Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate 600 mg; 200 mg; 300 mg Tablet, Film Coated, 30-count — NDC 31722-736-30 (Billing 31722-0736-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology ( 12.4 )].

12.2Pharmacodynamics Cardiac Electrophysiology Efavirenz: The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean C max of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C max observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between EFV concentration and QTc prolongation was observed.

Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions ( 5.4 )].

12.3Pharmacokinetics Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA ® capsule (200 mg) plus one VIREAD ® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state C max was 12.9 ± 3.7 μM (mean ± SD), C min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM·hr.

EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14 C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism.

EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1 to 2 hours postdose.

Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C max was 1.8 ± 0.7 mcg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 mcg•hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of FTC was 93%.

Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate.

FTC is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma FTC half-life is approximately 10 hours. Tenofovir DF: Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max ) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively.

The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology ( 12.4 )].

12.3Pharmacokinetics Efavirenz, emtricitabine and tenofovir disoproxil fumarate: One efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA ® capsule (200 mg) plus one VIREAD ® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state C max was 12.9 ± 3.7 μM (mean ± SD), C min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM·hr.

EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14 C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism.

EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1 to 2 hours postdose.

Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C max was 1.8 ± 0.7 mcg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 mcg•hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of FTC was 93%.

Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate.

FTC is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma FTC half-life is approximately 10 hours. Tenofovir DF: Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max ) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively.

The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion, with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours. Effects of Food on Oral Absorption Efavirenz, emtricitabine and tenofovir disoproxil fumarate has not been evaluated in the presence of food.

Administration of EFV tablets with a high-fat meal increased the mean AUC and C max of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either a high-fat meal or a light meal increased the mean AUC and C max of tenofovir by 35% and 15%, respectively, without affecting FTC exposures [see Dosage and Administration ( 2.2 ) and Patient Counseling Information ( 17 )] Specific Populations Race Efavirenz: The pharmacokinetics of EFV in HIV… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Efavirenz: The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean C max of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C max observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between EFV concentration and QTc prolongation was observed.

Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions ( 5.4 )].

14 CLINICAL STUDIES Clinical Study 934 (NCT00112047) supports the use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in antiretroviral treatment-naïve HIV-1 infected patients. Clinical Study 073 (NCT00365612) provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to efavirenz, emtricitabine and tenofovir disoproxil fumarate. In antiretroviral treatment-experienced patients, the use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets as assessed by treatment history or by genotypic or phenotypic testing [see Microbiology ( 12.4 )].

Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC + TDF administered in combination with EFV versus zidovudine/lamivudine fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received FTC/TDF fixed-dose combination with EFV in place of FTC + TDF with EFV. Subjects had a mean age of 38 years (range 18 to 80); 86% were male, 59% were Caucasian, and 23% were Black.

The mean baseline CD4+ cell count was 245 cells/mm 3 (range 2 to 1191), and median baseline plasma HIV-1 RNA was 5.01 log 10 copies/mL (range 3.56 to 6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥ 200 cells/mm 3 ), and 41% had CD4+ cell counts <200 cells/mm 3 . Fifty-one percent (51%) of subjects had baseline viral loads >100,000 copies/mL.

Treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline (N=487) are presented in Table 8. Table 8 Virologic Outcomes of Randomized Treatment at Weeks 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC + TDF +EFV (N=244) AZT/3TC +EFV (N=243) FTC + TDF +EFV (N=227) a AZT/3TC +EFV (N=229) a Responder b 84% 73% 71% 58% Virologic failure c 2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons d 10% 14% 20% 22% a .

Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue trial after Week 48 or Week 96 were excluded from analysis. b . Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. c . Includes confirmed viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. d .

Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons. Through Week 48, 84% and 73% of subjects in the FTC + TDF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial.

In addition, 80% and 70% of subjects in the FTC + TDF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm 3 in the FTC+TDF group and 158 cells/mm 3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm 3 at Week 144). Through 48 weeks, 7 subjects in the FTC + TDF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Study 073 : Study 073 was a 48-week open-label, randomized clinical trial in subj… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with EFV. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females.

No increases in tumor incidence above background were seen in males. In studies in which rats were administered EFV at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600 mg/day dose.

The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, EFV showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies.

These included bacterial mutation assays in S. typhimurium and E. coli , mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of EFV, the relevance to humans of neoplasms in EFV-treated mice is not known. Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats.

The reproductive performance of offspring born to female rats given EFV was not affected. Because of the rapid clearance of EFV in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of EFV. 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/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 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 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.

TDF 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 Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving EFV at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose. Tenofovir DF : Ten… [Excerpted — this section continues on DailyMed.]