Harvoni ledipasvir and sofosbuvir 45 mg; 200 mg Tablet, Film Coated, 28-count — NDC 61958-1803-1 (Billing 61958-1803-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].

12.2Pharmacodynamics Cardiac Electrophysiology Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent.

The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

12.3Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose.

Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively.

Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0–24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0–inf by approximately 2-fold, but did not significantly affect sofosbuvir C max .

The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food.

Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL.

Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [ 14 C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [ 14 C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces.

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside a… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].

12.3Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose.

Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively.

Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0–24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0–inf by approximately 2-fold, but did not significantly affect sofosbuvir C max .

The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food.

Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL.

Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [ 14 C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [ 14 C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces.

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.

After a single 400 mg oral dose of [ 14 C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. Elimination Following a single 90 mg oral dose of [ 14 C]-ledipasvir, mean total recovery of the [ 14 C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose.

These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor path… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent.

The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Description of Clinical Trials The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH); two trials in subjects with severe renal impairment (one of which included subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 10 [see Clinical Studies (14.2 , 14.3 , 14.4 , 14.5 , 14.6 , and 14.7) ]: Table 10 Trials Conducted with HARVONI with or without Ribavirin in Subjects with Chronic HCV Genotype 1, 4, 5, or 6 Infection Trial Population Study Arms (Number of Subjects Treated) ESRD = End stage renal disease; RBV = ribavirin; RI = Renal impairment; TN = Treatment-naïve subjects.

ION-3 Open-label. (NCT01851330) GT1, TN without cirrhosis HARVONI 8 weeks (215) HARVONI + RBV 8 weeks (216) HARVONI 12 weeks (216) ION-1 (NCT01701401) GT1, TN with or without cirrhosis HARVONI 12 weeks (214) HARVONI + RBV 12 weeks (217) HARVONI 24 weeks (217) HARVONI + RBV 24 weeks (217) ION-2 (NCT01768286) GT1, TE TE = Treatment-experienced subjects including those who have failed a peginterferon alfa + RBV based regimen with or without an HCV protease inhibitor. with or without cirrhosis HARVONI 12 weeks (109) HARVONI + RBV 12 weeks (111) HARVONI 24 weeks (109) HARVONI + RBV 24 weeks (111) SIRIUS Double-blind, placebo-controlled.

(NCT01965535) GT1, TE with cirrhosis HARVONI + RBV 12 Weeks (77) HARVONI 24 weeks (77) ION-4 (NCT02073656) GT1 and GT4 HCV/HIV-1 coinfected TN and TE with or without cirrhosis HARVONI 12 Weeks (N=327 for GT1; N=8 for GT4) 1119 (NCT02081079) GT4 and GT5, TN and TE with or without cirrhosis HARVONI 12 Weeks (N=44 for GT4; N=41 for GT5) ELECTRON-2 (NCT01826981) GT6, TN and TE with or without cirrhosis HARVONI 12 Weeks (25) SOLAR-1 and SOLAR-2 (NCT01938430 and NCT02010255) GT1 and GT4 pre-transplant with decompensated cirrhosis or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or FCH HARVONI + RBV 12 Weeks (336) HARVONI + RBV 24 weeks (334) 1116 (NCT02249182) GT1 or 4 TN and TE with or without cirrhosis in pediatric subjects 3 years of age and older HARVONI 12 Weeks (223) HARVONI 24 Weeks (1) 0154 (NCT01958281) GT1 TN and TE with severe RI without dialysis HARVONI 12 weeks (18) 4063 (NCT03036839) GT1, 5, or 6 TN and TE TE = Treatment experienced subjects including those who have failed either interferon/peginterferon alfa/ribavirin based regimens or HCV-specific direct-acting antiviral regimens that do not include an NS5A polymerase inhibitor. with or without compensated cirrhosis, with ESRD requiring dialysis HARVONI 8 Weeks (45) HARVONI 12 Weeks (12) HARVONI 24 Weeks (6) HARVONI was administered once daily by mouth in these trials.

For subjects without cirrhosis or with compensated cirrhosis who received ribavirin, the ribavirin dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of transplantation status. Ribavirin dose adjustments were performed according to the ribavirin labeling.

Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV te… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays. Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to 300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to 100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures approximately 10 and 4 times, respectively, higher than the exposure in humans at the recommended human dose (RHD).

Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo mouse micronucleus assays. Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and females respectively, the exposure in humans at the RHD.

Impairment of Fertility Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3 times the exposure in humans at the RHD. At the highest dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times, in males and females, respectively, the exposure in humans at the RHD.

Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, exposure to the predominant circulating metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.