Atripla (Page 10 of 12)

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.

Tenofovir Disoproxil Fumarate: The K65R substitution selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. 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 efavirenz 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, efavirenz 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 efavirenz, the relevance to humans of neoplasms in efavirenz-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 efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.

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/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), 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 Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir DF 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, tenofovir DF was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir DF 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 seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Tenofovir Disoproxil Fumarate: Tenofovir and tenofovir DF 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 administered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14 CLINICAL STUDIES

Clinical Study 934 supports the use of ATRIPLA tablets in antiretroviral treatment-naïve HIV-1 infected patients. Additional data in support of the use of ATRIPLA in treatment- naive patients can be found in the prescribing information for VIREAD.

Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to ATRIPLA.

In antiretroviral treatment-experienced patients, the use of ATRIPLA tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing [See Clinical Pharmacology (12.4)].

Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From weeks 96 to 144 of the study, subjects received emtricitabine/tenofovir DF fixed-dose combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥ 200 cells/mm3) and 41% had CD4+ cell counts <200 cells/mm3. 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 efavirenz resistance at baseline (n=487) are presented in Table 10.

Table 10 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)* AZT/3TC +EFV (N=229)*
*
Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.
Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
Includes confirmed viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
§
Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Responder 84% 73% 71% 58%
Virologic failure 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 § 10% 14% 20% 22%

Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF 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 study. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF 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/mm3 in the emtricitabine + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

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