CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. HARVONI is fixed-dose combination of ledipasvir and sofosbuvir which are direct-acting antiviral agents against the hepatitis virus [see Microbiology (12.4)]. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThorough 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 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 randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.. 12.3 Pharmacokinetics. AbsorptionThe 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 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to hours post-dose.Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 nghr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects.. Effect of FoodRelative to fasting conditions, the administration of single dose of HARVONI with moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food.. DistributionLedipasvir is greater than 99.8% bound to human plasma proteins. After single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-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 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.. MetabolismIn 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 single dose of 90 mg [14C]-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 (CatA) or carboxylesterase (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein (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 single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. EliminationFollowing single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-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 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 major route of elimination, with renal excretion being minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of HARVONI was 47 hours.Following single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of HARVONI were 0.5 and 27 hours, respectively.. Specific Populations. Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007.. Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR12 >90%) were achieved in male and female subjects across the Phase studies and the safety profiles are similar in females and males.. Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in 100 pediatric subjects 12 years of age and older infected with HCV genotype receiving daily dose of HARVONI (90 mg ledipasvir and 400 mg sofosbuvir). The pharmacokinetic properties of ledipasvir, sofosbuvir, and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 6. Exposures in pediatric subjects were similar to those observed in adults.Table 6Pharmacokinetic Properties of the Components of HARVONI in Pediatric Subjects 12 Years of Age and OlderPopulation PK derived parameters Geometric MeanLedipasvirLedipasvir N=100; Sofosbuvir N=72; GS-331007 N=100 Sofosbuvir GS-331007 AUCtau (nghr/mL)11200135013600Cmax (ng/mL)550660921The pharmacokinetics of ledipasvir or sofosbuvir have not been established in pediatric patients less than 12 years of age [see Use in Specific Populations (8.4), and Clinical Studies (14.6)].. Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5)].. Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed hour after hemodialysis, respectively. 4 hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected subjects with severe renal impairment or ESRD requiring dialysis treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent with those observed in HCV-negative subjects with ESRD requiring dialysis.. Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar in subjects with severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of ledipasvir [see Use in Specific Populations (8.7)]. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and Clinical Studies (14.5)]. Drug Interaction StudiesLedipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. Johns wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2.Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is major route of elimination. Sofosbuvir is not substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by CYP or UGT1A1 enzymes are not expected.The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table [see Drug Interactions (7.2)]. Table 7Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug(mg)Ledipasvir Dose(mg)Sofosbuvir Dose(mg)NMean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered DrugNo Effect=1.00Cmax AUCCmin NA not available/not applicable, ND not dosed.tenofovir DF tenofovir disoproxil fumarateAtazanavir/ritonavir emtricitabine/tenofovir DFData generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir emtricitabine/tenofovir DF or darunavir/ritonavir emtricitabine/tenofovir DF and HARVONI provided similar results. The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of emtricitabine/tenofovir DF. 300/100 200/300 once daily90 once daily400 once daily24ledipasvir1.68(1.54, 1.84)1.96(1.74, 2.21)2.18(1.91, 2.50)sofosbuvir1.01(0.88, 1.15)1.11(1.02, 1.21)NAGS-3310071.17(1.12, 1.23)1.31(1.25, 1.36)1.42(1.34, 1.49)Carbamazepine300 twice dailyND400 single dose24sofosbuvir0.52 (0.43, 0.62)0.52 (0.46, 0.59)NAGS-3310071.04 (0.97, 1.11)0.99 (0.94. 1.04)NACyclosporine600 single doseND400 single dose19sofosbuvir2.54(1.87, 3.45)4.53(3.26, 6.30)NAGS-3310070.60(0.53, 0.69)1.04(0.90, 1.20)NADarunavir/ritonavir800/100 once daily90 once dailyND23ledipasvir1.45(1.34, 1.56)1.39(1.28, 1.49)1.39(1.29, 1.51)ND400 single dose18sofosbuvir1.45(1.10, 1.92)1.34(1.12, 1.59)NAGS-3310070.97(0.90, 1.05)1.24(1.18, 1.30)NADarunavir/ritonavir emtricitabine/tenofovir DF 800/100 200/300 once daily90 once daily400 once daily23ledipasvir1.11(0.99, 1.24)1.12(1.00, 1.25)1.17(1.04, 1.31)sofosbuvir0.63(0.52, 0.75)0.73(0.65, 0.82)NAGS-3310071.10(1.04, 1.16)1.20(1.16, 1.24)1.26(1.20, 1.32)Efavirenz/emtricitabine/tenofovir DFAdministered as ATRIPLA(TM) (efavirenz, emtricitabine, tenofovir DF). 600/200/300 once daily90 once daily400 once daily14ledipasvir0.66(0.59, 0.75)0.66(0.59, 0.75)0.66(0.57, 0.76)sofosbuvir1.03(0.87, 1.23)0.94(0.81, 1.10)NAGS-3310070.86(0.76, 0.96)0.90(0.83, 0.97)1.07(1.02, 1.13)Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide150/150/200/10 once daily90 once daily400 once daily30ledipasvir1.65(1.53, 1.78)1.79(1.64, 1.96)1.93(1.74, 2.15)sofosbuvir1.28(1.13, 1.47)1.47(1.35,1.59)NAGS-3310071.29(1.24, 1.35)1.48(1.44, 1.53)1.66(1.60, 1.73)Famotidine40 single dose simultaneously with HARVONI90 single dose400 single dose12ledipasvir0.80(0.69, 0.93)0.89(0.76, 1.06)NAsofosbuvir1.15(0.88, 1.50)1.11(1.00, 1.24)NAGS-3310071.06(0.97, 1.14)1.06(1.02, 1.11)NA40 single dose 12 hours prior to HARVONI12ledipasvir0.83(0.69, 1.00)0.98(0.80, 1.20)NAsofosbuvir1.00(0.76, 1.32)0.95(0.82, 1.10)NAGS-3310071.13(1.07, 1.20)1.06(1.01, 1.12)NAMethadone30 to 130 dailyND400 once daily14sofosbuvir0.95(0.68, 1.33)1.30(1.00, 1.69)NAGS-3310070.73(0.65, 0.83)1.04(0.89, 1.22)NAOmeprazole20 once daily simultaneously with HARVONI 90 single dose400 single dose16ledipasvir0.89(0.61, 1.30)0.96(0.66, 1.39)NAsofosbuvir1.12(0.88, 1.42)1.00(0.80, 1.25)NAGS-3310071.14(1.01, 1.29)1.03(0.96, 1.12)NA20 once daily hours prior to ledipasvir30 single doseND17ledipasvir0.52(0.41, 0.66)0.58(0.48, 0.71)NARifabutin300 once dailyND400 single dose20sofosbuvir0.64 (0.53, 0.77)0.76 (0.63, 0.91)NAGS-3310071.15 (1.03, 1.27)1.03 (0.95, 1.12)NARifampin600 once daily90 single doseThis study was conducted in the presence of two other investigational HCV direct-acting agents. ND31ledipasvir0.65(0.56, 0.76)0.41(0.36, 0.48)NAND400 single dose17sofosbuvir0.23(0.19, 0.29)0.28(0.24, 0.32)NAGS-3310071.23(1.14, 1.34)0.95(0.88, 1.03)NASimeprevir150 once daily30 once dailyND22ledipasvir1.81(1.69, 2.94)1.92(1.77, 2.07)NATacrolimus5 single doseND400 single dose16sofosbuvir0.97(0.65, 1.43)1.13(0.81, 1.57)NAGS-3310070.97(0.83, 1.14)1.00(0.87, 1.13)NANo effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with raltegravir and the combination of abacavir and lamivudine; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine, and tenofovir disoproxil fumarate. Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table [see Drug Interactions (7)]. Table 8Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or HARVONIAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Ledipasvir Dose (mg)Sofosbuvir Dose (mg)NMean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or HARVONINo Effect=1.00Cmax AUCCmin NA not available/not applicable, ND not dosed.tenofovir DF tenofovir disoproxil fumarateAtazanavir/ritonavir emtricitabine /tenofovir DFData generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir emtricitabine/tenofovir DF or darunavir/ritonavir emtricitabine/tenofovir DF and HARVONI provided similar results. The effects of HARVONI on atazanavir and ritonavir are similar with or without the presence of emtricitabine/tenofovir DF. This magnitude of change in tenofovir exposure does not reflect the approximately 60-80% increase caused by the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130% higher when administered as tenofovir DF atazanavir/ritonavir HARVONI or tenofovir DF darunavir/ritonavir HARVONI and with food as compared to the tenofovir exposure observed following fasted administration of tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and HARVONI. atazanavir 300 once daily90 once daily400 once daily241.07(0.99, 1.14)1.27(1.18, 1.37)1.63(1.45, 1.84)ritonavir 100 once daily0.86(0.79, 0.93)0.97(0.89, 1.05)1.45(1.27, 1.64)tenofovir DF 300 once daily1.47(1.37, 1.58)1.35(1.29, 1.42)1.47(1.38, 1.57)Darunavir/ritonavir emtricitabine/tenofovir DF darunavir 800 once daily90 once daily400 once daily231.01(0.96, 1.06)1.04(0.99, 1.08)1.08(0.98, 1.20)ritonavir 100 once daily1.17(1.01, 1.35)1.25(1.15, 1.36)1.48(1.34, 1.63)tenofovir DF 300 once daily1.64(1.54, 1.74)1.50(1.42, 1.59)1.59(1.49, 1.70)Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamideelvitegravir 150 once daily90 once daily400 once daily300.98(0.90, 1.07)1.11(1.02, 1.20)1.46(1.28, 1.66)cobicistat 150 once daily1.23(1.15, 1.32)1.53(1.45, 1.62)3.25(2.88, 3.67)tenofovir alafenamide 10 once daily0.90(0.73, 1.11)0.86(0.78, 0.95)NANorelgestrominnorgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily90 once dailyND151.02(0.89, 1.16)1.03(0.90, 1.18)1.09(0.91, 1.31)ND400 once daily1.07(0.94, 1.22)1.06(0.92, 1.21)1.07(0.89, 1.28)Norgestrel90 once dailyND1.03(0.87, 1.23)0.99(0.82, 1.20)1.00(0.81, 1.23)ND400 once daily1.18(0.99, 1.41)1.19(0.98, 1.45)1.23(1.00, 1.51)Ethinyl estradiol90 once dailyND1.40(1.18, 1.66) 1.20(1.04, 1.39) 0.98(0.79, 1.22) ND400 once daily1.15(0.97, 1.36)1.09(0.94, 1.26)0.99(0.80, 1.23)Midazolam2.5 single dose90 single doseND301.07 (1.00, 1.14)0.99 (0.95, 1.04)NA0.95 (0.87, 1.04)0.89 (0.84, 0.95)NARaltegravir400 twice daily90 once dailyND280.82(0.66, 1.02)0.85(0.70, 1.02)1.15(0.90, 1.46)ND400 single dose190.57(0.44, 0.75)0.73(0.59, 0.91)0.95(0.81, 1.12)Simeprevir150 once daily30 once dailyND222.61(2.39, 2.86)2.69(2.44, 2.96)NATacrolimus5 single doseND400 single dose160.73(0.59, 0.90)1.09(0.84, 1.40)NATenofovir DF300 once dailyAdministered as ATRIPLA (efavirenz, emtricitabine, tenofovir DF). The effects of HARVONI on tenofovir exposures are similar when tenofovir is administered as ATRIPLA, COMPLERA, or TRUVADA dolutegravir. 90 once daily400 once daily151.79(1.56, 2.04)1.98(1.77, 2.23)2.63(2.32, 2.97)No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.. 12.4 Microbiology. Mechanism of ActionLedipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as chain terminator. In biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and 4a with IC50 values of 3.3 and 2.7 microM, respectively. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.. Antiviral ActivityIn HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates from treatment-naive HCV-infected subjects were 0. 02 nM for genotype 1a (range 0.007-1.0 nM; N=23) and 0.006 nM for genotype 1b (range 0.002-1.0 nM; N=34). Ledipasvir had median EC50 values ranging between 0.002 nM to 0.16 nM against 11 genotype subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The median EC50 value for subtype 4b was 199.6 nM (range 0.66-1799 nM; N=3); the two 4b isolates with EC50 values greater than 100 nM had NS5A resistance-associated polymorphisms L30S+M31M+P58S+Y93H. The median EC50 value of ledipasvir was 0.03 nM against genotype 5a isolates (range 0.008-0.081 nM; N=35). For genotype 6, the EC50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC50 values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the median EC50 values ranged from 60.6 nM to 430.1 nM.In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 5a or 6a ranged from 14-110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29-128 nM; N=67) and 102 nM for genotype 1b (range 45-170 nM; N=29). In replication competent virus assays, the EC50 value of sofosbuvir against genotype 1a was 30 nM. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.. Resistance. In Cell CultureHCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a, conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 1000-fold).HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype and replicons. Site-directed mutagenesis of the S282T substitution in replicons of genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials. Genotype 1In pooled analysis of subjects who received HARVONI in Phase trials (ION-3, ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and with genotype 1b HCV) qualified for resistance analysis due to virologic failure (35 with virologic relapse, with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep nucleotide sequence analysis data (assay sensitivity of 1%) were available for 37/37 and 36/37 subjects viruses, respectively.Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects viruses also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M.Of the genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from three of these subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H.At failure, 38% (14/37) of virologic failure subjects viruses had or more NS5A substitutions at resistance-associated positions.In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), there were 24 virologic failures with genotype infection (20 relapsers and subjects who discontinued treatment prior to achieving HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions K24R, M28T, Q30R/H/K, L31V, H58D/P, and/or Y93H/C were detected in 14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M, and/or Y93H/N were detected in 6/7 (86%) genotype 1b virologic failure subjects.In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to ledipasvir.Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with sofosbuvir failure were detected in the Phase trials (ION-3, ION-1, and ION-2). In addition, treatment-emergent NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV genotype 1a. The D61G substitution was previously described in subjects infected with HCV genotype 1a in liver pre-transplant trial. The E237G substitution was detected in subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2 trials. The clinical significance of these substitutions is currently unknown. The sofosbuvir-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the Phase trials. NS5B substitutions S282T, L320V/I, and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following weeks of treatment with HARVONI in Phase trial. Genotype 4, or 6Resistance analysis was performed for relapse subjects infected with HCV genotype (Study 1119 and ION-4, N=3), genotype (Study 1119, N=2) or genotype (ELECTRON-2, N=1) and treated with HARVONI for 12 weeks. All the relapse subjects with NS5A sequencing data (5 of 6) had pretreatment NS5A resistance-associated polymorphisms (single or combinations at positions 24, 28, 30, 31, and 58). NS5A resistance substitutions (Y93C or L28V) emerged in two of the genotype relapse subjects post-treatment who also had NS5A polymorphisms pretreatment that were retained post-treatment. Two of the relapsers with genotype HCV infection had an NS5B V321I substitution pretreatment, which was retained post-treatment. Three of the relapse subjects (1 each for genotype 4, 5, and 6) had virus with emergent sofosbuvir resistance-associated substitution S282T at relapse; the genotype relapse subject also had emergent nucleotide inhibitor substitution M289I. Persistence of Resistance-Associated SubstitutionsNo data are available on the persistence of ledipasvir or sofosbuvir resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients. The long-term clinical impact of the emergence or persistence of virus containing ledipasvir or sofosbuvir resistance-associated substitutions is unknown.. Effect of Baseline HCV Polymorphisms on Treatment Response Adults. Genotype 1Analyses were conducted to explore the association between pre-existing baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the Phase trials, 23% (370/1589) of subjects virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population or analysis of deep nucleotide sequences with 15% frequency threshold. In treatment-naive subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6% (3/48) after weeks and 1% (1/113) after 12 weeks of treatment with HARVONI. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after weeks and 1% (3/306) after 12 weeks of treatment with HARVONI. In treatment-experienced subjects in Study ION-2 whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. In another study in treatment-experienced subjects (SIRIUS), 0/15 (0%) subjects with NS5A polymorphisms at resistance-associated positions relapsed after 12 weeks of treatment with HARVONI ribavirin compared to 2/15 (13%) subjects treated with 24 weeks of HARVONI. SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to sofosbuvir and/or other NS5B nucleoside inhibitors. The NS5B S282T substitution associated with resistance to sofosbuvir was not detected in the baseline NS5B sequence of any subject in Phase trials by population or deep nucleotide sequence analysis.In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), after 12 weeks of treatment with HARVONI and ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively. In the Phase trials and SOLAR trials, the specific baseline NS5A resistance-associated polymorphisms observed among subjects who relapsed were M28T/V, Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates.. Genotype 4, or 6Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study 1119 (N=44) and ION-4 (N=8) identified HCV genotype subtypes (4a, 4b, 4d, 4f, 4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d (N=11; 21%); to subjects were infected with each of the other genotype subtypes. There were subjects with subtype 4r, of whom experienced virologic relapse, and both had combination of pretreatment NS5A resistance-associated polymorphisms (L28M/V+L30R).Phylogenetic analysis of HCV sequences from genotype 5-infected subjects in Study 1119 showed almost all were subtype 5a (N=39) with one subject not having subtype identified at screening or by analysis.Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in ELECTRON-2 identified HCV genotype subtypes (6a, 6e, 6l, 6m, 6p, 6q, and 6r). Thirty-two percent of the subjects had subtype 6a and 24% had subtype 6e. One to three subjects were infected with the other subtypes 6l, 6m, 6p, 6q, or 6r. The one subject who did not achieve SVR12 had subtype 6l.Although the data are limited, baseline HCV NS5A resistance-associated polymorphisms are not expected to impact the likelihood of achieving SVR when HARVONI is used as recommended to treat HCV genotype 4, 5, or 6-infected patients, based on the low virologic failure rate observed in Study 1119 and ELECTRON-2. The specific baseline polymorphisms observed in subjects with virologic failure were L28M/V, L30R, and P58T for genotype 4; L31M for genotype 5; and Q24K, F28V, R30A, and T58P for genotype 6.Relapse occurred in of genotype subjects who had baseline NS5B V321I, polymorphism at position associated with treatment failure to sofosbuvir and other nucleoside inhibitors; these two subjects also had baseline NS5A resistance-associated polymorphisms. For genotype and 6, SVR12 was achieved in subjects who had baseline NS5B polymorphisms at positions associated with resistance to sofosbuvir and other nucleoside inhibitors (N=1 with N142T in genotype 5; N=1 with M289I in genotype 5; N=15 with M289L/I in genotype 6). The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject with genotype 4, 5, or HCV in clinical trials by population or deep nucleotide sequence analysis.. PediatricsIn Study 1116, the presence of NS5A and NS5B resistance-associated polymorphisms did not impact treatment outcome; all pediatric subjects 12 years of age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-associated polymorphisms (18%; 17/96) achieved SVR following 12 weeks treatment with HARVONI.. Cross Resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between ledipasvir and other NS5A inhibitors is expected. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of ledipasvir/sofosbuvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionLedipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as chain terminator. In biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and 4a with IC50 values of 3.3 and 2.7 microM, respectively. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.. Antiviral ActivityIn HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates from treatment-naive HCV-infected subjects were 0. 02 nM for genotype 1a (range 0.007-1.0 nM; N=23) and 0.006 nM for genotype 1b (range 0.002-1.0 nM; N=34). Ledipasvir had median EC50 values ranging between 0.002 nM to 0.16 nM against 11 genotype subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The median EC50 value for subtype 4b was 199.6 nM (range 0.66-1799 nM; N=3); the two 4b isolates with EC50 values greater than 100 nM had NS5A resistance-associated polymorphisms L30S+M31M+P58S+Y93H. The median EC50 value of ledipasvir was 0.03 nM against genotype 5a isolates (range 0.008-0.081 nM; N=35). For genotype 6, the EC50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC50 values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the median EC50 values ranged from 60.6 nM to 430.1 nM.In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 5a or 6a ranged from 14-110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29-128 nM; N=67) and 102 nM for genotype 1b (range 45-170 nM; N=29). In replication competent virus assays, the EC50 value of sofosbuvir against genotype 1a was 30 nM. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.. Resistance. In Cell CultureHCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b. Additionally, Q30E substitution emerged in genotype 1a replicons. Site-directed mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E substitution in genotype 1a, conferred high levels of reduced susceptibility to ledipasvir (fold change in EC50 greater than 1000-fold).HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype and replicons. Site-directed mutagenesis of the S282T substitution in replicons of genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials. Genotype 1In pooled analysis of subjects who received HARVONI in Phase trials (ION-3, ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and with genotype 1b HCV) qualified for resistance analysis due to virologic failure (35 with virologic relapse, with breakthrough on-treatment due to documented non-adherence). Post-baseline NS5A and NS5B deep nucleotide sequence analysis data (assay sensitivity of 1%) were available for 37/37 and 36/37 subjects viruses, respectively.Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects viruses also had baseline NS5A polymorphisms at resistance-associated amino acid positions. The most common substitutions detected at failure were Q30R, Y93H or N, and L31M.Of the genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from three of these subjects also had baseline NS5A polymorphisms at resistance-associated positions. The most common substitution detected at failure was Y93H.At failure, 38% (14/37) of virologic failure subjects viruses had or more NS5A substitutions at resistance-associated positions.In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), there were 24 virologic failures with genotype infection (20 relapsers and subjects who discontinued treatment prior to achieving HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions K24R, M28T, Q30R/H/K, L31V, H58D/P, and/or Y93H/C were detected in 14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M, and/or Y93H/N were detected in 6/7 (86%) genotype 1b virologic failure subjects.In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A resistance-associated substitutions at failure showed 20- to >243-fold reduced susceptibility to ledipasvir.Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously associated with sofosbuvir failure were detected in the Phase trials (ION-3, ION-1, and ION-2). In addition, treatment-emergent NS5B substitutions at highly conserved positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected at low frequency by next generation sequencing in treatment failure subjects infected with HCV genotype 1a. The D61G substitution was previously described in subjects infected with HCV genotype 1a in liver pre-transplant trial. The E237G substitution was detected in subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2 trials. The clinical significance of these substitutions is currently unknown. The sofosbuvir-associated resistance substitution S282T in NS5B was not detected in any failure isolate from the Phase trials. NS5B substitutions S282T, L320V/I, and V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected in one subject at failure following weeks of treatment with HARVONI in Phase trial. Genotype 4, or 6Resistance analysis was performed for relapse subjects infected with HCV genotype (Study 1119 and ION-4, N=3), genotype (Study 1119, N=2) or genotype (ELECTRON-2, N=1) and treated with HARVONI for 12 weeks. All the relapse subjects with NS5A sequencing data (5 of 6) had pretreatment NS5A resistance-associated polymorphisms (single or combinations at positions 24, 28, 30, 31, and 58). NS5A resistance substitutions (Y93C or L28V) emerged in two of the genotype relapse subjects post-treatment who also had NS5A polymorphisms pretreatment that were retained post-treatment. Two of the relapsers with genotype HCV infection had an NS5B V321I substitution pretreatment, which was retained post-treatment. Three of the relapse subjects (1 each for genotype 4, 5, and 6) had virus with emergent sofosbuvir resistance-associated substitution S282T at relapse; the genotype relapse subject also had emergent nucleotide inhibitor substitution M289I. Persistence of Resistance-Associated SubstitutionsNo data are available on the persistence of ledipasvir or sofosbuvir resistance-associated substitutions. NS5A resistance-associated substitutions for other NS5A inhibitors have been found to persist for >1 year in some patients. The long-term clinical impact of the emergence or persistence of virus containing ledipasvir or sofosbuvir resistance-associated substitutions is unknown.. Effect of Baseline HCV Polymorphisms on Treatment Response Adults. Genotype 1Analyses were conducted to explore the association between pre-existing baseline NS5A polymorphisms at resistance-associated positions and relapse rates. In the pooled analysis of the Phase trials, 23% (370/1589) of subjects virus had baseline NS5A polymorphisms at resistance-associated positions (any change from reference at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population or analysis of deep nucleotide sequences with 15% frequency threshold. In treatment-naive subjects whose virus had baseline NS5A polymorphisms at resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6% (3/48) after weeks and 1% (1/113) after 12 weeks of treatment with HARVONI. Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after weeks and 1% (3/306) after 12 weeks of treatment with HARVONI. In treatment-experienced subjects in Study ION-2 whose virus had baseline NS5A polymorphisms at resistance-associated positions, relapse rates were 22% (5/23) after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. In another study in treatment-experienced subjects (SIRIUS), 0/15 (0%) subjects with NS5A polymorphisms at resistance-associated positions relapsed after 12 weeks of treatment with HARVONI ribavirin compared to 2/15 (13%) subjects treated with 24 weeks of HARVONI. SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F; and N=3 with N142T) who had baseline polymorphisms associated with resistance to sofosbuvir and/or other NS5B nucleoside inhibitors. The NS5B S282T substitution associated with resistance to sofosbuvir was not detected in the baseline NS5B sequence of any subject in Phase trials by population or deep nucleotide sequence analysis.In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), after 12 weeks of treatment with HARVONI and ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively. In the Phase trials and SOLAR trials, the specific baseline NS5A resistance-associated polymorphisms observed among subjects who relapsed were M28T/V, Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates.. Genotype 4, or 6Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study 1119 (N=44) and ION-4 (N=8) identified HCV genotype subtypes (4a, 4b, 4d, 4f, 4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d (N=11; 21%); to subjects were infected with each of the other genotype subtypes. There were subjects with subtype 4r, of whom experienced virologic relapse, and both had combination of pretreatment NS5A resistance-associated polymorphisms (L28M/V+L30R).Phylogenetic analysis of HCV sequences from genotype 5-infected subjects in Study 1119 showed almost all were subtype 5a (N=39) with one subject not having subtype identified at screening or by analysis.Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in ELECTRON-2 identified HCV genotype subtypes (6a, 6e, 6l, 6m, 6p, 6q, and 6r). Thirty-two percent of the subjects had subtype 6a and 24% had subtype 6e. One to three subjects were infected with the other subtypes 6l, 6m, 6p, 6q, or 6r. The one subject who did not achieve SVR12 had subtype 6l.Although the data are limited, baseline HCV NS5A resistance-associated polymorphisms are not expected to impact the likelihood of achieving SVR when HARVONI is used as recommended to treat HCV genotype 4, 5, or 6-infected patients, based on the low virologic failure rate observed in Study 1119 and ELECTRON-2. The specific baseline polymorphisms observed in subjects with virologic failure were L28M/V, L30R, and P58T for genotype 4; L31M for genotype 5; and Q24K, F28V, R30A, and T58P for genotype 6.Relapse occurred in of genotype subjects who had baseline NS5B V321I, polymorphism at position associated with treatment failure to sofosbuvir and other nucleoside inhibitors; these two subjects also had baseline NS5A resistance-associated polymorphisms. For genotype and 6, SVR12 was achieved in subjects who had baseline NS5B polymorphisms at positions associated with resistance to sofosbuvir and other nucleoside inhibitors (N=1 with N142T in genotype 5; N=1 with M289I in genotype 5; N=15 with M289L/I in genotype 6). The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B sequence of any subject with genotype 4, 5, or HCV in clinical trials by population or deep nucleotide sequence analysis.. PediatricsIn Study 1116, the presence of NS5A and NS5B resistance-associated polymorphisms did not impact treatment outcome; all pediatric subjects 12 years of age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-associated polymorphisms (18%; 17/96) achieved SVR following 12 weeks treatment with HARVONI.. Cross Resistance Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between ledipasvir and other NS5A inhibitors is expected. Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of ledipasvir/sofosbuvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below and elsewhere in labeling:Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2)]. Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2)]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with HARVONI were fatigue, headache and asthenia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at safetyfcgilead.com or US FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.If HARVONI is administered with ribavirin to adults, refer to the prescribing information for ribavirin for description of ribavirin-associated adverse reactions.. Clinical Trials in Adult SubjectsThe safety assessment of HARVONI was based on pooled data from three randomized, open-label Phase clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received HARVONI once daily by mouth for 8, 12 and 24 weeks, respectively [see Clinical Studies (14)]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and 24 weeks, respectively. The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI. Table lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks treatment with HARVONI in clinical trials. The majority of adverse reactions presented in Table occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.Table 3Adverse Reactions (All Grades) Reported in >=5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with HARVONIHARVONI8 weeksN=215HARVONI12 weeksN=539HARVONI24 weeksN=326Fatigue16%13%18%Headache11%14%17%Nausea6%7%9%Diarrhea4%3%7%Insomnia3%5%6%The safety assessment of HARVONI was also based on pooled data from three open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3)]. The subjects received HARVONI once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype infection with compensated liver disease. The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%).. Adverse Reactions in Subjects with CirrhosisThe safety assessment of HARVONI with or without ribavirin was based on randomized, double-blind and placebo-controlled trial in treatment-experienced genotype subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial. Subjects were randomized to receive 24 weeks of HARVONI once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once daily by mouth ribavirin [see Clinical Studies (14.2)]. Table presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table were Grade or in severity. Table 4Adverse Reactions with >=5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving HARVONI for 24 Weeks or HARVONI Ribavirin for 12 Weeks Compared to Placebo for 12 weeks HARVONI24 weeks(N=78)HARVONI RBV12 weeks(N=76)Placebo12 weeks(N=77)RBV ribavirinAsthenia31%36%23%Headache29%13%16%Fatigue18%4%1%Cough5%11%1%Myalgia9%4%0Dyspnea3%9%1%Irritability8%7%1%Dizziness5%1%0. Adverse Reactions in Subjects Coinfected with HIV-1The safety assessment of HARVONI was based on an open-label clinical trial in 335 genotype or subjects with HCV/HIV-1 coinfection who were on stable antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%).. Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated CirrhosisThe safety assessment of HARVONI with ribavirin in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase open-label clinical trials including 336 subjects who received HARVONI plus ribavirin for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials [see Clinical Studies (14.5)]. The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of HARVONI and/or ribavirin.Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with HARVONI plus ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with HARVONI plus RBV for 12 weeks.. Liver Transplant Recipients with Compensated Liver Disease:Among the 174 liver transplant recipients with compensated liver disease who received HARVONI with ribavirin for 12 weeks, (1%) subjects permanently discontinued HARVONI due to an adverse event. Subjects with Decompensated Liver Disease:Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received HARVONI with ribavirin for 12 weeks, (4%) subjects died, (2%) subjects underwent liver transplantation, and subject (<1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment. Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. total of (2%) subjects permanently discontinued HARVONI due to an adverse event. Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The following adverse reactions occurred in less than 5% of subjects receiving HARVONI in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness).Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and suicide have occurred in less than 1% of subjects treated with sofosbuvir in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.. Laboratory Abnormalities Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in 3%, less than 1%, and 2% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively. Bilirubin elevations of greater than 1.5xULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, HARVONI ribavirin for 12 weeks and HARVONI for 24 weeks, respectively, in the SIRIUS trial.. Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN were observed in less than 1%, 2%, and 3% of subjects treated with HARVONI for 8, 12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in 1%, 3%, and 9% of subjects with compensated cirrhosis treated with placebo, HARVONI ribavirin for 12 weeks, and HARVONI for 24 weeks, respectively, in the SIRIUS trial.. Creatine Kinase: Creatine kinase was not assessed in Phase trials ION-3, ION-1, or ION-2 of HARVONI. Creatine kinase was assessed in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10xULN was observed in 1% of subjects treated with HARVONI for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials.. Adverse Reactions in Adults with Severe Renal Impairment, Including those on DialysisIn an open-label trial (Trial 0154) in which adults with HCV with compensated liver disease (with or without cirrhosis) and severe renal impairment received HARVONI for 12 weeks (N=18), the most common adverse reaction was fatigue (17%) [see Clinical Studies (14.6)]. In an open-label clinical trial, Trial 4063, total of 95 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received HARVONI for (n=45), 12 (n=31), or 24 (n=19) weeks. The most common adverse reactions were insomnia and headache (each reported in 4% of subjects overall) [see Clinical Studies (14.6)]. Adverse Reactions in Pediatric Subjects 12 Years of Age and OlderThe safety assessment of HARVONI in pediatric subjects 12 years of age and older is based on data from Phase 2, open-label clinical trial (Study 1116) that enrolled 100 subjects without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 weeks. The adverse reactions observed were consistent with those observed in clinical studies of HARVONI in adults. Limited safety data are available in pediatric subjects receiving HARVONI for 24 weeks. No Grade or adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving HARVONI for 24 weeks [see Clinical Studies (14.6)].. 6.2Postmarketing Experience. The following adverse reactions have been identified during post approval use of HARVONI. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Cardiac DisordersSerious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with HARVONI [see Warnings and Precautions (5.2), Drug Interactions (7.2)]. Skin and Subcutaneous Tissue DisordersSkin rashes, sometimes with blisters or angioedema-like swellingAngioedema.

BOXED WARNING SECTION.

WARNING: RISK OF HEPATITIS VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV. Test all patients for evidence of current or prior hepatitis virus (HBV) infection before initiating treatment with HARVONI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)]. WARNING: RISK OF HEPATITIS VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBVSee full prescribing information for complete boxed warning.Hepatitis virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and Mutagenesis. Ledipasvir: Ledipasvir was not genotoxic in 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 6-month rasH2 transgenic mouse study (up to 300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in 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 times, respectively, higher than the exposure in humans at the recommended human dose (RHD). Sofosbuvir: Sofosbuvir was not genotoxic in 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 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately and 18 times (in mice) and 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 times the exposure in humans at the RHD. At the highest dose levels without effects, exposures of ledipasvir were approximately and 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 times the exposure in humans at the RHD.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Description of Clinical Trials. The efficacy and safety of HARVONI were evaluated in four trials in genotype HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A), one trial in genotype or HCV/HIV-1 coinfected subjects, two trials in genotype 4, 5, or HCV mono-infected subjects, two trials in genotype or HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh 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 HCV pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table [see Clinical Studies (14.2, 14.3, 14.4, 14.5, and 14.6)]: Table 9Trials Conducted with HARVONI with or without Ribavirin in Subjects with Chronic HCV Genotype 1, 4, or InfectionTrialPopulationStudy Arms(Number of Subjects Treated)ESRD= End stage renal disease; RBV= ribavirin; RI= Renal impairment; TN: Treatment-naive subjects.ION-3Open-label. (NCT01851330)GT1, TN without cirrhosisHARVONI weeks (215)HARVONI RBV weeks (216)HARVONI 12 weeks (216)ION-1 (CT01701401)GT1, TN with or without cirrhosisHARVONI 12 weeks (214)HARVONI RBV 12 weeks (217)HARVONI 24 weeks (217)HARVONI RBV 24 weeks (217)ION-2 (NCT01768286)GT1, TETE Treatment-experienced subjects including those who have failed peginterferon alfa RBV- based regimen with or without an HCV protease inhibitor. with or without cirrhosisHARVONI 12 weeks (109)HARVONI RBV 12 weeks (111)HARVONI 24 weeks (109)HARVONI RBV 24 weeks (111)SIRIUSDouble-blind, placebo-controlled. (NCT01965535)GT1, TE with cirrhosisHARVONI RBV 12 Weeks (77)HARVONI 24 weeks (77)ION-4 (NCT20273656)GT1 and GT4 HCV/HIV-1 coinfectedTN and TE with or without cirrhosisHARVONI 12 Weeks(N=327 for GT1; N=8 for GT4)Study 1119 (NCT02081079)GT4 and GT5, TN and TE with or without cirrhosisHARVONI 12 Weeks(N=44 for GT4; N=41 for GT5)ELECTRON-2 (NCT01829681)GT6, TN and TE with or without cirrhosisHARVONI 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 FCHHARVONI RBV 12 Weeks (336)HARVONI RBV 24 weeks (334)Study 1116 (NCT02249182)GT1 with or without cirrhosis in pediatric subjects12 years of age and olderHARVONI 12 Weeks (100)0154 (NCT01958281)GT1 TN and TE with severe RI without dialysisHARVONI 12 weeks (18)4063 (NCT03036839)GT1, 5, or TN and TETE Treatment- experienced subjects including those who have failed either interferon/peginterferon alfa/ribavirin-based regiments or HCV-specific direct-acting antiviral regimens that do not include an NS5A polymerase inhibitor. with or without compensated cirrhosis, with ESRD requiring dialysisHARVONI 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 test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.. 14.2Clinical Trials in Subjects with Genotype HCV. Treatment-Naive Adults without Cirrhosis ION-3 (Study 0108)ION-3 was randomized, open-label trial in treatment-naive non-cirrhotic subjects with genotype HCV. Subjects were randomized in 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for weeks, HARVONI for 12 weeks, or HARVONI ribavirin for weeks.Demographics and baseline characteristics were balanced across the treatment groups. Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV infection; 73% had non-C/C IL28B alleles (CT or TT).Table 10 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the SVR12 observed with HARVONI. Therefore, the HARVONI ribavirin arm is not presented in Table 10.Table 10Study ION-3: SVR12 after and 12 Weeks of Treatment in Treatment-Naive Non-Cirrhotic Subjects with Genotype HCVHARVONI8 Weeks(N=215)HARVONI12 Weeks(N=216)SVR1294% (202/215)96% (208/216)Outcome for Subjects without SVR On-Treatment Virologic Failure 0/2150/216 RelapseThe denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. 5% (11/215)1% (3/216) OtherOther includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up). 1% (2/215)2% (5/216)SVR by GenotypeOne subject without confirmed subtype for genotype infection was excluded from this subgroup analysis. Genotype 1a 93% (159/171)96% (165/172) Genotype 1b98% (42/43)98% (43/44)The treatment difference between the 8-week treatment of HARVONI and 12-week treatment of HARVONI was -2.3% (97.5% confidence interval -7.2% to 2.5%). Among subjects with baseline HCV RNA less than million IU per mL, the SVR12 was 97% (119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week treatment of HARVONI. Relapse rates by baseline viral load are presented in Table 11.Table 11Study ION-3: Relapse Rates by Baseline Viral Load after and 12 Weeks of Treatment in Treatment-Naive Non-Cirrhotic Subjects with Genotype HCVHARVONI8 Weeks(N=215)HARVONI12 Weeks(N=216)Number of Responders at End of Treatment215216Baseline HCV RNAHCV RNA values were determined using the Roche TaqMan Assay; subjects HCV RNA may vary from visit to visit. HCV RNA <6 million IU/mL2% (2/123)2% (2/131) HCV RNA >=6 million IU/mL10% (9/92)1% (1/85). Treatment-Naive Adults with or without Cirrhosis ION-1 (Study 0102)ION-1 was randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in 865 treatment-naive subjects with genotype HCV including those with cirrhosis. Subjects were randomized in 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 1b). Demographics and baseline characteristics were balanced across the treatment groups. Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.Table 12 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the ION-1 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI ribavirin arm is not presented in Table 12.Table 12Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naive Subjects with Genotype HCV with and without CirrhosisHARVONI 12 Weeks(N=214)SVR12Excluding one subject with genotype infection. 99% (210/213)Outcome for Subjects without SVR On-Treatment Virologic Failure 0/213 Relapse The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. <1% (1/212) Other Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 1% (2/213)SVR12 for selected subgroups are presented in Table 13.Table 13Study ION-1: SVR12 for Selected Subgroups after 12 Weeks of Treatment in Treatment-Naive Subjects with Genotype HCV with and without CirrhosisHARVONI 12 Weeks(N=214)GenotypeOne subject without confirmed subtype for genotype infection and one subject with genotype infection were excluded from this subgroup analysis. Genotype 1a 98% (142/145) Genotype 1b100% (67/67)CirrhosisSubjects with missing cirrhosis status were excluded from this subgroup analysis. No99% (176/177) Yes94% (32/34). Previously-Treated Adults with or without Cirrhosis ION-2 (Study 0109)ION-2 was randomized, open-label trial that evaluated 12 and 24 weeks of treatment with HARVONI with or without ribavirin in genotype HCV-infected subjects with or without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. Subjects were randomized in 1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI ribavirin for 24 weeks. Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV therapy (relapse/breakthrough vs nonresponse).Demographics and baseline characteristics were balanced across the treatment groups. Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty-seven percent (47%) of the subjects failed prior therapy of pegylated interferon and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were non-responder. Fifty-three percent (53%) of the subjects failed prior therapy of pegylated interferon and ribavirin with an HCV protease inhibitor. Among these subjects, 62% were relapse/breakthrough and 38% were non-responder.Table 14 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the HARVONI ribavirin arms are not presented in Table 14.Table 14Study ION-2: SVR12 after 12 and 24 Weeks of Treatment in Subjects with Genotype HCV with or without Cirrhosis Who Failed Prior TherapyHARVONI12 Weeks(N=109)HARVONI24 Weeks(N=109)SVR1294% (102/109)99% (108/109)Outcome for Subjects without SVR On-Treatment Virologic Failure0/1090/109 RelapseThe denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. 6% (7/108)0/109 OtherOther includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). 0/1091% (1/109)Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in the ION-2 study also achieved SVR24. SVR12 and relapse rates for selected subgroups are presented in Tables 15 and 16.Table 15Study ION-2: SVR12 for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype HCV Who Failed Prior TherapyHARVONI12 Weeks(N=109)HARVONI24 Weeks(N=109)RBV ribavirinGenotype Genotype 1a95% (82/86)99% (84/85) Genotype 1b87% (20/23)100% (24/24)CirrhosisSubjects with missing cirrhosis status were excluded from this subgroup analysis. No95% (83/87)99% (85/86) Yes86% (19/22)100% (22/22)Prior HCV Therapy Peg-IFN RBV93% (40/43)100% (58/58) HCV protease inhibitor Peg-IFN RBV94% (62/66)98% (49/50)Response to Prior HCV Therapy Relapse/Breakthrough95% (57/60)100% (60/60) Non-responder92% (45/49)98% (48/49)Table 16Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24 Weeks of Treatment in Subjects with Genotype HCV Who Failed Prior TherapyHARVONI12 Weeks(N=109)HARVONI24 Weeks(N=109)Number of Responders at End of Treatment108109CirrhosisSubjects with missing cirrhosis status were excluded from this subgroup analysis. No5% (4/86)These non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. 0% (0/86) Yes14% (3/22)0% (0/22)Presence of Baseline NS5A Resistance-Associated PolymorphismsNS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93. No2% (2/85)0% (0/90) Yes22% (5/23)0% (0/19)IL28B Status C/C0% (0/10)0% (0/16) Non-C/C7% (7/98)0% (0/93). Previously-Treated Adults with Cirrhosis SIRIUS (Study 0121)SIRIUS was randomized, double-blind and placebo-controlled trial that evaluated the efficacy of HARVONI ribavirin for 12 weeks or HARVONI without ribavirin for 24 weeks in genotype HCV-infected subjects with compensated cirrhosis who failed prior therapy with Peg-IFN ribavirin regimen followed by subsequent Peg-IFN ribavirin an HCV protease inhibitor regimen. Subjects were randomized in 1:1 ratio to receive placebo for 12 weeks followed by HARVONI ribavirin for 12 weeks or HARVONI for 24 weeks. Randomization was stratified by HCV genotype (1a vs 1b) and response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved HCV RNA less than LLOQ).Demographics and baseline characteristics were balanced across the treatment groups. Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74% of the subjects were male; 97% were White; mean body mass index was 27 kg/m2 (range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B alleles (CT or TT). One subject discontinued therapy while on placebo, and was not included in the efficacy analysis.The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively. All subjects who did not achieve SVR12 relapsed.. 14.3Clinical Trials in Subjects with Genotype 4, 5, or HCV. Below are trial descriptions, SVR12, and relapse data in the genotype 4, 5, and HCV populations. Trial results in the genotype 4, 5, and HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously-treated and subjects with cirrhosis. Genotype 4In two open-label studies (Study 1119 and ION-4), HARVONI was administered for 12 weeks to treatment-naive and previously-treated adult subjects with genotype HCV infection. Study 1119 enrolled 44 treatment-naive or previously-treated subjects with genotype HCV, with or without cirrhosis. ION-4 enrolled treatment-naive and previously- treated subjects with genotype HCV infection who were coinfected with HIV-1, none of whom had cirrhosis. In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. In ION-4, all subjects achieved SVR12.. Genotype 5In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment-naive or previously- treated adult subjects with genotype HCV infection, with or without cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. Genotype 6In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to 25 treatment-naive or previously- treated adult subjects with genotype HCV infection, with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar based upon prior HCV treatment history and cirrhosis status. The single subject who relapsed discontinued study treatment early (at approximately Week 8).. 14.4Clinical Trials in Subjects Coinfected with HCV and HIV-1. ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with HARVONI without ribavirin in HCV treatment-naive and previously-treated adult subjects with genotype or HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN ribavirin, Peg-IFN ribavirin an HCV protease inhibitor, or sofosbuvir ribavirin. Subjects were on stable HIV-1 antiretroviral therapy that included emtricitabine tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had genotype infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-experienced.Table 17 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment. Table 17Study ION-4: SVR12 in Subjects with Genotype or HCV Coinfected with HIV-1HARVONI 12 Weeks(N=335)SVR1296% (321/335)Outcome for Subjects without SVR On-Treatment Virologic Failure <1% (2/335) RelapseThe denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment. 3% (10/333) OtherOther includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow-up). <1% (2/335)SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously- treated and had cirrhosis. The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not change during treatment. Median CD4+ cell count increase of 29 cells/mm3 was observed at the end of treatment with HARVONI for 12 weeks.. 14.5Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with HARVONI in combination with ribavirin in HCV treatment-naive and previously- treated adult subjects with genotype and infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 16). Subjects with CPT score greater than 12 were excluded. Within each group, subjects were randomized in 1:1 ratio to receive HARVONI ribavirin for 12 weeks or HARVONI ribavirin for 24 weeks. 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 [see Clinical Studies (14.1)].Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had genotype and HCV infection, respectively; 78% of the subjects failed prior HCV therapy. Table 18 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype HCV treated with HARVONI ribavirin for 12 weeks. The SVR12 rates observed with 24 weeks of HARVONI ribavirin were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the HARVONI ribavirin 24 weeks arm are not presented in Table 18.Table 18Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After 12 Weeks of Treatment with HARVONI and Ribavirin in Subjects with Genotype HCV Who Were Post Liver Transplant and/or Who Had Decompensated Liver DiseaseHARVONI RBV 12 weeksN=307SVR12 (N=300)Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to transplant were excluded. Two subjects were excluded due to failure to meet the inclusion criteria for any of the treatment groups (i.e., did not have decompensated cirrhosis and had also not received liver transplant). Relapse (N=288) , Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior to reaching the 12-week post-treatment follow-up visit. Pre-transplant CPT B87% (45/52)12% (6/51) CPT C88% (35/40)5% (2/37)Post-transplant Metavir score F0-F395% (94/99)3% (3/97) CPT A98% (55/56)0% (0/55) CPT B89% (41/46)2% (1/42) CPT C57% (4/7)33% (2/6)There were subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm, and all subjects achieved SVR12.In genotype HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with HARVONI ribavirin for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented. 14.6Clinical Trials in Subjects with Severe Renal Impairment, Including those Requiring Dialysis. Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with HARVONI in 18 treatment-naive and treatment-experienced (subjects with prior exposure to an HCV NS5B polymerase inhibitor were excluded) genotype HCV-infected adults with severe renal impairment not requiring dialysis. At baseline, two subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6). The SVR rate was 100% (18/18).As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that evaluated 8, 12, and 24 weeks of treatment with HARVONI in total of 63 adults with chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years). The SVR rates for the 8, 12, and 24 week HARVONI treatment groups are shown in Table 19.Table 19 Trial 4063: SVR12 after 8, 12, and 24 Weeks of Treatment in Adults with HCV with or without Cirrhosis and with Severe Renal Impairment Requiring DialysisHARVONI Weeks (N=45)HARVONI 12 Weeks (N=12)HARVONI 24 Weeks (N=6)PopulationTreatment-naive, GT HCV Non-cirrhoticTreatment-naive and treatment-experiencedSubjects with prior exposure to an HCV NS5A inhibitor were excluded. GT 1, 5, 6One subject had an indeterminant HCV GT. HCV Non-cirrhoticTreatment-experience, GT HCV with compensated cirrhosisSVR1293% (42/45)100% (12/12)83% (5/6)Outcome for subjects without SVR On-treatment virologic failure0/450/120/6 Relapse0/440/120/6 OtherOther outcomes include subjects who did not achieve SVR and did not meet virologic failure criteria. All subjects who failed without virologic relapse or on-treatment virologice failure died prior to follow-up Week 12. None of these deaths were assessed as treatment-related. 7% (3/45)0/1217% (1/6). 14.7Clinical Trial in Pediatric Subjects. The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with HARVONI once daily in genotype HCV treatment-naive (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.HARVONI was evaluated in 100 subjects 12 years to <18 years of age with HCV genotype infection. Demographics and baseline characteristics were balanced across treatment-naive and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin). Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 91% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection. One subject (treatment-naive) had known compensated cirrhosis. The majority of subjects (84%) had been infected through vertical transmission.The SVR12 rate was 98% overall (98% [78/80] in treatment-naive subjects and 100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment virologic failure or relapse. Two subjects were lost to follow-up.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for list of contraindications for ribavirin [see Dosage and Administration (2.2)].. If used in combination with ribavirin, all contraindications to ribavirin also apply to HARVONI combination therapy. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. HARVONI is fixed-dose combination tablet containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is nucleotide analog inhibitor of HCV NS5B polymerase.Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.. Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2S)-1-(6S)-6-[5-(9,9-difluoro-7-2-[(1R,3S,4S)-2-(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl-2-azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl-3-methyl-1-oxobutan-2-yl]carbamate.It has molecular formula of C49H54F2N8O6 and molecular weight of 889.00. It has the following structural formula:Ledipasvir is practically insoluble (less than 0.1 mg/mL) across the pH range of 3.0-7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL).. Chemical Structure. Sofosbuvir: The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has molecular formula of C22H29FN3O9P and molecular weight of 529.45. It has the following structural formula:Sofosbuvir is white to off-white crystalline solid with solubility of at least mg/mL across the pH range of 2-7.7 at 37C and is slightly soluble in water.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1)Recommended adult and pediatric dosage: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. (2.2, 2.3)HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables below, respectively. (2.2, 2.3)If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. (2.2)Recommended adult treatment regimen and duration: (2.2)Adult Patient PopulationRegimen and DurationGenotype 1Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI12 weeksTreatment-experienced without cirrhosisHARVONI12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)HARVONI24 weeksTreatment-naive and treatment-experienced with decompensated cirrhosis (Child-Pugh or C)HARVONI ribavirin12 weeksGenotype or 4Treatment-naive and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A)HARVONI ribavirin12 weeksGenotype 4, 5, or 6Treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI12 weeksRecommended treatment duration for pediatric patients 12 years of age and older or weighing at least 35 kg. (2.3)Pediatric Patient Population 12 Years of Age and Older or Weighing at Least 35 KgRegimen and DurationGenotype 1Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI 12 weeksTreatment-experienced without cirrhosisHARVONI12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)HARVONI24 weeksGenotype 4, 5, or 6Treatment-naive and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI12 weeksFor patients with any degree of renal impairment including end stage renal disease on dialysis, no HARVONI dosage adjustment is recommended. (2.4). Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1). Recommended adult and pediatric dosage: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. (2.2, 2.3). HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables below, respectively. (2.2, 2.3). If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. (2.2). Recommended adult treatment regimen and duration: (2.2). Recommended treatment duration for pediatric patients 12 years of age and older or weighing at least 35 kg. (2.3). For patients with any degree of renal impairment including end stage renal disease on dialysis, no HARVONI dosage adjustment is recommended. (2.4). 2.1Testing Prior to the Initiation of Therapy. Test all patients for evidence of current or prior HBV infection by measuring hepatitis surface antigen (HBsAg) and hepatitis core antibody (anti-HBc) before initiating HCV treatment with HARVONI [see Warnings and Precautions (5.1)].. 2.2Recommended Dosage in Adults. The recommended dosage of HARVONI is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3)].Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14)]. Table shows the recommended HARVONI treatment regimen and duration based on patient population. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table [see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.Table 1Recommended Treatment Regimen and Duration for HARVONI in Adult Patients with Genotype 1, 4, 5, or HCVPatient PopulationTreatment Regimen and DurationGenotype 1Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI 12 weeksHARVONI for weeks can be considered in treatment-naive genotype patients without cirrhosis who have pretreatment HCV RNA less than million IU/mL [see Clinical Studies (14.2)] Treatment-experiencedTreatment-experienced patients have failed peginterferon alfa ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis HARVONI 12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)HARVONI 24 weeksHARVONI ribavirin for 12 weeks can be considered in treatment-experienced genotype patients with cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)] See footnote for ribavirin dosage recommendations. Treatment-naive and treatment-experienced with decompensated cirrhosis (Child-Pugh or C)HARVONI ribavirinIn patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those >=75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. 12 weeksGenotype or 4Treatment-naive and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A)HARVONI ribavirinThe daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those >=75 kg) administered orally in two divided doses with food. 12 weeksGenotype 4, 5, or 6Treatment-naive and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI 12 weeksFor further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Clinical Studies (14.5)].. 2.3Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg. The recommended dosage of HARVONI in pediatric patients 12 years of age and older or weighing at least 35 kg is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food for 12 weeks [see Clinical Pharmacology (12.3) and Clinical Studies (14.6)].Table shows the recommended HARVONI duration based on pediatric patient population. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table [see Use in Specific Populations (8.4)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.Table 2Recommended Regimen and Duration for HARVONI in Pediatric Patients 12 Years of Age or Older or Weighing at Least 35 kg with Genotype 1, 4, 5, or HCV without Cirrhosis or with Compensated CirrhosisPatient PopulationTreatment Regimen and DurationGenotype 1Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI 12 weeksTreatment-experiencedTreatment-experienced patients have failed an interferon based regimen with or without ribavirin. without cirrhosisHARVONI 12 weeksTreatment-experienced with compensated cirrhosis (Child-Pugh A)HARVONI 24 weeksGenotype 4, 5, or 6Treatment-naive and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)HARVONI 12 weeks. 2.4 Renal Impairment. No dosage adjustment of HARVONI is recommended in patients with any degree of renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage and Administration (2.3)]. Take HARVONI with or without ribavirin according to the recommendations in Table [see Adverse Reactions (6.1), Use in Specific Populations (8.6) and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. HARVONI is available as white colored, diamond shaped, film-coated tablet debossed with GSI on one side and 7985 on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.. Tablets: 90 mg ledipasvir and 400 mg sofosbuvir. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended. (5.2, 6.2, 7.2)P-gp inducers (e.g., rifampin, St. Johns wort): May alter concentrations of ledipasvir and sofosbuvir. Use of HARVONI with P-gp inducers is not recommended. (5.3, 7, 12.3)Consult the full prescribing information prior to use for potential drug interactions. (5.2, 5.3, 7, 12.3)Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. (7.2). Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended. (5.2, 6.2, 7.2). P-gp inducers (e.g., rifampin, St. Johns wort): May alter concentrations of ledipasvir and sofosbuvir. Use of HARVONI with P-gp inducers is not recommended. (5.3, 7, 12.3). Consult the full prescribing information prior to use for potential drug interactions. (5.2, 5.3, 7, 12.3). Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. (7.2). 7.1Potential for Drug Interaction. As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with HARVONI.After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses.Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters.Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin, St. Johns wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.3)].. 7.2Established and Potentially Significant Drug Interactions. Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.Table provides listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual agents, or are predicted drug interactions that may occur with HARVONI [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].Table 5Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted InteractionThis table is not all inclusive. Concomitant Drug Class: Drug NameEffect on Concentration decrease, increase Clinical Commenttenofovir DF tenofovir disoproxil fumarateAcid Reducing Agents: ledipasvirLedipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. Antacids (e.g., aluminum and magnesium hydroxide)It is recommended to separate antacid and HARVONI administration by hours.H2-receptor antagonistsThese interactions have been studied in healthy adults. (e.g., famotidine)H2-receptor antagonists may be administered simultaneously with or 12 hours apart from HARVONI at dose that does not exceed doses comparable to famotidine 40 mg twice daily.Proton-pump inhibitors (e.g., omeprazole)Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions. Antiarrhythmics:amiodaroneEffect on amiodarone, ledipasvir, and sofosbuvir concentrations unknownCoadministration of amiodarone with HARVONI may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with HARVONI is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2), Adverse Reactions (6.2)]. digoxin digoxinCoadministration of HARVONI with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with HARVONI.Anticonvulsants:carbamazepinephenytoinphenobarbital ledipasvir sofosbuvirCoadministration of HARVONI with carbamazepine, phenytoin, or phenobarbital is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.Antimycobacterials:rifabutinrifampinrifapentine ledipasvir sofosbuvirCoadministration of HARVONI with rifampin, rifabutin, or rifapentine is not recommended [see Warnings and Precautions (5.3)]. HIV Antiretrovirals:Regimens containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat tenofovirMonitor for tenofovir-associated adverse reactions in patients receiving HARVONI concomitantly with regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring.Regimens containing tenofovir DF and an HIV protease inhibitor/ritonavir or cobicistat atazanavir/ritonavir or cobicistat emtricitabine/tenofovir DF darunavir/ritonavir or cobicistat emtricitabine/tenofovir DF lopinavir/ritonavir emtricitabine/tenofovir DF tenofovirThe safety of increased tenofovir concentrations in the setting of HARVONI and an HIV protease inhibitor/ritonavir or cobicistat has not been established.Consider alternative HCV or antiretroviral therapy to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for recommendations on renal monitoring.elvitegravir, cobicistat, emtricitabine, tenofovir DF tenofovirThe safety of increased tenofovir concentrations in the setting of HARVONI and the combination of elvitegravir, cobicistat, emtricitabine and tenofovir DF has not been established. Coadministration is not recommended.tipranavir/ritonavir ledipasvir sofosbuvirCoadministration of HARVONI with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of HARVONI. Coadministration is not recommended.HCV Products:simeprevir ledipasvir simeprevir Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of HARVONI with simeprevir is not recommended.Herbal Supplements:St. Johns wort (Hypericum perforatum) ledipasvir sofosbuvirCoadministration of HARVONI with St. Johns wort, P-gp inducer, is not recommended [see Warnings and Precautions (5.3)]. HMG-CoA Reductase Inhibitors:rosuvastatin rosuvastatin Coadministration of HARVONI with rosuvastatin may significantly increase the concentration of rosuvastatin which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of HARVONI with rosuvastatin is not recommended.atorvastatin atorvastatinCoadministration of HARVONI with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.. atazanavir/ritonavir or cobicistat emtricitabine/tenofovir DF darunavir/ritonavir or cobicistat emtricitabine/tenofovir DF lopinavir/ritonavir emtricitabine/tenofovir DF. 7.3Drugs without Clinically Significant Interactions with HARVONI. Based on drug interaction studies conducted with the components of HARVONI (ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have been either observed or are expected when HARVONI is used with the following drugs [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table for use of HARVONI with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. If HARVONI is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical trials of HARVONI included 225 subjects aged 65 and over (9% of total number of subjects in the clinical studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. HARVONI tablets, 90 mg/400 mg, are white, diamond-shaped, film-coated, debossed with GSI on one side and 7985 on the other side of the tablet. Each bottle contains 28 tablets, silica gel desiccant, polyester coil, and is closed with child-resistant closure.. Store below 30 (86 F).Dispense only in original container.Do not use if seal over bottle opening is broken or missing.. Dispense only in original container.. Do not use if seal over bottle opening is broken or missing.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. HARVONI is fixed-dose combination of ledipasvir, hepatitis virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis virus (HCV) in:Adults with genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosisAdults with genotype infection with decompensated cirrhosis, in combination with ribavirin Adults with genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirinPediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or without cirrhosis or with compensated cirrhosis. (1). Adults with genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosis. Adults with genotype infection with decompensated cirrhosis, in combination with ribavirin Adults with genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin. Pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or without cirrhosis or with compensated cirrhosis. (1). Adult Patients:HARVONI is indicated for the treatment of adult patients with chronic hepatitis virus (HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]:genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosisgenotype infection with decompensated cirrhosis, for use in combination with ribavirin genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin. genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosis. genotype infection with decompensated cirrhosis, for use in combination with ribavirin genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin. Pediatric Patients:HARVONI is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosis [see Dosage and Administration (2.3) and Clinical Studies (14.6)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the approved patient labeling (Patient Information).. Risk of Hepatitis Virus Reactivation in Patients Coinfected with HCV and HBVInform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have history of HBV infection [see Warnings and Precautions (5.1)].. Serious Symptomatic Bradycardia When Coadministered with AmiodaroneAdvise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions (7.2)]. Drug InteractionsInform patients that HARVONI may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products including St. Johns wort [see Warnings and Precautions (5.2, 5.3) and Drug Interactions (7)]. PregnancyAdvise patients to avoid pregnancy during combination treatment with HARVONI and ribavirin and for months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of pregnancy [see Use in Specific Populations (8.1)].. Administration Advise patients to take HARVONI every day at the regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses and to take HARVONI for the duration that is recommended by the physician.

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. When administered to lactating rats, ledipasvir was detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk, without clear effects on nursing pups [see Data]. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. The development and health benefits of breastfeeding should be considered along with the mothers clinical need for HARVONI and any potential adverse effects on the breastfed child from HARVONI or from the underlying maternal condition. If HARVONI is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation.. Data. Ledipasvir: No effects of ledipasvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to ledipasvir was approximately times the exposure in humans at the RHD. Although not measured directly, ledipasvir was likely present in the milk of lactating rats, since systemic exposure (AUC) to ledipasvir of approximately 25% that of maternal exposure was observed in nursing pups on lactation day 10.. Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed hour post-dose.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and Mutagenesis. Ledipasvir: Ledipasvir was not genotoxic in 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 6-month rasH2 transgenic mouse study (up to 300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in 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 times, respectively, higher than the exposure in humans at the recommended human dose (RHD). Sofosbuvir: Sofosbuvir was not genotoxic in 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 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately and 18 times (in mice) and 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 times the exposure in humans at the RHD. At the highest dose levels without effects, exposures of ledipasvir were approximately and 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 times the exposure in humans at the RHD.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No specific antidote is available for overdose with HARVONI. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with HARVONI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 28 Tablet Bottle Label. 61958-1802-6 28 tablets Harvoni(TM) (ledipasvir, sofosbuvir) Tablets 90 mg 400 mg GILEAD ACCESS PROGRAMNote to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with Harvoni(TM). harvoni-03.jpg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype infection in treatment-naive and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-naive, 20 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of HARVONI for treatment of HCV genotypes 4, 5, or infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype and similar efficacy and exposures across HCV genotypes 1, 4, 5, and in adults [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3 and 14.6)].In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3)]. No data are available regarding the safety of HARVONI in pediatric patients with renal impairment [see Use in Specific Populations (8.6)].The safety and efficacy of HARVONI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThorough 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 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 randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe 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 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to hours post-dose.Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 nghr/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected subjects.. Effect of FoodRelative to fasting conditions, the administration of single dose of HARVONI with moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase trials were similar in HCV-infected subjects who received HARVONI with food or without food. HARVONI can be administered without regard to food.. DistributionLedipasvir is greater than 99.8% bound to human plasma proteins. After single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-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 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.. MetabolismIn 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 single dose of 90 mg [14C]-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 (CatA) or carboxylesterase (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein (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 single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. EliminationFollowing single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-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 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 major route of elimination, with renal excretion being minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of HARVONI was 47 hours.Following single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of HARVONI were 0.5 and 27 hours, respectively.. Specific Populations. Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007.. Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in females than males; however, the relationship between gender and ledipasvir exposures was not considered clinically relevant, as high response rates (SVR12 >90%) were achieved in male and female subjects across the Phase studies and the safety profiles are similar in females and males.. Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in 100 pediatric subjects 12 years of age and older infected with HCV genotype receiving daily dose of HARVONI (90 mg ledipasvir and 400 mg sofosbuvir). The pharmacokinetic properties of ledipasvir, sofosbuvir, and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 6. Exposures in pediatric subjects were similar to those observed in adults.Table 6Pharmacokinetic Properties of the Components of HARVONI in Pediatric Subjects 12 Years of Age and OlderPopulation PK derived parameters Geometric MeanLedipasvirLedipasvir N=100; Sofosbuvir N=72; GS-331007 N=100 Sofosbuvir GS-331007 AUCtau (nghr/mL)11200135013600Cmax (ng/mL)550660921The pharmacokinetics of ledipasvir or sofosbuvir have not been established in pediatric patients less than 12 years of age [see Use in Specific Populations (8.4), and Clinical Studies (14.6)].. Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007 [see Use in Specific Populations (8.5)].. Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied with single dose of 90 mg ledipasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed hour after hemodialysis, respectively. 4 hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected subjects with severe renal impairment or ESRD requiring dialysis treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent with those observed in HCV-negative subjects with ESRD requiring dialysis.. Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied with single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar in subjects with severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of ledipasvir [see Use in Specific Populations (8.7)]. The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and Clinical Studies (14.5)]. Drug Interaction StudiesLedipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. Johns wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not substrate for renal transporters, including organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2.Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro, no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary excretion of unchanged ledipasvir is major route of elimination. Sofosbuvir is not substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with HARVONI mediated by CYP or UGT1A1 enzymes are not expected.The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and GS-331007 are shown in Table [see Drug Interactions (7.2)]. Table 7Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug(mg)Ledipasvir Dose(mg)Sofosbuvir Dose(mg)NMean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered DrugNo Effect=1.00Cmax AUCCmin NA not available/not applicable, ND not dosed.tenofovir DF tenofovir disoproxil fumarateAtazanavir/ritonavir emtricitabine/tenofovir DFData generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir emtricitabine/tenofovir DF or darunavir/ritonavir emtricitabine/tenofovir DF and HARVONI provided similar results. The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of emtricitabine/tenofovir DF. 300/100 200/300 once daily90 once daily400 once daily24ledipasvir1.68(1.54, 1.84)1.96(1.74, 2.21)2.18(1.91, 2.50)sofosbuvir1.01(0.88, 1.15)1.11(1.02, 1.21)NAGS-3310071.17(1.12, 1.23)1.31(1.25, 1.36)1.42(1.34, 1.49)Carbamazepine300 twice dailyND400 single dose24sofosbuvir0.52 (0.43, 0.62)0.52 (0.46, 0.59)NAGS-3310071.04 (0.97, 1.11)0.99 (0.94. 1.04)NACyclosporine600 single doseND400 single dose19sofosbuvir2.54(1.87, 3.45)4.53(3.26, 6.30)NAGS-3310070.60(0.53, 0.69)1.04(0.90, 1.20)NADarunavir/ritonavir800/100 once daily90 once dailyND23ledipasvir1.45(1.34, 1.56)1.39(1.28, 1.49)1.39(1.29, 1.51)ND400 single dose18sofosbuvir1.45(1.10, 1.92)1.34(1.12, 1.59)NAGS-3310070.97(0.90, 1.05)1.24(1.18, 1.30)NADarunavir/ritonavir emtricitabine/tenofovir DF 800/100 200/300 once daily90 once daily400 once daily23ledipasvir1.11(0.99, 1.24)1.12(1.00, 1.25)1.17(1.04, 1.31)sofosbuvir0.63(0.52, 0.75)0.73(0.65, 0.82)NAGS-3310071.10(1.04, 1.16)1.20(1.16, 1.24)1.26(1.20, 1.32)Efavirenz/emtricitabine/tenofovir DFAdministered as ATRIPLA(TM) (efavirenz, emtricitabine, tenofovir DF). 600/200/300 once daily90 once daily400 once daily14ledipasvir0.66(0.59, 0.75)0.66(0.59, 0.75)0.66(0.57, 0.76)sofosbuvir1.03(0.87, 1.23)0.94(0.81, 1.10)NAGS-3310070.86(0.76, 0.96)0.90(0.83, 0.97)1.07(1.02, 1.13)Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide150/150/200/10 once daily90 once daily400 once daily30ledipasvir1.65(1.53, 1.78)1.79(1.64, 1.96)1.93(1.74, 2.15)sofosbuvir1.28(1.13, 1.47)1.47(1.35,1.59)NAGS-3310071.29(1.24, 1.35)1.48(1.44, 1.53)1.66(1.60, 1.73)Famotidine40 single dose simultaneously with HARVONI90 single dose400 single dose12ledipasvir0.80(0.69, 0.93)0.89(0.76, 1.06)NAsofosbuvir1.15(0.88, 1.50)1.11(1.00, 1.24)NAGS-3310071.06(0.97, 1.14)1.06(1.02, 1.11)NA40 single dose 12 hours prior to HARVONI12ledipasvir0.83(0.69, 1.00)0.98(0.80, 1.20)NAsofosbuvir1.00(0.76, 1.32)0.95(0.82, 1.10)NAGS-3310071.13(1.07, 1.20)1.06(1.01, 1.12)NAMethadone30 to 130 dailyND400 once daily14sofosbuvir0.95(0.68, 1.33)1.30(1.00, 1.69)NAGS-3310070.73(0.65, 0.83)1.04(0.89, 1.22)NAOmeprazole20 once daily simultaneously with HARVONI 90 single dose400 single dose16ledipasvir0.89(0.61, 1.30)0.96(0.66, 1.39)NAsofosbuvir1.12(0.88, 1.42)1.00(0.80, 1.25)NAGS-3310071.14(1.01, 1.29)1.03(0.96, 1.12)NA20 once daily hours prior to ledipasvir30 single doseND17ledipasvir0.52(0.41, 0.66)0.58(0.48, 0.71)NARifabutin300 once dailyND400 single dose20sofosbuvir0.64 (0.53, 0.77)0.76 (0.63, 0.91)NAGS-3310071.15 (1.03, 1.27)1.03 (0.95, 1.12)NARifampin600 once daily90 single doseThis study was conducted in the presence of two other investigational HCV direct-acting agents. ND31ledipasvir0.65(0.56, 0.76)0.41(0.36, 0.48)NAND400 single dose17sofosbuvir0.23(0.19, 0.29)0.28(0.24, 0.32)NAGS-3310071.23(1.14, 1.34)0.95(0.88, 1.03)NASimeprevir150 once daily30 once dailyND22ledipasvir1.81(1.69, 2.94)1.92(1.77, 2.07)NATacrolimus5 single doseND400 single dose16sofosbuvir0.97(0.65, 1.43)1.13(0.81, 1.57)NAGS-3310070.97(0.83, 1.14)1.00(0.87, 1.13)NANo effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007 was observed with raltegravir and the combination of abacavir and lamivudine; emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine, and tenofovir disoproxil fumarate. Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are shown in Table [see Drug Interactions (7)]. Table 8Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or HARVONIAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Ledipasvir Dose (mg)Sofosbuvir Dose (mg)NMean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or HARVONINo Effect=1.00Cmax AUCCmin NA not available/not applicable, ND not dosed.tenofovir DF tenofovir disoproxil fumarateAtazanavir/ritonavir emtricitabine /tenofovir DFData generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of atazanavir/ritonavir emtricitabine/tenofovir DF or darunavir/ritonavir emtricitabine/tenofovir DF and HARVONI provided similar results. The effects of HARVONI on atazanavir and ritonavir are similar with or without the presence of emtricitabine/tenofovir DF. This magnitude of change in tenofovir exposure does not reflect the approximately 60-80% increase caused by the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130% higher when administered as tenofovir DF atazanavir/ritonavir HARVONI or tenofovir DF darunavir/ritonavir HARVONI and with food as compared to the tenofovir exposure observed following fasted administration of tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and HARVONI. atazanavir 300 once daily90 once daily400 once daily241.07(0.99, 1.14)1.27(1.18, 1.37)1.63(1.45, 1.84)ritonavir 100 once daily0.86(0.79, 0.93)0.97(0.89, 1.05)1.45(1.27, 1.64)tenofovir DF 300 once daily1.47(1.37, 1.58)1.35(1.29, 1.42)1.47(1.38, 1.57)Darunavir/ritonavir emtricitabine/tenofovir DF darunavir 800 once daily90 once daily400 once daily231.01(0.96, 1.06)1.04(0.99, 1.08)1.08(0.98, 1.20)ritonavir 100 once daily1.17(1.01, 1.35)1.25(1.15, 1.36)1.48(1.34, 1.63)tenofovir DF 300 once daily1.64(1.54, 1.74)1.50(1.42, 1.59)1.59(1.49, 1.70)Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamideelvitegravir 150 once daily90 once daily400 once daily300.98(0.90, 1.07)1.11(1.02, 1.20)1.46(1.28, 1.66)cobicistat 150 once daily1.23(1.15, 1.32)1.53(1.45, 1.62)3.25(2.88, 3.67)tenofovir alafenamide 10 once daily0.90(0.73, 1.11)0.86(0.78, 0.95)NANorelgestrominnorgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily90 once dailyND151.02(0.89, 1.16)1.03(0.90, 1.18)1.09(0.91, 1.31)ND400 once daily1.07(0.94, 1.22)1.06(0.92, 1.21)1.07(0.89, 1.28)Norgestrel90 once dailyND1.03(0.87, 1.23)0.99(0.82, 1.20)1.00(0.81, 1.23)ND400 once daily1.18(0.99, 1.41)1.19(0.98, 1.45)1.23(1.00, 1.51)Ethinyl estradiol90 once dailyND1.40(1.18, 1.66) 1.20(1.04, 1.39) 0.98(0.79, 1.22) ND400 once daily1.15(0.97, 1.36)1.09(0.94, 1.26)0.99(0.80, 1.23)Midazolam2.5 single dose90 single doseND301.07 (1.00, 1.14)0.99 (0.95, 1.04)NA0.95 (0.87, 1.04)0.89 (0.84, 0.95)NARaltegravir400 twice daily90 once dailyND280.82(0.66, 1.02)0.85(0.70, 1.02)1.15(0.90, 1.46)ND400 single dose190.57(0.44, 0.75)0.73(0.59, 0.91)0.95(0.81, 1.12)Simeprevir150 once daily30 once dailyND222.61(2.39, 2.86)2.69(2.44, 2.96)NATacrolimus5 single doseND400 single dose160.73(0.59, 0.90)1.09(0.84, 1.40)NATenofovir DF300 once dailyAdministered as ATRIPLA (efavirenz, emtricitabine, tenofovir DF). The effects of HARVONI on tenofovir exposures are similar when tenofovir is administered as ATRIPLA, COMPLERA, or TRUVADA dolutegravir. 90 once daily400 once daily151.79(1.56, 2.04)1.98(1.77, 2.23)2.63(2.32, 2.97)No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryIf HARVONI is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy.No adequate human data are available to establish whether or not HARVONI poses risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of HARVONI (ledipasvir or sofosbuvir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures (AUC) to ledipasvir were approximately (rats) and (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were >=3 (rats) and (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to ledipasvir and GS-331007 were approximately and times, respectively, the exposure in humans at the RHD.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data. Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 180 mg/kg/day) on gestation days to 18 and to 20, respectively, and also to rats (oral doses up to 100 mg/kg/day) on gestation day to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to ledipasvir were >=4 (rats) and (rabbits) times the exposure in humans at the RHD.. Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days to 18 and to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were >=3 (rats) and (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately to (rats) and to 17 (rabbits) times the exposure in humans at the RHD.

RECENT MAJOR CHANGES SECTION.

Dosage and AdministrationRenal Impairment (2.4)11/2019.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationHARVONI(TM) (har-VOE-nee)(ledipasvir and sofosbuvir)tablets This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: 11/2019 Important: If you take HARVONI with ribavirin, you should also read the Medication Guide for ribavirin.What is the most important information should know about HARVONIHARVONI can cause serious side effects, including,Hepatitis virus reactivation: Before starting treatment with HARVONI, your healthcare provider will do blood tests to check for hepatitis virus infection. If you have ever had hepatitis virus infection, the hepatitis virus could become active again during or after treatment of hepatitis virus with HARVONI. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop taking HARVONI.For more information about side effects, see the section What are the possible side effects of HARVONIWhat is HARVONIHARVONI is prescription medicine used to treat adults with chronic (lasting long time) hepatitis virus (HCV): genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosisgenotype infection with advanced cirrhosis (decompensated) in combination with ribavirin genotype or infection without cirrhosis or with compensated cirrhosis who have had liver transplant, in combination with ribavirinHARVONI is used to treat children 12 years of age and older or weighing at least 77 pounds (at least 35 kg) with chronic HCV genotype 1, 4, 5, or without cirrhosis or with compensated cirrhosis.It is not known if HARVONI is safe and effective in children with HCV under 12 years of age and weighing less than 77 pounds (less than 35 kg).Before taking HARVONI, tell your healthcare provider about all of your medical conditions, including if you: have ever had hepatitis virus infectionhave liver problems other than hepatitis infectionhave had liver transplanthave kidney problems or you are on dialysishave HIV infectionare pregnant or plan to become pregnant. It is not known if HARVONI will harm your unborn baby.Males and females who take HARVONI in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information. are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into your breast milk.Talk to your healthcare provider about the best way to feed your baby during treatment with HARVONI. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. HARVONI and other medicines may affect each other. This can cause you to have too much or not enough HARVONI or other medicines in your body. This may affect the way HARVONI or your other medicines work, or may cause side effects. Keep list of your medicines to show your healthcare provider and pharmacist.You can ask your healthcare provider or pharmacist for list of medicines that interact with HARVONI.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take HARVONI with other medicines.How should take HARVONI Take HARVONI exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to.Do not stop taking HARVONI without first talking with your healthcare provider. Take HARVONI tablet one time each day and at the same time each day. Take HARVONI with or without food.It is important that you do not miss or skip doses of HARVONI during treatment.If you take too much HARVONI, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of HARVONIHARVONI can cause serious side effects, including:Hepatitis virus reactivation. See What is the most important information should know about HARVONISlow heart rate (bradycardia). HARVONI treatment may result in slowing of the heart rate along with other symptoms when taken with amiodarone (Cordarone(TM), Nexterone(TM), Pacerone(TM)), medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for heart pacemaker when amiodarone is taken with HARVONI. Get medical help right away if you take amiodarone with HARVONI and get any of the following symptoms:fainting or near-faintingdizziness or lightheadednessnot feeling wellweaknessextreme tirednessshortness of breathchest painsconfusionmemory problemsThe most common side effects of HARVONI include:tirednessheadacheweaknessThese are not all the possible side effects of HARVONI. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to the US FDA at 1-800-FDA-1088.How should store HARVONIStore HARVONI below 30C (86F).Keep HARVONI in its original container. Do not use HARVONI if the seal over the bottle opening is broken or missing.Keep HARVONI and all medicines out of the reach of children.General information about the safe and effective use of HARVONIMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use HARVONI for condition for which it was not prescribed. Do not give HARVONI to other people, even if they have the same symptoms you have. It may harm them.You can ask your healthcare provider or pharmacist for information about HARVONI that is written for health professionals. What are the ingredients in HARVONIActive ingredients: ledipasvir and sofosbuvirInactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.The tablet film-coat contains: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Manufactured and distributed for:Gilead Sciences, Inc., Foster City, CA 94404For more information go to www.HARVONI.com.HARVONI is trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.(C)2019 Gilead Sciences, Inc. All rights reserved.205834-GS-010A. genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosis. genotype infection with advanced cirrhosis (decompensated) in combination with ribavirin genotype or infection without cirrhosis or with compensated cirrhosis who have had liver transplant, in combination with ribavirin. have ever had hepatitis virus infection. have liver problems other than hepatitis infection. have had liver transplant. have kidney problems or you are on dialysis. have HIV infection. are pregnant or plan to become pregnant. It is not known if HARVONI will harm your unborn baby.Males and females who take HARVONI in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information. Males and females who take HARVONI in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information.. are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into your breast milk.Talk to your healthcare provider about the best way to feed your baby during treatment with HARVONI. Talk to your healthcare provider about the best way to feed your baby during treatment with HARVONI.. You can ask your healthcare provider or pharmacist for list of medicines that interact with HARVONI.. Take HARVONI exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to.. Do not stop taking HARVONI without first talking with your healthcare provider. Take HARVONI tablet one time each day and at the same time each day. Take HARVONI with or without food.. It is important that you do not miss or skip doses of HARVONI during treatment.. Hepatitis virus reactivation. See What is the most important information should know about HARVONI. Slow heart rate (bradycardia). HARVONI treatment may result in slowing of the heart rate along with other symptoms when taken with amiodarone (Cordarone(TM), Nexterone(TM), Pacerone(TM)), medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for heart pacemaker when amiodarone is taken with HARVONI. Get medical help right away if you take amiodarone with HARVONI and get any of the following symptoms:. fainting or near-fainting. dizziness or lightheadedness. not feeling well. weakness. extreme tiredness. shortness of breath. chest pains. confusion. memory problems. tiredness. headache. weakness. Store HARVONI below 30C (86F).. Keep HARVONI in its original container. Do not use HARVONI if the seal over the bottle opening is broken or missing.

SPL UNCLASSIFIED SECTION.

Adult Patients:HARVONI is indicated for the treatment of adult patients with chronic hepatitis virus (HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]:genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosisgenotype infection with decompensated cirrhosis, for use in combination with ribavirin genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin. genotype 1, 4, 5, or infection without cirrhosis or with compensated cirrhosis. genotype infection with decompensated cirrhosis, for use in combination with ribavirin genotype or infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin.

STORAGE AND HANDLING SECTION.

Store below 30 (86 F).Dispense only in original container.Do not use if seal over bottle opening is broken or missing.. Dispense only in original container.. Do not use if seal over bottle opening is broken or missing.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric Use: No data are available regarding the safety of HARVONI in pediatric patients with renal impairment. (8.4). Pediatric Use: No data are available regarding the safety of HARVONI in pediatric patients with renal impairment. (8.4). 8.1 Pregnancy. Risk SummaryIf HARVONI is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy.No adequate human data are available to establish whether or not HARVONI poses risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of HARVONI (ledipasvir or sofosbuvir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures (AUC) to ledipasvir were approximately (rats) and (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were >=3 (rats) and (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to ledipasvir and GS-331007 were approximately and times, respectively, the exposure in humans at the RHD.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data. Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 180 mg/kg/day) on gestation days to 18 and to 20, respectively, and also to rats (oral doses up to 100 mg/kg/day) on gestation day to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to ledipasvir were >=4 (rats) and (rabbits) times the exposure in humans at the RHD.. Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days to 18 and to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were >=3 (rats) and (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately to (rats) and to 17 (rabbits) times the exposure in humans at the RHD.. 8.2 Lactation. Risk SummaryIt is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. When administered to lactating rats, ledipasvir was detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk, without clear effects on nursing pups [see Data]. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups. The development and health benefits of breastfeeding should be considered along with the mothers clinical need for HARVONI and any potential adverse effects on the breastfed child from HARVONI or from the underlying maternal condition. If HARVONI is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation.. Data. Ledipasvir: No effects of ledipasvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to ledipasvir was approximately times the exposure in humans at the RHD. Although not measured directly, ledipasvir was likely present in the milk of lactating rats, since systemic exposure (AUC) to ledipasvir of approximately 25% that of maternal exposure was observed in nursing pups on lactation day 10.. Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed hour post-dose.. 8.3 Females and Males of Reproductive Potential. If HARVONI is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.. 8.4 Pediatric Use. The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype infection in treatment-naive and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-naive, 20 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of HARVONI for treatment of HCV genotypes 4, 5, or infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype and similar efficacy and exposures across HCV genotypes 1, 4, 5, and in adults [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3 and 14.6)].In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3)]. No data are available regarding the safety of HARVONI in pediatric patients with renal impairment [see Use in Specific Populations (8.6)].The safety and efficacy of HARVONI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients.. 8.5 Geriatric Use. Clinical trials of HARVONI included 225 subjects aged 65 and over (9% of total number of subjects in the clinical studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].. 8.6Renal Impairment. No dosage adjustment of HARVONI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.4), Adverse Reactions (6.1), and Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4) ]. Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment.. 8.7Hepatic Impairment. No dosage adjustment of HARVONI is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.5)]. Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with HARVONI and ribavirin [see Adverse Reactions (6.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk of Hepatitis Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1)Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with HARVONI is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. (5.2, 6.2, 7.2). Risk of Hepatitis Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1). Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with HARVONI is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. (5.2, 6.2, 7.2). 5.1Risk of Hepatitis Virus Reactivation in Patients Coinfected with HCV and HBV. Hepatitis virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with HARVONI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with HARVONI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.. 5.2Serious Symptomatic Bradycardia When Coadministered with Amiodarone. Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI. Bradycardia has generally occurred within hours to days, but cases have been observed up to weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.Coadministration of amiodarone with HARVONI is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered HARVONI:Counsel patients about the risk of serious symptomatic bradycardiaCardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on daily basis through at least the first weeks of treatment. Patients who are taking HARVONI who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.Due to amiodarones long half-life, patients discontinuing amiodarone just prior to starting HARVONI should also undergo similar cardiac monitoring as outlined above.Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.2)].. Counsel patients about the risk of serious symptomatic bradycardia. Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on daily basis through at least the first weeks of treatment. 5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers The concomitant use of HARVONI and P-gp inducers may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to reduced therapeutic effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin, St. Johns wort) is not recommended [see Drug Interactions (7.2)].. 5.4Risks Associated with Ribavirin Combination Treatment. If HARVONI is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].