Ledipasvir and Sofosbuvir

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) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with ledipasvir and sofosbuvir were fatigue, headache, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Asegua Therapeutics at 1-800-445-3235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If ledipasvir and sofosbuvir is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety assessment of ledipasvir and sofosbuvir was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir. Table 4 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 of treatment with ledipasvir and sofosbuvir in clinical trials. The majority of adverse reactions presented in Table 4 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 4 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir 8 weeks (N=215) Ledipasvir and Sofosbuvir 12 weeks (N=539) Ledipasvir and Sofosbuvir 24 weeks (N=326) Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety assessment of ledipasvir and sofosbuvir 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 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3) ] . The subjects received ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 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 Cirrhosis The safety assessment of ledipasvir and sofosbuvir with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial . Subjects were randomized to receive 24 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth + ribavirin [see Clinical Studies (14.2) ] . Table 5 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of ledipasvir and sofosbuvir or 12 weeks of ledipasvir and sofosbuvir + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 5 were Grade 1 or 2 in severity. Table 5 Adverse Reactions with ≥5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving Ledipasvir and Sofosbuvir for 24 Weeks or Ledipasvir and Sofosbuvir + Ribavirin for 12 Weeks Compared to Placebo for 12 weeks Ledipasvir and Sofosbuvir 24 weeks (N=78) Ledipasvir and Sofosbuvir + RBV 12 weeks (N=76) Placebo 12 weeks (N=77) RBV=ribavirin Asthenia 31% 36% 23% Headache 29% 13% 16% Fatigue 18% 4% 1% Cough 5% 11% 1% Myalgia 9% 4% 0 Dyspnea 3% 9% 1% Irritability 8% 7% 1% Dizziness 5% 1% 0 Adverse Reactions in Subjects Coinfected with HIV-1 The safety assessment of ledipasvir and sofosbuvir was based on an open-label clinical trial in 335 genotype 1 or 4 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 Cirrhosis The safety assessment of ledipasvir and sofosbuvir with ribavirin in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir plus ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with ledipasvir and sofosbuvir plus ribavirin for 12 weeks. Liver Transplant Recipients with Compensated Liver Disease: Among the 174 liver transplant recipients with compensated liver disease who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with ribavirin for 12 weeks, 2 (1%) subjects permanently discontinued ledipasvir and sofosbuvir due to an adverse event. Subjects with Decompensated Liver Disease: Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with ribavirin for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 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. A total of 4 (2%) subjects permanently discontinued ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 1.5×ULN were observed in 3%, less than 1%, and 2% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8, 12, and 24 weeks, respectively. Bilirubin elevations of greater than 1.5×ULN were observed in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir + ribavirin for 12 weeks, and ledipasvir and sofosbuvir for 24 weeks, respectively, in the SIRIUS trial. Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in less than 1%, 2%, and 3% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8, 12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater than 3×ULN were observed in 1%, 3%, and 9% of subjects with compensated cirrhosis treated with placebo, ledipasvir and sofosbuvir + ribavirin for 12 weeks, and ledipasvir and sofosbuvir for 24 weeks, respectively, in the SIRIUS trial. Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1, or ION-2 of ledipasvir and sofosbuvir. Creatine kinase was assessed in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10×ULN was observed in 1% of subjects treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 Dialysis In an open-label trial (Trial 0154) in which adults with HCV with compensated liver disease (with or without cirrhosis) and severe renal impairment received ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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, a total of 95 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8 (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 3 Years of Age and Older The safety assessment of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir and sofosbuvir (HARVONI) tablets (45 mg/200 mg), or ledipasvir and sofosbuvir (HARVONI) oral pellets in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116). In total, 226 subjects were enrolled, which included 223 subjects without cirrhosis or with compensated cirrhosis who were treated with ledipasvir and sofosbuvir for 12 weeks; one genotype 1 treatment-experienced subject with cirrhosis who was treated with ledipasvir and sofosbuvir for 24 weeks; and two genotype 3 subjects who were treated with ledipasvir and sofosbuvir + ribavirin for 24 weeks. The adverse reactions observed were consistent with those observed in clinical studies of ledipasvir and sofosbuvir tablets (90 mg/400 mg) in adults. Limited safety data are available in pediatric subjects receiving ledipasvir and sofosbuvir for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving ledipasvir and sofosbuvir for 24 weeks [see Clinical Studies (14.7) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ledipasvir and sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2) , Drug Interactions (7.2) ]. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

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

11 DESCRIPTION Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are fixed-dose combination tablets containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a 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 a coating material containing the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is methyl [(2 S )-1-{(6 S )-6-[5-(9,9-difluoro-7-{2-[(1 R ,3 S ,4 S )-2-{(2 S )-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1 H -benzimidazol-6-yl}-9 H -fluoren-2-yl)-1 H -imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C 49 H 54 F 2 N 8 O 6 and a 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 )-(((2 R ,3 R ,4 R ,5 R )-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C 22 H 29 FN 3 O 9 P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL across the pH range of 2–7.7 at 37°C and is slightly soluble in water. Chemical Structure

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 treatment regimen and duration in patients 3 years of age and older: ( 2.2 ) HCV Genotype Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Treatment-experienced without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Recommended dosage in adults: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) Instructions for Use should be followed for preparation and administration of ledipasvir and sofosbuvir (HARVONI) oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables in the full prescribing information. ( 2.3 , 2.4 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with any degree of renal impairment, including end stage renal disease on dialysis, no ledipasvir and sofosbuvir dosage adjustment is recommended. ( 2.6 ) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with ledipasvir and sofosbuvir [see Warnings and Precautions (5.1) ] . 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV Table 1 shows the recommended ledipasvir and sofosbuvir treatment regimen and duration based on patient population . Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration for Ledipasvir and Sofosbuvir in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV HCV Genotype Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Ledipasvir and sofosbuvir for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2) ] . Treatment-experienced Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Ledipasvir and sofosbuvir + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical Studies (14.2) ] . Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations. 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced , without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks 2.3 Recommended Dosage in Adults The recommended dosage of ledipasvir and sofosbuvir in adults with genotype 1, 4, 5 or 6 HCV is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . The 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. In 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. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) , and Clinical Studies (14.5) ] . 2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and Older The recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV is based on weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in combination with ledipasvir and sofosbuvir for pediatric patients. Take ledipasvir and sofosbuvir (with or without food) once daily [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) , and Clinical Studies (14.7) ] . Ledipasvir and sofosbuvir (HARVONI) oral pellets can be taken in pediatric patients who cannot swallow the tablet formulation. Table 2 Dosing for Pediatric Patients 3 Years and Older Body Weight (kg) Dosing of Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir Daily Dose at least 35 one Ledipasvir and Sofosbuvir 90 mg/400 mg tablet once daily or two Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablets once daily or two 45 mg/200 mg packets of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 90 mg/400 mg per day 17 to less than 35 one Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablet once daily or one 45 mg/200 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 45 mg/200 mg per day less than17 one 33.75 mg/150 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 33.75 mg/150 mg per day Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Ledipasvir and Sofosbuvir for Pediatric Patients 3 Years and Older Body Weight (kg) Oral Ribavirin Daily Dosage The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day (divided dose AM and PM) 47–49 600 mg per day (1 × 200 mg AM, 2 × 200 mg PM) 50–65 800 mg per day (2 × 200 mg AM, 2 × 200 mg PM) 66–80 1000 mg per day (2 × 200 mg AM, 3 × 200 mg PM) greater than 80 1200 mg per day (3 × 200 mg AM, 3 × 200 mg PM) 2.5 Preparation and Administration of Ledipasvir and Sofosbuvir (HARVONI) Oral Pellets See the ledipasvir and sofosbuvir (HARVONI) oral pellets full Instructions for Use for details on the preparation and administration of ledipasvir and sofosbuvir (HARVONI) pellets. Do not chew ledipasvir and sofosbuvir (HARVONI) oral pellets. If ledipasvir and sofosbuvir (HARVONI) oral pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take ledipasvir and sofosbuvir (HARVONI) oral pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste. 2.6 Renal Impairment No dosage adjustment of ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) with or without ribavirin according to the recommendations in Table 1 [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.

1 INDICATIONS AND USAGE Ledipasvir and sofosbuvir is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2 and 2.3) and Clinical Studies (14) ]: genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin Ledipasvir and sofosbuvir is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years of age and older: Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin. ( 1 )

10 OVERDOSAGE No specific antidote is available for overdose with ledipasvir and sofosbuvir. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with ledipasvir and sofosbuvir 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%.

7 DRUG INTERACTIONS Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of ledipasvir and sofosbuvir with amiodarone is not recommended. ( 5.2 , 6.2 , 7.2 ) P-gp inducers (e.g., rifampin, St. John's wort): May alter concentrations of ledipasvir and sofosbuvir. Use of ledipasvir and sofosbuvir 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 ) 7.1 Potential for Drug Interaction Any interactions that have been identified with ledipasvir or sofosbuvir individually may occur with ledipasvir and sofosbuvir. After oral administration of ledipasvir and sofosbuvir, 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. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir [see Warnings and Precautions (5.3) ] . 7.2 Established 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 a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either ledipasvir and sofosbuvir tablets (90 mg/400 mg) or ledipasvir and sofosbuvir as individual agents, or are predicted drug interactions that may occur with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2 , 5.3) and Clinical Pharmacology (12.3) ] . Table 6 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase Clinical Comment tenofovir DF = tenofovir disoproxil fumarate Acid Reducing Agents: ↓ ledipasvir Ledipasvir 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 ledipasvir and sofosbuvir administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -receptor antagonists may be administered simultaneously with or 12 hours apart from ledipasvir and sofosbuvir at a 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 ledipasvir and sofosbuvir under fasted conditions. Antiarrhythmics: amiodarone Effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown Coadministration of amiodarone with ledipasvir and sofosbuvir may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. digoxin ↑ digoxin Coadministration of ledipasvir and sofosbuvir with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with ledipasvir and sofosbuvir. Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with carbamazepine, phenytoin, or phenobarbital is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir 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 ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving ledipasvir and sofosbuvir concomitantly with a 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 ↑ tenofovir The safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir 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 ↑ tenofovir The safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir and the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF has not been established. Coadministration is not recommended. tipranavir/ritonavir ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended. HCV Products: simeprevir ↑ ledipasvir ↑ simeprevir Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of ledipasvir and sofosbuvir with simeprevir is not recommended. Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with St. John's wort, a P-gp inducer, is not recommended [see Warnings and Precautions (5.3) ]. HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of ledipasvir and sofosbuvir with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of ledipasvir and sofosbuvir with rosuvastatin is not recommended. atorvastatin ↑ atorvastatin Coadministration of ledipasvir and sofosbuvir 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. 7.3 Drugs without Clinically Significant Interactions with Ledipasvir and Sofosbuvir Based on drug interaction studies conducted with ledipasvir, sofosbuvir, or ledipasvir and sofosbuvir tablets (90 mg/400 mg) no clinically significant drug interactions have been either observed or are expected when ledipasvir and sofosbuvir 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 6 for use of ledipasvir and sofosbuvir with certain HIV antiretroviral regimens [see Drug Interactions (7.2) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ]. 12.2 Pharmacodynamics Cardiac Electrophysiology Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent. The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. 12.3 Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0–24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir tablets (90 mg/400 mg) with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0–inf by approximately 2-fold, but did not significantly affect sofosbuvir C max . The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food. Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [ 14 C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [ 14 C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [ 14 C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. Elimination Following a single 90 mg oral dose of [ 14 C]-ledipasvir, mean total recovery of the [ 14 C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg) was 47 hours. Following a single 400 mg oral dose of [ 14 C]-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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 C max 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 3 studies and the safety profiles are similar in females and males. Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in HCV genotype 1, 3, or 4 infected pediatric subjects 3 years of age and older receiving a daily dose of ledipasvir and sofosbuvir as described below in Table 7. Exposures in pediatric subjects were similar to those observed in adults. Table 7 Pharmacokinetic Properties of Ledipasvir, Sofosbuvir, and GS-331007 in Pediatric Subjects 3 Years of Age and Older Population PK derived parameters Weight Group Dose PK Parameter Geometric Mean (%CV) Ledipasvir Sofosbuvir GS-331007 90/400 mg AUC tau (ng∙hr/mL) 11200 (45.7) 1350 (45.2) 13600 (18.9) ≥35 kg Ledipasvir N=100; Sofosbuvir N=72; GS-331007 N=100 C max (ng/mL) 550 (44.2) 660 (51.1) 921 (17.8) 45/200 mg AUC tau (ng∙hr/mL) 8750 (46.6) 1420 (34.2) 10700 (30.9) 17 to <35 kg Ledipasvir N=86; Sofosbuvir N=66; GS-331007 N=86 C max (ng/mL) 440 (42.7) 690 (24.8) 958 (26.1) 33.75/150 mg AUC tau (ng∙hr/mL) 7460 (31.0) 1720 (23.2) 12200 (15.2) <17 kg Ledipasvir N=9; Sofosbuvir N=9; GS-331007 N=9 C max (ng/mL) 405 (25.7) 791 (16.6) 1070 (13.0) The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ] . Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have a 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 a 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 m 2 ), moderate (eGFR between 30 to less than 50 mL/min/1.73 m 2 ), severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m 2 ), the sofosbuvir AUC 0–inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC 0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC 0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.6) 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC 0–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 B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC 0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC 0–24 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 Studies Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir [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; ledipasvir and sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a 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 a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with ledipasvir and sofosbuvir 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 8 [see Drug Interactions (7) ]. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered Drug No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine/ tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir 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 daily 90 once daily 400 once daily 24 ledipasvir 1.68 (1.54, 1.84) 1.96 (1.74, 2.21) 2.18 (1.91, 2.50) sofosbuvir 1.01 (0.88, 1.15) 1.11 (1.02, 1.21) NA GS-331007 1.17 (1.12, 1.23) 1.31 (1.25, 1.36) 1.42 (1.34, 1.49) Carbamazepine 300 twice daily ND 400 single dose 24 sofosbuvir 0.52 (0.43, 0.62) 0.52 (0.46, 0.59) NA GS-331007 1.04 (0.97, 1.11) 0.99 (0.94, 1.04) NA Cyclosporine 600 single dose ND 400 single dose 19 sofosbuvir 2.54 (1.87, 3.45) 4.53 (3.26, 6.30) NA GS-331007 0.60 (0.53, 0.69) 1.04 (0.90, 1.20) NA Darunavir/ ritonavir 800/100 once daily 90 once daily ND 23 ledipasvir 1.45 (1.34, 1.56) 1.39 (1.28, 1.49) 1.39 (1.29, 1.51) ND 400 single dose 18 sofosbuvir 1.45 (1.10, 1.92) 1.34 (1.12, 1.59) NA GS-331007 0.97 (0.90, 1.05) 1.24 (1.18, 1.30) NA Darunavir/ ritonavir + emtricitabine/ tenofovir DF 800/100 + 200/300 once daily 90 once daily 400 once daily 23 ledipasvir 1.11 (0.99, 1.24) 1.12 (1.00, 1.25) 1.17 (1.04, 1.31) sofosbuvir 0.63 (0.52, 0.75) 0.73 (0.65, 0.82) NA GS-331007 1.10 (1.04, 1.16) 1.20 (1.16, 1.24) 1.26 (1.20, 1.32) Efavirenz/ emtricitabine/ tenofovir DF Administered as Atripla ® (efavirenz, emtricitabine, tenofovir DF). 600/200/300 once daily 90 once daily 400 once daily 14 ledipasvir 0.66 (0.59, 0.75) 0.66 (0.59, 0.75) 0.66 (0.57, 0.76) sofosbuvir 1.03 (0.87, 1.23) 0.94 (0.81, 1.10) NA GS-331007 0.86 (0.76, 0.96) 0.90 (0.83, 0.97) 1.07 (1.02, 1.13) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide 150/150/200/10 once daily 90 once daily 400 once daily 30 ledipasvir 1.65 (1.53, 1.78) 1.79 (1.64, 1.96) 1.93 (1.74, 2.15) sofosbuvir 1.28 (1.13, 1.47) 1.47 (1.35, 1.59) NA GS-331007 1.29 (1.24, 1.35) 1.48 (1.44, 1.53) 1.66 (1.60, 1.73) Famotidine 40 single dose simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 12 ledipasvir 0.80 (0.69, 0.93) 0.89 (0.76, 1.06) NA sofosbuvir 1.15 (0.88, 1.50) 1.11 (1.00, 1.24) NA GS-331007 1.06 (0.97, 1.14) 1.06 (1.02, 1.11) NA 40 single dose 12 hours prior to ledipasvir and sofosbuvir tablets 12 ledipasvir 0.83 (0.69, 1.00) 0.98 (0.80, 1.20) NA sofosbuvir 1.00 (0.76, 1.32) 0.95 (0.82, 1.10) NA GS-331007 1.13 (1.07, 1.20) 1.06 (1.01, 1.12) NA Methadone 30 to 130 daily ND 400 once daily 14 sofosbuvir 0.95 (0.68, 1.33) 1.30 (1.00, 1.69) NA GS-331007 0.73 (0.65, 0.83) 1.04 (0.89, 1.22) NA Omeprazole 20 once daily simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 16 ledipasvir 0.89 (0.61, 1.30) 0.96 (0.66, 1.39) NA sofosbuvir 1.12 (0.88, 1.42) 1.00 (0.80, 1.25) NA GS-331007 1.14 (1.01, 1.29) 1.03 (0.96, 1.12) NA 20 once daily 2 hours prior to ledipasvir 30 single dose ND 17 ledipasvir 0.52 (0.41, 0.66) 0.58 (0.48, 0.71) NA Rifabutin 300 once daily ND 400 single dose 20 sofosbuvir 0.64 (0.53, 0.77) 0.76 (0.63, 0.91) NA GS-331007 1.15 (1.03, 1.27) 1.03 (0.95, 1.12) NA Rifampin 600 once daily 90 single dose This study was conducted in the presence of two other investigational HCV direct-acting agents. ND 31 ledipasvir 0.65 (0.56, 0.76) 0.41 (0.36, 0.48) NA ND 400 single dose 17 sofosbuvir 0.23 (0.19, 0.29) 0.28 (0.24, 0.32) NA GS-331007 1.23 (1.14, 1.34) 0.95 (0.88, 1.03) NA Simeprevir 150 once daily 30 once daily ND 22 ledipasvir 1.81 (1.69, 2.94) 1.92 (1.77, 2.07) NA Tacrolimus 5 single dose ND 400 single dose 16 sofosbuvir 0.97 (0.65, 1.43) 1.13 (0.81, 1.57) NA GS-331007 0.97 (0.83, 1.14) 1.00 (0.87, 1.13) NA No 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 9 [see Drug Interactions (7) ]. Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine /tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir provided similar results. , The effects of ledipasvir and sofosbuvir 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 + ledipasvir and sofosbuvir or tenofovir DF + darunavir/ritonavir + ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir. atazanavir 300 once daily 90 once daily 400 once daily 24 1.07 (0.99, 1.14) 1.27 (1.18, 1.37) 1.63 (1.45, 1.84) ritonavir 100 once daily 0.86 (0.79, 0.93) 0.97 (0.89, 1.05) 1.45 (1.27, 1.64) tenofovir DF 300 once daily 1.47 (1.37, 1.58) 1.35 (1.29, 1.42) 1.47 (1.38, 1.57) Darunavir/ ritonavir + emtricitabine/ tenofovir DF , darunavir 800 once daily 90 once daily 400 once daily 23 1.01 (0.96, 1.06) 1.04 (0.99, 1.08) 1.08 (0.98, 1.20) ritonavir 100 once daily 1.17 (1.01, 1.35) 1.25 (1.15, 1.36) 1.48 (1.34, 1.63) tenofovir DF 300 once daily 1.64 (1.54, 1.74) 1.50 (1.42, 1.59) 1.59 (1.49, 1.70) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide elvitegravir 150 once daily 90 once daily 400 once daily 30 0.98 (0.90, 1.07) 1.11 (1.02, 1.20) 1.46 (1.28, 1.66) cobicistat 150 once daily 1.23 (1.15, 1.32) 1.53 (1.45, 1.62) 3.25 (2.88, 3.67) tenofovir alafenamide 10 once daily 0.90 (0.73, 1.11) 0.86 (0.78, 0.95) NA Norelgestromin norgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily 90 once daily ND 15 1.02 (0.89, 1.16) 1.03 (0.90, 1.18) 1.09 (0.91, 1.31) ND 400 once daily 1.07 (0.94, 1.22) 1.06 (0.92, 1.21) 1.07 (0.89, 1.28) Norgestrel 90 once daily ND 1.03 (0.87, 1.23) 0.99 (0.82, 1.20) 1.00 (0.81, 1.23) ND 400 once daily 1.18 (0.99, 1.41) 1.19 (0.98, 1.45) 1.23 (1.00, 1.51) Ethinyl estradiol 90 once daily ND 1.40 (1.18, 1.66) 1.20 (1.04, 1.39) 0.98 (0.79, 1.22) ND 400 once daily 1.15 (0.97, 1.36) 1.09 (0.94, 1.26) 0.99 (0.80, 1.23) Midazolam 2.5 single dose 90 single dose ND 30 1.07 (1.00, 1.14) 0.99 (0.95, 1.04) NA 0.95 (0.87, 1.04) 0.89 (0.84, 0.95) NA Raltegravir 400 twice daily 90 once daily ND 28 0.82 (0.66, 1.02) 0.85 (0.70, 1.02) 1.15 (0.90, 1.46) ND 400 single dose 19 0.57 (0.44, 0.75) 0.73 (0.59, 0.91) 0.95 (0.81, 1.12) Simeprevir 150 once daily 30 once daily ND 22 2.61 (2.39, 2.86) 2.69 (2.44, 2.96) NA Tacrolimus 5 single dose ND 400 single dose 16 0.73 (0.59, 0.90) 1.09 (0.84, 1.40) NA Tenofovir DF 300 once daily Administered as Atripla (efavirenz, emtricitabine, tenofovir DF). The effects of ledipasvir and sofosbuvir on tenofovir exposures are similar when tenofovir is administered as Atripla, Complera ® , or Truvada + dolutegravir. 90 once daily 400 once daily 15 1.79 (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 Action Ledipasvir 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 a 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 a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and 4a with IC 50 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 Activity In HCV replicon assays, the EC 50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC 50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates from treatment-naïve 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 EC 50 values ranging between 0.002 nM to 0.16 nM against 11 genotype 4 subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The median EC 50 value for subtype 4b was 199.6 nM (range 0.66–1799 nM; N=3); the two 4b isolates with EC 50 values greater than 100 nM had NS5A resistance-associated polymorphisms L30S+M31M+P58S+Y93H. The median EC 50 value of ledipasvir was 0.03 nM against genotype 5a isolates (range 0.008–0.081 nM; N=35). For genotype 6, the EC 50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC 50 values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the median EC 50 values ranged from 60.6 nM to 430.1 nM. In HCV replicon assays, the EC 50 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 EC 50 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 EC 50 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 Culture HCV 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, a 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 EC 50 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 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials Genotype 1 In a pooled analysis of subjects who received ledipasvir and sofosbuvir tablets in Phase 3 trials (ION-3, ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and 8 with genotype 1b HCV) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 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 8 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 7 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 2 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 1 infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving HCV RNA 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 3 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 a liver pre-transplant trial. The E237G substitution was detected in 3 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 3 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 8 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in a Phase 2 trial. Genotype 4, 5 or 6 Resistance analysis was performed for 6 relapse subjects infected with HCV genotype 4 (Study 1119 and ION-4, N=3), genotype 5 (Study 1119, N=2) or genotype 6 (ELECTRON-2, N=1) and treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 4 relapse subjects post-treatment who also had NS5A polymorphisms pretreatment that were retained post-treatment. Two of the relapsers with genotype 4 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 5 relapse subject also had emergent nucleotide inhibitor substitution M289I. Persistence of Resistance-Associated Substitutions No 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 1 Analyses 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 3 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 a 15% frequency threshold. In treatment-naïve 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 8 weeks and 1% (1/113) after 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg). Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks of treatment with ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg). 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) + ribavirin compared to 2/15 (13%) subjects treated with 24 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg). 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 3 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) and ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively. In the Phase 3 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, 5 or 6 Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study 1119 (N=44) and ION-4 (N=8) identified 7 HCV genotype 4 subtypes (4a, 4b, 4d, 4f, 4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d (N=11; 21%); 1 to 3 subjects were infected with each of the other genotype 4 subtypes. There were 3 subjects with subtype 4r, 2 of whom experienced virologic relapse, and both had a combination of 2 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 a subtype identified at screening or by analysis. Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in ELECTRON-2 identified 7 HCV genotype 6 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 ledipasvir and sofosbuvir 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 2 of 3 genotype 4 subjects who had baseline NS5B V321I, a polymorphism at a position associated with treatment failure to sofosbuvir and other nucleoside inhibitors; these two subjects also had baseline NS5A resistance-associated polymorphisms. For genotype 5 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 6 HCV in clinical trials by population or deep nucleotide sequence analysis. Pediatrics In Study 1116, the presence of NS5A and NS5B resistance-associated polymorphisms did not impact treatment outcome; all pediatric subjects 3 years of age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-associated polymorphisms (14%; 32/223) achieved SVR following 12 weeks treatment with ledipasvir and sofosbuvir tablets. 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.

12.1 Mechanism of Action Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].

12.2 Pharmacodynamics Cardiac Electrophysiology Thorough QT studies have been conducted for ledipasvir and sofosbuvir. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent. The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0–24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0–24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir tablets (90 mg/400 mg) with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0–inf by approximately 2-fold, but did not significantly affect sofosbuvir C max . The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food. Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity ranged between 0.51 and 0.66. Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [ 14 C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14 C-radioactivity was approximately 0.7. Metabolism In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [ 14 C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (greater than 98%). Unchanged ledipasvir is the major species present in feces. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [ 14 C]-sofosbuvir, GS-331007 accounted for approximately greater than 90% of total systemic exposure. Elimination Following a single 90 mg oral dose of [ 14 C]-ledipasvir, mean total recovery of the [ 14 C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg) was 47 hours. Following a single 400 mg oral dose of [ 14 C]-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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 C max 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 3 studies and the safety profiles are similar in females and males. Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in HCV genotype 1, 3, or 4 infected pediatric subjects 3 years of age and older receiving a daily dose of ledipasvir and sofosbuvir as described below in Table 7. Exposures in pediatric subjects were similar to those observed in adults. Table 7 Pharmacokinetic Properties of Ledipasvir, Sofosbuvir, and GS-331007 in Pediatric Subjects 3 Years of Age and Older Population PK derived parameters Weight Group Dose PK Parameter Geometric Mean (%CV) Ledipasvir Sofosbuvir GS-331007 90/400 mg AUC tau (ng∙hr/mL) 11200 (45.7) 1350 (45.2) 13600 (18.9) ≥35 kg Ledipasvir N=100; Sofosbuvir N=72; GS-331007 N=100 C max (ng/mL) 550 (44.2) 660 (51.1) 921 (17.8) 45/200 mg AUC tau (ng∙hr/mL) 8750 (46.6) 1420 (34.2) 10700 (30.9) 17 to <35 kg Ledipasvir N=86; Sofosbuvir N=66; GS-331007 N=86 C max (ng/mL) 440 (42.7) 690 (24.8) 958 (26.1) 33.75/150 mg AUC tau (ng∙hr/mL) 7460 (31.0) 1720 (23.2) 12200 (15.2) <17 kg Ledipasvir N=9; Sofosbuvir N=9; GS-331007 N=9 C max (ng/mL) 405 (25.7) 791 (16.6) 1070 (13.0) The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ] . Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 80 years) analyzed, age did not have a 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 a 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 m 2 ), moderate (eGFR between 30 to less than 50 mL/min/1.73 m 2 ), severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m 2 ), the sofosbuvir AUC 0–inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS-331007 AUC 0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC 0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.6) 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC 0–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 B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC 0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC 0–24 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 Studies Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir [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; ledipasvir and sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a 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 a major route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with ledipasvir and sofosbuvir 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 8 [see Drug Interactions (7) ]. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Ledipasvir, Sofosbuvir, and GS-331007 PK With/Without Coadministered Drug No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine/ tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir 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 daily 90 once daily 400 once daily 24 ledipasvir 1.68 (1.54, 1.84) 1.96 (1.74, 2.21) 2.18 (1.91, 2.50) sofosbuvir 1.01 (0.88, 1.15) 1.11 (1.02, 1.21) NA GS-331007 1.17 (1.12, 1.23) 1.31 (1.25, 1.36) 1.42 (1.34, 1.49) Carbamazepine 300 twice daily ND 400 single dose 24 sofosbuvir 0.52 (0.43, 0.62) 0.52 (0.46, 0.59) NA GS-331007 1.04 (0.97, 1.11) 0.99 (0.94, 1.04) NA Cyclosporine 600 single dose ND 400 single dose 19 sofosbuvir 2.54 (1.87, 3.45) 4.53 (3.26, 6.30) NA GS-331007 0.60 (0.53, 0.69) 1.04 (0.90, 1.20) NA Darunavir/ ritonavir 800/100 once daily 90 once daily ND 23 ledipasvir 1.45 (1.34, 1.56) 1.39 (1.28, 1.49) 1.39 (1.29, 1.51) ND 400 single dose 18 sofosbuvir 1.45 (1.10, 1.92) 1.34 (1.12, 1.59) NA GS-331007 0.97 (0.90, 1.05) 1.24 (1.18, 1.30) NA Darunavir/ ritonavir + emtricitabine/ tenofovir DF 800/100 + 200/300 once daily 90 once daily 400 once daily 23 ledipasvir 1.11 (0.99, 1.24) 1.12 (1.00, 1.25) 1.17 (1.04, 1.31) sofosbuvir 0.63 (0.52, 0.75) 0.73 (0.65, 0.82) NA GS-331007 1.10 (1.04, 1.16) 1.20 (1.16, 1.24) 1.26 (1.20, 1.32) Efavirenz/ emtricitabine/ tenofovir DF Administered as Atripla ® (efavirenz, emtricitabine, tenofovir DF). 600/200/300 once daily 90 once daily 400 once daily 14 ledipasvir 0.66 (0.59, 0.75) 0.66 (0.59, 0.75) 0.66 (0.57, 0.76) sofosbuvir 1.03 (0.87, 1.23) 0.94 (0.81, 1.10) NA GS-331007 0.86 (0.76, 0.96) 0.90 (0.83, 0.97) 1.07 (1.02, 1.13) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide 150/150/200/10 once daily 90 once daily 400 once daily 30 ledipasvir 1.65 (1.53, 1.78) 1.79 (1.64, 1.96) 1.93 (1.74, 2.15) sofosbuvir 1.28 (1.13, 1.47) 1.47 (1.35, 1.59) NA GS-331007 1.29 (1.24, 1.35) 1.48 (1.44, 1.53) 1.66 (1.60, 1.73) Famotidine 40 single dose simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 12 ledipasvir 0.80 (0.69, 0.93) 0.89 (0.76, 1.06) NA sofosbuvir 1.15 (0.88, 1.50) 1.11 (1.00, 1.24) NA GS-331007 1.06 (0.97, 1.14) 1.06 (1.02, 1.11) NA 40 single dose 12 hours prior to ledipasvir and sofosbuvir tablets 12 ledipasvir 0.83 (0.69, 1.00) 0.98 (0.80, 1.20) NA sofosbuvir 1.00 (0.76, 1.32) 0.95 (0.82, 1.10) NA GS-331007 1.13 (1.07, 1.20) 1.06 (1.01, 1.12) NA Methadone 30 to 130 daily ND 400 once daily 14 sofosbuvir 0.95 (0.68, 1.33) 1.30 (1.00, 1.69) NA GS-331007 0.73 (0.65, 0.83) 1.04 (0.89, 1.22) NA Omeprazole 20 once daily simultaneously with ledipasvir and sofosbuvir tablets 90 single dose 400 single dose 16 ledipasvir 0.89 (0.61, 1.30) 0.96 (0.66, 1.39) NA sofosbuvir 1.12 (0.88, 1.42) 1.00 (0.80, 1.25) NA GS-331007 1.14 (1.01, 1.29) 1.03 (0.96, 1.12) NA 20 once daily 2 hours prior to ledipasvir 30 single dose ND 17 ledipasvir 0.52 (0.41, 0.66) 0.58 (0.48, 0.71) NA Rifabutin 300 once daily ND 400 single dose 20 sofosbuvir 0.64 (0.53, 0.77) 0.76 (0.63, 0.91) NA GS-331007 1.15 (1.03, 1.27) 1.03 (0.95, 1.12) NA Rifampin 600 once daily 90 single dose This study was conducted in the presence of two other investigational HCV direct-acting agents. ND 31 ledipasvir 0.65 (0.56, 0.76) 0.41 (0.36, 0.48) NA ND 400 single dose 17 sofosbuvir 0.23 (0.19, 0.29) 0.28 (0.24, 0.32) NA GS-331007 1.23 (1.14, 1.34) 0.95 (0.88, 1.03) NA Simeprevir 150 once daily 30 once daily ND 22 ledipasvir 1.81 (1.69, 2.94) 1.92 (1.77, 2.07) NA Tacrolimus 5 single dose ND 400 single dose 16 sofosbuvir 0.97 (0.65, 1.43) 1.13 (0.81, 1.57) NA GS-331007 0.97 (0.83, 1.14) 1.00 (0.87, 1.13) NA No 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 9 [see Drug Interactions (7) ]. Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Ledipasvir Dose (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Ledipasvir, Sofosbuvir, or Ledipasvir and Sofosbuvir No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed. tenofovir DF = tenofovir disoproxil fumarate Atazanavir/ ritonavir + emtricitabine /tenofovir DF Data generated from simultaneous dosing with ledipasvir and sofosbuvir. Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and ledipasvir and sofosbuvir provided similar results. , The effects of ledipasvir and sofosbuvir 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 + ledipasvir and sofosbuvir or tenofovir DF + darunavir/ritonavir + ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir. atazanavir 300 once daily 90 once daily 400 once daily 24 1.07 (0.99, 1.14) 1.27 (1.18, 1.37) 1.63 (1.45, 1.84) ritonavir 100 once daily 0.86 (0.79, 0.93) 0.97 (0.89, 1.05) 1.45 (1.27, 1.64) tenofovir DF 300 once daily 1.47 (1.37, 1.58) 1.35 (1.29, 1.42) 1.47 (1.38, 1.57) Darunavir/ ritonavir + emtricitabine/ tenofovir DF , darunavir 800 once daily 90 once daily 400 once daily 23 1.01 (0.96, 1.06) 1.04 (0.99, 1.08) 1.08 (0.98, 1.20) ritonavir 100 once daily 1.17 (1.01, 1.35) 1.25 (1.15, 1.36) 1.48 (1.34, 1.63) tenofovir DF 300 once daily 1.64 (1.54, 1.74) 1.50 (1.42, 1.59) 1.59 (1.49, 1.70) Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide elvitegravir 150 once daily 90 once daily 400 once daily 30 0.98 (0.90, 1.07) 1.11 (1.02, 1.20) 1.46 (1.28, 1.66) cobicistat 150 once daily 1.23 (1.15, 1.32) 1.53 (1.45, 1.62) 3.25 (2.88, 3.67) tenofovir alafenamide 10 once daily 0.90 (0.73, 1.11) 0.86 (0.78, 0.95) NA Norelgestromin norgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily 90 once daily ND 15 1.02 (0.89, 1.16) 1.03 (0.90, 1.18) 1.09 (0.91, 1.31) ND 400 once daily 1.07 (0.94, 1.22) 1.06 (0.92, 1.21) 1.07 (0.89, 1.28) Norgestrel 90 once daily ND 1.03 (0.87, 1.23) 0.99 (0.82, 1.20) 1.00 (0.81, 1.23) ND 400 once daily 1.18 (0.99, 1.41) 1.19 (0.98, 1.45) 1.23 (1.00, 1.51) Ethinyl estradiol 90 once daily ND 1.40 (1.18, 1.66) 1.20 (1.04, 1.39) 0.98 (0.79, 1.22) ND 400 once daily 1.15 (0.97, 1.36) 1.09 (0.94, 1.26) 0.99 (0.80, 1.23) Midazolam 2.5 single dose 90 single dose ND 30 1.07 (1.00, 1.14) 0.99 (0.95, 1.04) NA 0.95 (0.87, 1.04) 0.89 (0.84, 0.95) NA Raltegravir 400 twice daily 90 once daily ND 28 0.82 (0.66, 1.02) 0.85 (0.70, 1.02) 1.15 (0.90, 1.46) ND 400 single dose 19 0.57 (0.44, 0.75) 0.73 (0.59, 0.91) 0.95 (0.81, 1.12) Simeprevir 150 once daily 30 once daily ND 22 2.61 (2.39, 2.86) 2.69 (2.44, 2.96) NA Tacrolimus 5 single dose ND 400 single dose 16 0.73 (0.59, 0.90) 1.09 (0.84, 1.40) NA Tenofovir DF 300 once daily Administered as Atripla (efavirenz, emtricitabine, tenofovir DF). The effects of ledipasvir and sofosbuvir on tenofovir exposures are similar when tenofovir is administered as Atripla, Complera ® , or Truvada + dolutegravir. 90 once daily 400 once daily 15 1.79 (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.

20210625

7

3 DOSAGE FORMS AND STRENGTHS Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are available as orange, diamond-shaped, film-coated tablets debossed with "ASE" on one side and "9875" on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. Tablets: 90 mg of ledipasvir and 400 mg of sofosbuvir. ( 3 )

Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir LEDIPASVIR LEDIPASVIR SOFOSBUVIR SOFOSBUVIR ALCOHOL COPOVIDONE K25-31 LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SILICON DIOXIDE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE WATER TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 TALC FD&C YELLOW NO. 6 POLYVINYL ALCOHOL, UNSPECIFIED ASE;9875

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays. Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to 300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to 100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures approximately 10 and 4 times, respectively, higher than the exposure in humans at the recommended human dose (RHD). Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo mouse micronucleus assays. Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and females respectively, the exposure in humans at the RHD. Impairment of Fertility Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3 times the exposure in humans at the RHD. At the highest dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times, in males and females, respectively, the exposure in humans at the RHD. Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, exposure to the predominant circulating metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays. Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to 300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to 100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures approximately 10 and 4 times, respectively, higher than the exposure in humans at the recommended human dose (RHD). Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo mouse micronucleus assays. Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day), resulting in exposures of the predominant circulating metabolite GS-331007 of approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and females respectively, the exposure in humans at the RHD. Impairment of Fertility Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora lutea and implantation sites were reduced slightly at maternal exposures approximately 3 times the exposure in humans at the RHD. At the highest dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times, in males and females, respectively, the exposure in humans at the RHD. Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, exposure to the predominant circulating metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.

NDA205834

Ledipasvir and Sofosbuvir

Ledipasvir and Sofosbuvir

72626-2601

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Mechanism of Action Ledipasvir 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 a 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 a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and 4a with IC 50 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 Activity In HCV replicon assays, the EC 50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC 50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates from treatment-naïve 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 EC 50 values ranging between 0.002 nM to 0.16 nM against 11 genotype 4 subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The median EC 50 value for subtype 4b was 199.6 nM (range 0.66–1799 nM; N=3); the two 4b isolates with EC 50 values greater than 100 nM had NS5A resistance-associated polymorphisms L30S+M31M+P58S+Y93H. The median EC 50 value of ledipasvir was 0.03 nM against genotype 5a isolates (range 0.008–0.081 nM; N=35). For genotype 6, the EC 50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC 50 values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the median EC 50 values ranged from 60.6 nM to 430.1 nM. In HCV replicon assays, the EC 50 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 EC 50 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 EC 50 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 Culture HCV 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, a 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 EC 50 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 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir. In Clinical Trials Genotype 1 In a pooled analysis of subjects who received ledipasvir and sofosbuvir tablets in Phase 3 trials (ION-3, ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and 8 with genotype 1b HCV) qualified for resistance analysis due to virologic failure (35 with virologic relapse, 2 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 8 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 7 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 2 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 1 infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving HCV RNA 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 3 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 a liver pre-transplant trial. The E237G substitution was detected in 3 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 3 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 8 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in a Phase 2 trial. Genotype 4, 5 or 6 Resistance analysis was performed for 6 relapse subjects infected with HCV genotype 4 (Study 1119 and ION-4, N=3), genotype 5 (Study 1119, N=2) or genotype 6 (ELECTRON-2, N=1) and treated with ledipasvir and sofosbuvir tablets (90 mg/400 mg) 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 4 relapse subjects post-treatment who also had NS5A polymorphisms pretreatment that were retained post-treatment. Two of the relapsers with genotype 4 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 5 relapse subject also had emergent nucleotide inhibitor substitution M289I. Persistence of Resistance-Associated Substitutions No 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 1 Analyses 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 3 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 a 15% frequency threshold. In treatment-naïve 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 8 weeks and 1% (1/113) after 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg). Relapse rates among subjects without baseline NS5A polymorphisms at resistance-associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks of treatment with ledipasvir and sofosbuvir tablets. 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg). 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) + ribavirin compared to 2/15 (13%) subjects treated with 24 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg). 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 3 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 ledipasvir and sofosbuvir tablets (90 mg/400 mg) and ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively. In the Phase 3 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, 5 or 6 Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study 1119 (N=44) and ION-4 (N=8) identified 7 HCV genotype 4 subtypes (4a, 4b, 4d, 4f, 4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d (N=11; 21%); 1 to 3 subjects were infected with each of the other genotype 4 subtypes. There were 3 subjects with subtype 4r, 2 of whom experienced virologic relapse, and both had a combination of 2 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 a subtype identified at screening or by analysis. Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in ELECTRON-2 identified 7 HCV genotype 6 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 ledipasvir and sofosbuvir 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 2 of 3 genotype 4 subjects who had baseline NS5B V321I, a polymorphism at a position associated with treatment failure to sofosbuvir and other nucleoside inhibitors; these two subjects also had baseline NS5A resistance-associated polymorphisms. For genotype 5 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 6 HCV in clinical trials by population or deep nucleotide sequence analysis. Pediatrics In Study 1116, the presence of NS5A and NS5B resistance-associated polymorphisms did not impact treatment outcome; all pediatric subjects 3 years of age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-associated polymorphisms (14%; 32/223) achieved SVR following 12 weeks treatment with ledipasvir and sofosbuvir tablets. 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.

PRINCIPAL DISPLAY PANEL - 14 Tablet Blister Pack Card Carton NDC 72626-2601-1 ASEGUA™ THERAPEUTICS Ledipasvir and Sofosbuvir 90 mg / 400 mg tablets Take 1 tablet once daily Rx only Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with Ledipasvir and Sofosbuvir Contents: Two blister cards Each blister card contains 14 tablets. Authorized generic of Harvoni ® PRINCIPAL DISPLAY PANEL - 14 Tablet Blister Pack Card Carton

Indications and Usage ( 1 ) 8/2019 Dosage and Administration Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV ( 2.2 ) 8/2019 Recommended Dosage in Pediatric Patients 3 Years of Age and Older ( 2.4 ) 8/2019 Preparation and Administration of Ledipasvir and Sofosbuvir (HARVONI) Oral Pellets ( 2.5 ) 8/2019 Renal Impairment ( 2.6 ) 11/2019

Manufactured for: Asegua Therapeutics LLC An affiliate of Gilead Sciences, Inc. Foster City, CA 94404 Asegua is a trademark of Asegua Therapeutics LLC. All other trademarks referenced herein are the property of their respective owners. 205834-AG-011

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Inform 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 a history of HBV infection [see Warnings and Precautions (5.1) ] . Serious Symptomatic Bradycardia When Coadministered with Amiodarone Advise 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 Interactions Inform patients that ledipasvir and sofosbuvir 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. John's wort [see Warnings and Precautions (5.2 , 5.3) and Drug Interactions (7) ]. Pregnancy Advise patients to avoid pregnancy during combination treatment with ledipasvir and sofosbuvir and ribavirin and for 6 months after completion of treatment. Inform patients to notify their healthcare provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1) ] . Hepatitis C Virus Transmission Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken. Administration Advise patients to take ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir for the duration that is recommended by the physician. For ledipasvir and sofosbuvir (HARVONI) oral pellets, advise patients or caregivers to read and follow the Instructions for Use for preparing the correct dose.

14 CLINICAL STUDIES 14.1 Description of Clinical Trials The efficacy and safety of ledipasvir and sofosbuvir were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH); two trials in subjects with severe renal impairment (one of which included subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 10 [see Clinical Studies (14.2 , 14.3 , 14.4 , 14.5 , 14.6 , and 14.7) ]: Table 10 Trials Conducted with Ledipasvir and Sofosbuvir with or without Ribavirin in Subjects with Chronic HCV Genotype 1, 4, 5, or 6 Infection Trial Population Study Arms (Number of Subjects Treated) ESRD = End stage renal disease; RBV = ribavirin; RI = Renal impairment; TN = Treatment-naïve subjects ION-3 Open-label. (NCT01851330) GT1, TN without cirrhosis Ledipasvir and sofosbuvir 8 weeks (215) Ledipasvir and sofosbuvir + RBV 8 weeks (216) Ledipasvir and sofosbuvir 12 weeks (216) ION-1 (NCT01701401) GT1, TN with or without cirrhosis Ledipasvir and sofosbuvir 12 weeks (214) Ledipasvir and sofosbuvir + RBV 12 weeks (217) Ledipasvir and sofosbuvir 24 weeks (217) Ledipasvir and sofosbuvir + RBV 24 weeks (217) ION-2 (NCT01768286) GT1, TE TE = Treatment-experienced subjects including those who have failed a peginterferon alfa + RBV based regimen with or without an HCV protease inhibitor. with or without cirrhosis Ledipasvir and sofosbuvir 12 weeks (109) Ledipasvir and sofosbuvir + RBV 12 weeks (111) Ledipasvir and sofosbuvir 24 weeks (109) Ledipasvir and sofosbuvir + RBV 24 weeks (111) SIRIUS Double-blind, placebo-controlled. (NCT01965535) GT1, TE with cirrhosis Ledipasvir and sofosbuvir + RBV 12 Weeks (77) Ledipasvir and sofosbuvir 24 weeks (77) ION-4 (NCT02073656) GT1 and GT4 HCV/HIV-1 coinfected TN and TE with or without cirrhosis Ledipasvir and sofosbuvir 12 Weeks (N=327 for GT1; N=8 for GT4) 1119 (NCT02081079) GT4 and GT5, TN and TE with or without cirrhosis Ledipasvir and sofosbuvir 12 Weeks (N=44 for GT4; N=41 for GT5) ELECTRON-2 (NCT01826981) GT6, TN and TE with or without cirrhosis Ledipasvir and sofosbuvir 12 Weeks (25) SOLAR-1 and SOLAR-2 (NCT01938430 and NCT02010255) GT1 and GT4 pre-transplant with decompensated cirrhosis or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or FCH Ledipasvir and sofosbuvir + RBV 12 Weeks (336) Ledipasvir and sofosbuvir + RBV 24 weeks (334) 1116 (NCT02249182) GT1 or 4 TN and TE with or without cirrhosis in pediatric subjects 3 years of age and older Ledipasvir and sofosbuvir 12 Weeks (223) Ledipasvir and sofosbuvir 24 Weeks (1) 0154 (NCT01958281) GT1 TN and TE with severe RI without dialysis Ledipasvir and sofosbuvir 12 weeks (18) 4063 (NCT03036839) GT1, 5, or 6 TN and TE TE = Treatment experienced subjects including those who have failed either interferon/peginterferon alfa/ribavirin based regimens or HCV-specific direct-acting antiviral regimens that do not include an NS5A polymerase inhibitor. with or without compensated cirrhosis, with ESRD requiring dialysis Ledipasvir and sofosbuvir 8 Weeks (45) Ledipasvir and sofosbuvir 12 Weeks (12) Ledipasvir and sofosbuvir 24 Weeks (6) Ledipasvir and sofosbuvir 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 a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a 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 a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment. 14.2 Clinical Trials in Subjects with Genotype 1 HCV Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108) ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with genotype 1 HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three treatment groups and stratified by HCV genotype (1a vs 1b): ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 8 weeks, ledipasvir and sofosbuvir tablets (90 mg/400 mg) for 12 weeks, or ledipasvir and sofosbuvir tablets (90 mg/400 mg) + ribavirin for 8 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/m 2 (range: 18 to 56 kg/m 2 ); 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 11 presents the SVR12 for the ledipasvir and sofosbuvir treatment groups in the ION-3 trial after 8 and 12 weeks of ledipasvir and sofosbuvir treatment. Ribavirin was not shown to increase the SVR12 observed with ledipasvir and sofosbuvir. Therefore, the ledipasvir and sofosbuvir + ribavirin arm is not presented in Table 11. Table 11 Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects with Genotype 1 HCV Ledipasvir and Sofosbuvir 8 Weeks (N=215) Ledipasvir and Sofosbuvir 12 Weeks (N=216) SVR12 94% (202/215) 96% (208/216) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/215 0/216 Relapse The denominator for relapse is the number of subjects with HCV RNA

8.5 Geriatric Use Clinical trials of ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir is warranted in geriatric patients [see Clinical Pharmacology (12.3) ] .

8.4 Pediatric Use The safety, pharmacokinetics, and efficacy of ledipasvir and sofosbuvir for treatment of HCV genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186 treatment-naïve, 40 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of ledipasvir and sofosbuvir for treatment of HCV genotypes 5 or 6 infection in pediatric patients 3 years of age and older are supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and pediatric patients [see Dosage and Administration (2.2 and 2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3 , 14.6 , 14.7) ] . Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1 infection who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis. 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 ledipasvir and sofosbuvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6) ]. The safety and efficacy of ledipasvir and sofosbuvir have not been established in pediatric patients less than 3 years of age.

8.1 Pregnancy Risk Summary If ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with 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 4 (rats) and 2 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (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 5 and 7 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 6 to 18 and 7 to 20, respectively, and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 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 2 (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 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 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 7 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times the exposure in humans at the RHD.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: No data are available regarding the safety of ledipasvir and sofosbuvir in pediatric patients with renal impairment. ( 8.4 ) 8.1 Pregnancy Risk Summary If ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with 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 4 (rats) and 2 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (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 5 and 7 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 6 to 18 and 7 to 20, respectively, and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 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 2 (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 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 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 7 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times the exposure in humans at the RHD. 8.2 Lactation Risk Summary It is not known whether ledipasvir, sofosbuvir, 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 mother's clinical need for ledipasvir and sofosbuvir and any potential adverse effects on the breastfed child from ledipasvir and sofosbuvir or from the underlying maternal condition. If ledipasvir and sofosbuvir is administered with ribavirin, the nursing mother's 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 5 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 7 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 a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post-dose. 8.3 Females and Males of Reproductive Potential If ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir for treatment of HCV genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186 treatment-naïve, 40 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of ledipasvir and sofosbuvir for treatment of HCV genotypes 5 or 6 infection in pediatric patients 3 years of age and older are supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and pediatric patients [see Dosage and Administration (2.2 and 2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3 , 14.6 , 14.7) ] . Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1 infection who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis. 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 ledipasvir and sofosbuvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6) ]. The safety and efficacy of ledipasvir and sofosbuvir have not been established in pediatric patients less than 3 years of age. 8.5 Geriatric Use Clinical trials of ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir is warranted in geriatric patients [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment No dosage adjustment of ledipasvir and sofosbuvir 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) , 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. 8.7 Hepatic Impairment No dosage adjustment of ledipasvir and sofosbuvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2.3) , 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 ledipasvir and sofosbuvir and ribavirin [see Adverse Reactions (6.1) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are orange, diamond-shaped, film-coated, debossed with "ASE" on one side and "9875" on the other side of the tablet. Each carton contains 28 tablets (2 blister cards each containing 14 tablets) (NDC 72626-2601-1). Store at room temperature below 30 °C (86 °F).

Store at room temperature below 30 °C (86 °F).

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ledipasvir and sofosbuvir. 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 B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( 5.1 )