in mass balance studies: elvitegravir (single dose administration of [ 14 C] elvitegravir, coadministered with 100 mg RTV); cobicistat (single-dose administration of [ 14 C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14 C] emtricitabine after multiple dosin… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action STRIBILD is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and TDF [see Microbiology (12.4) ] .

12.3Pharmacokinetics The pharmacokinetic properties of the components of STRIBILD are provided in Table 6. The multiple dose pharmacokinetic parameters of elvitegravir, cobicistat, emtricitabine, and tenofovir are provided in Table 7. Table 6 Pharmacokinetic Properties of the Components of STRIBILD Elvitegravir Cobicistat Emtricitabine Tenofovir NC=Not Calculated Absorption T max (h) 4 3 3 2 Effect of light meal (relative to fasting) Values refer to mean systemic exposure (90% confidence interval).

STRIBILD light meal=~373 kcal, 20% fat; STRIBILD high fat meal=~800 kcal, 50% fat. Increase = ↑; Decrease = ↓ ↑34% (↑19, ↑51) ↑3% (↓10, ↑17) ↓5% (↓9, 0) ↑24% (↑18, ↑30) Effect of high fat meal (relative to fasting) ↑87% (↑66, ↑110) ↓17% (↓27, ↓5) ↓4% (↓8, 0) ↑23% (↑17, ↑29) Distribution % Bound to human plasma proteins ~99 ~98 <4 <0.7 Source of protein binding data Ex vivo In vitro In vitro In vitro Blood-to-plasma ratio 0.73 0.5

0.6NC Metabolism Metabolism CYP3A (major) UGT1A1/3 (minor) CYP3A (major) CYP2D6 (minor) Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion T 1/2 (h) t 1/2 values refer to median terminal plasma half-life. 12.9 3.5 10 12–18 % Of dose excreted in urine Dosing in mass balance studies: elvitegravir (single dose administration of [ 14 C] elvitegravir, coadministered with 100 mg RTV); cobicistat (single-dose administration of [ 14 C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14 C] emtricitabine after multiple dosing of emtricitabine for ten days); mass balance study not conducted for tenofovir.

6.78.2 70 70–80 % Of dose excreted in feces 94.8 86.2

13.7NC Table 7 Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects Parameter Mean ± SD [range, min:max] Elvitegravir From Population Pharmacokinetic analysis, N=419. Cobicistat From Intensive Pharmacokinetic analysis, N=61–62, except cobicistat C trough N=53. Emtricitabine Tenofovir SD=Standard Deviation C max (microgram per mL) 1.7 ± 0.4 [0.4:3.7] 1.1 ± 0.4 [0.1:2.1] 1.9 ± 0.5 [0.6:3.6] 0.45 ± 0.2 [0.2:1.2] AUC tau (microgram∙hour per mL) 23.0 ± 7.5 [4.4:69.8] 8.3 ± 3.8 [0.5:18.3] 12.7 ± 4.5 [5.2:34.1] 4.4 ± 2.2 [2.1:18.2] C trough (microgram per mL) 0.45 ± 0.26 [0.05:2.34] 0.05 ± 0.13 [0.01:0.92] 0.14 ± 0.25 [0.04:1.94] 0.10 ± 0.08 [0.04:0.58] Specific Populations Geriatric Patients The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5) ].

Pediatric Patients Exposures (AUC) of elvitegravir and tenofovir in 14 pediatric subjects aged 12 to less than 18 years who received STRIBILD in Study 112 were increased by 30% and 37%, respectively, compared with exposures achieved in adults following administration of STRIBILD, but were deemed acceptable based on the overall safety profile of these agents and exposure-safety assessments. The other components of STRIBILD had similar exposures in adolescents compared with adults [see Use in Specific Populations (8.4) ].

Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. TDF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects less than 12 years of age have not been established [see Use in Specific Populations (8.4) ].

Race, Gender No clinically significant differences in pharmacokinetics of STRIBILD have been identified based on race or gender. Patients with Renal Impairment Elvitegravir and Cobicistat: A study of the pharmacokinetics of cobicistat+elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per minute). No clini… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effects on Electrocardiogram Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known. Elvitegravir: In a thorough QT/QTc study in 126 healthy subjects, elvitegravir (coadministered with 100 mg ritonavir) 125 mg and 250 mg (0.83 and 1.67 times the dose in STRIBILD) did not affect the QT/QTc interval and did not prolong the PR interval.

Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose.

Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation. Effects on Serum Creatinine The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an eGFR of at least 80 mL per minute (N=18) and with an eGFR of 50 to 79 mL per minute (N=12). A statistically significant change of eGFR CG from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an eGFR of at least 80 mL per minute (−9.9 ± 13.1 mL/min) and subjects with an eGFR of 50 to 79 mL per minute (−11.9 ± 7.0 mL per minute).

These decreases in eGFR CG were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an eGFR of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR CG , without affecting the actual glomerular filtration rate.

14 CLINICAL STUDIES

14.1Description of Clinical Trials The efficacy and safety of STRIBILD were evaluated in the studies summarized in Table 13. Table 13 Trials Conducted with STRIBILD in Subjects with HIV-1 Infection Trial Population Study Arms (N) Randomized and dosed. Timepoint (Week) Study 102 Randomized, double blind, active-controlled trial. , Patients had estimated creatinine clearance greater than or equal to 70 mL/min at screening.

Adults with no antiretroviral treatment history STRIBILD (348) ATRIPLA (352) 144 Study 103 , STRIBILD (353) TRUVADA+atazanavir+ritonavir (355) Study 115 , Randomized, open label, active-controlled trial. Virologically suppressed adults without a history of virologic failure HIV-1 RNA less than 50 copies per mL. STRIBILD (293) TRUVADA+PI+ritonavir (140) 48 Study 121 , STRIBILD (291) TRUVADA+NNRTI (143) Study 112 Open label trial.

Treatment-naïve adolescents between the ages of 12 to less than 18 years STRIBILD (50) 48

14.2Clinical Trial Results in HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (N=352) once daily. The mean age was 38 years (range 18–67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino.

The mean baseline plasma HIV-1 RNA was 4.8 log 10 copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm 3 (range 3–1348), and 13% had CD4+ cell counts less than 200 cells per mm 3 . Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg + RTV 100 mg + TRUVADA (N=355) once daily. The mean age was 38 years (range 19–72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino.

The mean baseline plasma HIV-1 RNA was 4.8 log 10 copies per mL (range 1.7–6.6). The mean baseline CD4+ cell count was 370 cells per mm 3 (range 5–1132), and 13% had CD4+ cell count less than 200 cells per mm 3 . Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL). Treatment outcomes of Study 102 and Study 103 through 144 weeks are presented in Table 14. Table 14 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 144 Week-144 window is between Day 967 and 1050 (inclusive).

Study 102 Study 103 STRIBILD N=348 ATRIPLA N=352 STRIBILD N=353 ATV+RTV+TRUVADA N=355 Virologic Success HIV-1 RNA <50 copies/mL 80% 75% 78% 75% Treatment Difference 4.9% (95% CI = −1.3%, 11.1%) 3.1% (95% CI = −3.2%, 9.4%) Virologic Failure Includes subjects who had ≥50 copies/mL in the Week-144 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 value of ≥50 copies/mL.

7% 10% 8% 7% No Virologic Data in Week 144 Window Discontinued Study Drug Due to AE or Death Includes patients who discontinued due to an adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. 6% 8% 6% 8% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mL 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.

5% 7% 8% 9% Missing Data During Window but on Study Drug 1% 0% 1% 1% In Study 102, the mean increase from baseline in CD4+ cell count at Week 144 was 298 cells per mm 3 in the STRIBILD-treated subjects and 272… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Elvitegravir: Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively in male and female, the human systemic exposure.

Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation. Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.

Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose. Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose.

In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.

Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or rat micronucleus assays. Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.

Emtricitabine : In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 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 (28 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays. Emtricitabine 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. Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therap… [Excerpted — this section continues on DailyMed.]