ZEPATIER

6 ADVERSE REACTIONS The following adverse reaction is described below and elsewhere in the labeling: Increased Risk of ALT Elevations [see Warnings and Precautions (5.2) ]. In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea. In subjects receiving ZEPATIER with ribavirin for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 ZEPATIER is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety of ZEPATIER in adult subjects was assessed based on 2 placebo-controlled trials and 7 uncontrolled Phase 2 and 3 clinical trials in approximately 1700 subjects with chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14) ] . Adverse Reactions with ZEPATIER in Treatment-Naïve Subjects C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naïve (TN) subjects with HCV infection who received ZEPATIER or placebo one tablet once daily for 12 weeks. Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 3 . In subjects treated with ZEPATIER who reported an adverse reaction, 73% had adverse reactions of mild severity. The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis. No subjects treated with ZEPATIER or placebo had serious adverse reactions. The proportion of subjects treated with ZEPATIER or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group. Table 3: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve Subjects with HCV Treated with ZEPATIER for 12 Weeks in C-EDGE TN C-EDGE TN ZEPATIER N=316 % 12 weeks Placebo N=105 % 12 weeks Fatigue 11% 10% Headache 10% 9% C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naïve HCV/HIV co-infected subjects who received ZEPATIER one tablet once daily for 12 weeks. Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with ZEPATIER for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. Median increase in CD4+ T-cell counts of 31 cells per mm 3 was observed at the end of 12 weeks of treatment. Adverse Reactions with ZEPATIER with or without Ribavirin in Treatment-Experienced Subjects C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects. Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with ZEPATIER one tablet once daily for 12 weeks or ZEPATIER one tablet once daily with ribavirin for 16 weeks are presented in Table 4 . No subjects treated with ZEPATIER without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks with serious adverse reactions was 1%. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis. Table 4: Adverse Reactions (Moderate or Severe Intensity) Reported in ≥2% of PegIFN/RBV-Experienced Subjects with HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER + Ribavirin for 16 Weeks in C-EDGE TE C-EDGE TE ZEPATIER N=105 % 12 weeks ZEPATIER + Ribavirin N=106 % 16 weeks Anemia 0% 8% Headache 0% 6% Fatigue 5% 4% Dyspnea 0% 4% Rash or Pruritus 0% 4% Irritability 1% 3% Abdominal pain 2% 2% Depression 1% 2% Arthralgia 0% 2% Diarrhea 2% 0% The type and severity of adverse reactions with ZEPATIER with or without ribavirin in 10 treatment-experienced subjects with HCV/HIV co-infection were comparable to those reported in subjects without HIV co-infection. Median increase in CD4+ T-cell counts of 32 cells/mm 3 was observed at the end of 12 weeks of treatment with ZEPATIER alone. In subjects treated with ZEPATIER with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm 3 at the end of treatment. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection. C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with ZEPATIER once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. Adverse Reactions with ZEPATIER in Subjects with Severe Renal Impairment including Subjects on Hemodialysis The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER) [see Clinical Studies (14.4) ] . The adverse reactions (all intensity) occurring in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 5 . In subjects treated with ZEPATIER who reported an adverse reaction, 76% had adverse reactions of mild severity. The proportion of subjects treated with ZEPATIER or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm. Table 5: Adverse Reactions (All Intensity) Reported in ≥5% of Treatment-Naïve or PegIFN/RBV-Experienced Subjects with Stage 4 or 5 Chronic Kidney Disease and HCV Treated with ZEPATIER for 12 Weeks in C-SURFER ZEPATIER N=122 % 12 weeks Placebo N=113 % 12 weeks Nausea 11% 8% Headache 11% 5% Fatigue 5% 8% Laboratory Abnormalities in Subjects Receiving ZEPATIER with or without Ribavirin Serum ALT Elevations During clinical trials with ZEPATIER with or without ribavirin, regardless of treatment duration, 1% (12/1599) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with ZEPATIER or after completion of therapy [see Warnings and Precautions (5.2) ] . The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentrations [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations. Serum Bilirubin Elevations During clinical trials with ZEPATIER with or without ribavirin, regardless of treatment duration, elevations in bilirubin at greater than 2.5 times ULN were observed in 6% of subjects receiving ZEPATIER with ribavirin compared to less than 1% in those receiving ZEPATIER alone. These bilirubin increases were predominately indirect and generally observed in association with ribavirin co-administration. Bilirubin elevations were typically not associated with serum ALT elevations. Decreased Hemoglobin During clinical trials with ZEPATIER with or without ribavirin, the mean change from baseline in hemoglobin levels in subjects treated with ZEPATIER for 12 weeks was –0.3 g per dL and with ZEPATIER with ribavirin for 16 weeks was approximately –2.2 g per dL. Hemoglobin declined during the first 8 weeks of treatment, remained low during the remainder of treatment, and normalized to baseline levels during follow-up. Less than 1% of subjects treated with ZEPATIER with ribavirin had hemoglobin levels decrease to less than 8.5 g per dL during treatment. No subjects treated with ZEPATIER alone had a hemoglobin level less than 8.5 g per dL. Clinical Trial in Pediatric Subjects Adverse Reactions in Pediatric Subjects 12 Years of Age and Older The safety of ZEPATIER was assessed in pediatric subjects 12 years of age and older based on data from 22 subjects, without cirrhosis, who were treated with ZEPATIER for 12 weeks in a Phase 2b, open-label clinical trial (MK-5172-079). The adverse reactions observed were consistent with those observed in clinical trials of ZEPATIER in adults [see Clinical Studies (14.6) ] . The adverse drug reactions observed in greater than or equal to 5% of subjects receiving ZEPATIER were headache (14%) and nausea (9%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ZEPATIER. Because these 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. Skin and Subcutaneous Tissue Disorders Angioedema Hepatobiliary Disorders Hepatic decompensation, hepatic failure [see Warnings and Precautions (5.3) ]

4 CONTRAINDICATIONS ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to the expected significantly increased grazoprevir plasma concentration and the increased risk of alanine aminotransferase (ALT) elevations [see Warnings and Precautions (5.2) , Use in Specific Populations (8.9) , and Clinical Pharmacology (12.3) ] . ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of hepatic decompensation due to the risk of hepatic decompensation [see Warnings and Precautions (5.3) , Use in Specific Populations (8.9) ] . ZEPATIER is contraindicated with inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz [see Warnings and Precautions (5.5) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] . If ZEPATIER 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. Table 2 lists drugs that are contraindicated with ZEPATIER. Table 2: Drugs that are Contraindicated with ZEPATIER Drug Class Drug(s) within Class that are Contraindicated Clinical Comment This table is not a comprehensive list of all drugs that strongly induce CYP3A. This table may not include all OATP1B1/3 inhibitors that significantly increase grazoprevir plasma concentrations. Anticonvulsants Phenytoin Carbamazepine May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction. Antimycobacterials Rifampin May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction. Herbal Products St. John's Wort (Hypericum perforatum) May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction. HIV Medications Efavirenz Efavirenz is included as a strong CYP3A inducer in this table, since co-administration reduced grazoprevir exposure by ≥80% [see Table 9 ] . May lead to loss of virologic response to ZEPATIER due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by CYP3A induction. HIV Medications Atazanavir Darunavir Lopinavir Saquinavir Tipranavir May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Immunosuppressants Cyclosporine May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Patients with moderate or severe hepatic impairment (Child-Pugh B or C). ( 4 ) OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations, strong CYP3A inducers, and efavirenz. ( 4 ) If ZEPATIER is administered with ribavirin, the contraindications to ribavirin also apply. ( 4 )

11 DESCRIPTION ZEPATIER is a fixed-dose combination tablet containing elbasvir and grazoprevir for oral administration. Elbasvir is an HCV NS5A inhibitor, and grazoprevir is an HCV NS3/4A protease inhibitor. Each tablet contains 50 mg elbasvir and 100 mg grazoprevir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium lauryl sulfate, and vitamin E polyethylene glycol succinate. The tablets are film-coated with a coating material containing the following inactive ingredients: carnauba wax, ferrosoferric oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Elbasvir: The IUPAC name for elbasvir is Dimethyl N , N' -([(6 S )-6-phenylindolo[1,2- c ][1,3]benzoxazine-3,10-diyl]bis{1 H -imidazole-5,2-diyl-(2 S )-pyrrolidine-2,1-diyl[(2 S )-3-methyl-1-oxobutane-1,2-diyl]})dicarbamate. It has a molecular formula of C 49 H 55 N 9 O 7 and a molecular weight of 882.02. It has the following structural formula: Elbasvir is practically insoluble in water (less than 0.1 mg per mL) and very slightly soluble in ethanol (0.2 mg per mL), but is very soluble in ethyl acetate and acetone. Chemical Structure Grazoprevir: The IUPAC name for grazoprevir is (1a R ,5 S ,8 S ,10 R ,22a R )- N -[(1 R ,2 S )-1-[(Cyclopropylsulfonamido)carbonyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8 H -7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12- b ]quinoxaline-8-carboxamide. It has a molecular formula of C 38 H 50 N 6 O 9 S and a molecular weight of 766.90. It has the following structural formula: Grazoprevir is practically insoluble in water (less than 0.1 mg per mL) but is freely soluble in ethanol and some organic solvents (e.g., acetone, tetrahydrofuran and N,N-dimethylformamide). Chemical Structure

2 DOSAGE AND ADMINISTRATION Testing Prior to Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) Genotype 1a: Testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended. ( 2.1 ) Obtain hepatic laboratory testing. ( 2.1 ) Recommended dosage in adult and pediatric patients 12 years of age and older or weighing at least 30 kg: One tablet taken orally once daily with or without food. ( 2.2 ) Dosage Regimens and Durations for ZEPATIER in Patients with Genotype 1 or 4 HCV with or without Cirrhosis Patient Population Treatment Duration Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced Peginterferon alfa + ribavirin. without baseline NS5A polymorphisms Polymorphisms at amino acid positions 28, 30, 31, or 93. ZEPATIER 12 weeks Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms ZEPATIER + ribavirin 16 weeks Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced ZEPATIER 12 weeks Genotype 1a or 1b: PegIFN/RBV/PI-experienced Peginterferon alfa + ribavirin + HCV NS3/4A protease inhibitor. ZEPATIER + ribavirin 12 weeks Genotype 4: Treatment-naïve ZEPATIER 12 weeks Genotype 4: PegIFN/RBV-experienced ZEPATIER + ribavirin 16 weeks HCV/HIV-1 co-infection: Follow the dosage recommendations in the table above. ( 2.2 ) Renal Impairment, including hemodialysis: No dosage adjustment of ZEPATIER is recommended. Refer to ribavirin prescribing information for ribavirin dosing and dosage modifications. ( 2.3 ) 2.1 Testing Prior to the Initiation of Therapy Testing for HBV Infection 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 ZEPATIER [see Warnings and Precautions (5.1) ] . NS5A Resistance Testing in HCV Genotype 1a-Infected Patients Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to initiation of treatment with ZEPATIER to determine dosage regimen and duration [see Dosage and Administration (2.2) , Table 1 ] . In subjects receiving ZEPATIER for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93 [see Microbiology (12.4) , Table 12 ] . Hepatic Laboratory Testing Obtain hepatic laboratory testing prior to and during treatment with ZEPATIER [see Warnings and Precautions (5.2 , 5.3) ]. 2.2 Recommended Dosage in Adult and Pediatric Patients 12 Years of Age and Older or Weighing at Least 30 kg ZEPATIER is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 mg of grazoprevir in a single tablet. The recommended dosage of ZEPATIER is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . ZEPATIER is used in combination with ribavirin in certain patient populations (see Table 1 ). When administered with ZEPATIER, the recommended dosage of ribavirin in patients without renal impairment is weight-based administered in two divided doses with food. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information. Treatment Regimen and Duration of Therapy Relapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups [see Clinical Studies (14) ]. Table 1 below provides the recommended ZEPATIER treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis. Table 1: Recommended Dosage Regimens and Durations for ZEPATIER for Treatment of HCV Genotype 1 or 4 in Patients with or without Cirrhosis Patient Population Treatment Duration Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced Patients who have failed treatment with peginterferon alfa (PegIFN) + ribavirin (RBV). without baseline NS5A polymorphisms NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93. See section 2.1 Testing prior to the initiation of therapy, subsection NS5A resistance testing in HCV genotype 1a-infected patients. ZEPATIER 12 weeks Genotype 1a: Treatment-naïve or PegIFN/RBV-experienced with baseline NS5A polymorphisms ZEPATIER + RBV For patients with CrCl greater than 50 mL per minute, the recommended dosage of ribavirin is weight-based (less than 66 kg = 800 mg per day, 66 to 80 kg = 1000 mg per day, 81 to 105 kg = 1200 mg per day, greater than 105 kg = 1400 mg per day) administered in two divided doses with food. For patients with CrCl less than or equal to 50 mL per minute, including patients receiving hemodialysis, refer to the ribavirin tablet prescribing information for the correct ribavirin dosage. In pediatric patients, the dosing for ribavirin is weight-based in two divided doses. Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage regimen. 16 weeks Genotype 1b: Treatment-naïve or PegIFN/RBV-experienced ZEPATIER 12 weeks Genotype 1a The optimal ZEPATIER-based treatment regimen and duration of therapy for PegIFN/RBV/PI-experienced genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, and 93 has not been established. or 1b: PegIFN/RBV/PI-experienced Patients who have failed treatment with PegIFN + RBV + HCV NS3/4A protease inhibitor (PI): boceprevir, simeprevir, or telaprevir. ZEPATIER + RBV 12 weeks Genotype 4: Treatment-Naïve ZEPATIER 12 weeks Genotype 4: PegIFN/RBV-experienced ZEPATIER + RBV 16 weeks 2.3 Renal Impairment No dosage adjustment of ZEPATIER is recommended in patients with any degree of renal impairment including patients on hemodialysis. Administer ZEPATIER with or without ribavirin according to the recommendations in Table 1 [see Use in Specific Populations (8.8) and Clinical Studies (14.4) ] . Refer to the ribavirin tablet prescribing information for the correct ribavirin dosage for patients with CrCl less than or equal to 50 mL per minute. 2.4 Hepatic Impairment No dosage adjustment of ZEPATIER is recommended in patients with mild hepatic impairment (Child-Pugh A). ZEPATIER is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Contraindications (4) , Warnings and Precautions (5.3) , Use in Specific Populations (8.9) , and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE Human experience of overdose with ZEPATIER is limited. No specific antidote is available for overdose with ZEPATIER. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. Hemodialysis does not remove elbasvir or grazoprevir since elbasvir and grazoprevir are highly bound to plasma protein [see Clinical Pharmacology (12.3) ] .

7 DRUG INTERACTIONS Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended as they may decrease the plasma concentration of ZEPATIER. ( 7 ) Co-administration of ZEPATIER with certain strong CYP3A inhibitors is not recommended as they may increase the plasma concentration of ZEPATIER. ( 7 ) 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 ) Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.5 , 7 , 12.3 ) 7.1 Potential for Drug Interactions Grazoprevir is a substrate of OATP1B1/3 transporters. Co-administration of ZEPATIER with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations is contraindicated [see Contraindications (4) , Clinical Pharmacology (12.3) , and Table 2 ] . Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate or strong inducers of CYP3A with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of ZEPATIER with strong CYP3A inducers or efavirenz is contraindicated [see Contraindications (4) , Clinical Pharmacology (12.3) , and Table 2 ]. Co-administration of ZEPATIER with moderate CYP3A inducers is not recommended [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) , and Table 6 ]. Co-administration of ZEPATIER with strong CYP3A inhibitors may increase elbasvir and grazoprevir concentrations. Co-administration of ZEPATIER with certain strong CYP3A inhibitors is not recommended [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) , and Table 6 ] . 7.2 Established and other Potentially Significant Drug Interactions If dose adjustments of concomitant medications are made due to treatment with ZEPATIER, doses should be readjusted after administration of ZEPATIER is completed. 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 CYP450 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 ZEPATIER, the components of ZEPATIER (elbasvir [EBR] and grazoprevir [GZR]) as individual agents, or are predicted drug interactions that may occur with ZEPATIER [see Contraindications (4) , Warnings and Precautions (5.5) , and Clinical Pharmacology (12.3) ] . Table 6: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted Interactions This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase Clinical Comment Antibiotics : Nafcillin ↓ EBR ↓ GZR Co-administration of ZEPATIER with nafcillin may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. Antifungals: oral Ketoconazole These interactions have been studied in healthy adults. ↑ EBR ↑ GZR Co-administration of oral ketoconazole is not recommended. Endothelin Antagonists: Bosentan ↓ EBR ↓ GZR Co-administration of ZEPATIER with bosentan may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. Immunosuppressants: Tacrolimus ↑ tacrolimus Frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of co-administration is recommended. HIV Medications: Etravirine ↓ EBR ↓ GZR Co-administration of ZEPATIER with etravirine may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. Elvitegravir/ cobicistat/ emtricitabine/ tenofovir (disoproxil fumarate or alafenamide) ↑ EBR ↑ GZR Co-administration of cobicistat-containing regimens is not recommended. HMG-CoA Reductase Inhibitors See Drug Interactions (7.3) for a list of HMG Co-A reductase inhibitors without clinically relevant interactions with ZEPATIER. : Atorvastatin ↑ atorvastatin The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with ZEPATIER. Rosuvastatin ↑ rosuvastatin The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with ZEPATIER. Fluvastatin Lovastatin Simvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin Statin-associated adverse events such as myopathy should be closely monitored. The lowest necessary dose should be used when co-administered with ZEPATIER. Wakefulness-Promoting Agents: Modafinil ↓ EBR ↓ GZR Co-administration of ZEPATIER with modafinil may lead to reduced therapeutic effect of ZEPATIER. Co-administration is not recommended. 7.3 Drugs without Clinically Significant Interactions with ZEPATIER The interaction between the components of ZEPATIER (elbasvir or grazoprevir) or ZEPATIER and the following drugs were evaluated in clinical studies, and no dose adjustments are needed when ZEPATIER is used with the following drugs individually: acid reducing agents (proton pump inhibitors, H2 blockers, antacids), buprenorphine/naloxone, digoxin, dolutegravir, methadone, mycophenolate mofetil, oral contraceptive pills, phosphate binders, pitavastatin, pravastatin, prednisone, raltegravir, ribavirin, rilpivirine, tenofovir disoproxil fumarate, and sofosbuvir [see Clinical Pharmacology (12.3) ] . No clinically relevant drug-drug interaction is expected when ZEPATIER is co-administered with abacavir, emtricitabine, entecavir, and lamivudine.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZEPATIER is a fixed-dose combination of elbasvir and grazoprevir 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 elbasvir and grazoprevir. The effect of elbasvir 700 mg on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a concentration 3 to 4 times the therapeutic concentration, elbasvir does not prolong QTc to any clinically relevant extent. The effect of grazoprevir 1600 mg (16 times the approved dose) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a concentration 40 times the therapeutic concentration, grazoprevir does not prolong QTc to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetic properties of elbasvir and grazoprevir have been evaluated in non-HCV-infected adult subjects and in HCV-infected adult subjects. Elbasvir pharmacokinetics were similar in healthy subjects and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects. Ribavirin co-administration with ZEPATIER had no clinically relevant impact on plasma AUC and C max of elbasvir and grazoprevir compared to administration of ZEPATIER alone. The geometric mean steady-state pharmacokinetic parameter values for elbasvir and grazoprevir in non-cirrhotic HCV-infected subjects are provided in Table 7 . Following once daily administration of ZEPATIER to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days. Table 7: Geometric Mean (90% Confidence Interval) for Elbasvir and Grazoprevir Steady State Pharmacokinetic Parameter Values in Non-Cirrhotic HCV-Infected Subjects Estimated Based on Population Pharmacokinetic Modeling Geometric Mean (90% Confidence Interval) AUC 0-24 (ng•hr/mL) C max (ng/mL) C 24 (ng/mL) Elbasvir 1920 (1880, 1960) 121 (118, 123) 48.4 (47.3, 49.6) Grazoprevir 1420 (1400, 1530) 165 (161, 176) 18.0 (17.8, 19.9) Absorption Following administration of ZEPATIER to HCV-infected subjects, elbasvir peak concentrations occur at a median T max of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median T max of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%. Effect of Food Relative to fasting conditions, the administration of a single dose of ZEPATIER with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC 0-inf and C max of approximately 11% and 15%, respectively, and increases in grazoprevir AUC 0-inf and C max of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food [see Dosage and Administration (2.2) ] . Distribution Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling. In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter. Elimination The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects. Metabolism Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma. Excretion The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Specific Populations Pediatric Population The pharmacokinetics of elbasvir and grazoprevir were evaluated in 22 pediatric subjects 12 years of age and older, with HCV genotype 1 or 4, who received a daily dose of ZEPATIER (50 mg elbasvir/100 mg grazoprevir). The pharmacokinetic properties of elbasvir and grazoprevir in pediatric subjects 12 years of age and older are provided in Table 8. Exposures in pediatric subjects were comparable to those observed in adults. Table 8: Geometric Mean (90% Confidence Interval) for Elbasvir and Grazoprevir Steady State Pharmacokinetic Parameter Values in Non-Cirrhotic HCV-Infected Pediatric Subjects Ages 12 to <18 Years PK Parameters AUC 0-24 and C max N=22; C trough N=21 Geometric Mean (90% Confidence Interval) AUC 0-24 (ng•hr/mL) C max (ng/mL) C 24 (ng/mL) Elbasvir 2120 (1800, 2510) 167 (140, 199) 50.3 (41.7, 60.6) Grazoprevir 1110 (871, 1410) 188 (140, 253) 11.7 (9.43, 14.5) Geriatric Population In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age. Gender In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. Weight/BMI In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53 kg subject compared to a 77 kg subject. This change is not clinically relevant for grazoprevir. Race/Ethnicity In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans. Renal Impairment In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound. Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant [see Use in Specific Populations (8.8) ]. Hepatic Impairment The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A [CP-A], score of 5-6), moderate hepatic impairment (Child-Pugh Category B [CP-B], score of 7-9) and severe hepatic impairment (Child-Pugh Category C [CP-C], score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects including CP-A subjects with compensated cirrhosis. Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects. Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects. Drug Interaction Studies Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co-administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. Table 9 summarizes the effects of co-administered drugs on the exposures of the individual components of ZEPATIER (elbasvir and grazoprevir). Table 10 summarizes the effects of the individual components of ZEPATIER on the exposures of the co-administered drugs. For information regarding clinical recommendations, [see Contraindications (4) , Warnings and Precautions (5) , and Drug Interactions (7) ]. Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations. Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see Tables 6 and 10 ). Elbasvir inhibited P-gp in vitro , but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see Table 10 ) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro . Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Clinically significant drug interactions with ZEPATIER as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data. Table 9: Drug Interactions: Changes in Pharmacokinetics of Elbasvir or Grazoprevir in the Presence of Co-Administered Drug Co-Administered Drug Regimen of Co-Administered Drug Regimen of EBR or/and GZR N Geometric Mean Ratio [90% CI] of EBR and GZR PK with/without Co-Administered Drug (No Effect=1.00) AUC AUC 0-inf for single-dose, AUC 0-24 for once daily. C max C24 Abbreviations: EBR, elbasvir; GZR, grazoprevir; IV, intravenous; PO, oral; EBR + GZR, administration of EBR and GZR as separate pills; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet. Antifungal Ketoconazole 400 mg once daily EBR 50 mg single-dose 7 EBR 1.80 (1.41, 2.29) 1.29 (1.00, 1.66) 1.89 (1.37, 2.60) 400 mg once daily GZR 100 mg single-dose 8 GZR 3.02 (2.42, 3.76) 1.13 (0.77, 1.67) 2.01 (1.49, 2.71) Antimycobacterial Rifampin 600 mg single-dose IV EBR 50 mg single-dose 14 EBR 1.22 (1.06, 1.40) 1.41 (1.18, 1.68) 1.31 (1.12, 1.53) 600 mg single-dose PO EBR 50 mg single-dose 14 EBR 1.17 (0.98, 1.39) 1.29 (1.06, 1.58) 1.21 (1.03, 1.43) 600 mg PO once daily GZR 200 mg once daily 12 GZR 0.93 (0.75, 1.17) 1.16 (0.82, 1.65) 0.10 (0.07, 0.13) 600 mg IV single-dose GZR 200 mg single-dose 12 GZR 10.21 (8.68, 12.00) 10.94 (8.92, 13.43) 1.77 (1.40, 2.24) 600 mg PO single-dose GZR 200 mg once daily 12 GZR 8.35 (7.38, 9.45) AUC 0-24 6.52 (5.16, 8.24) 1.62 (1.32, 1.98) HCV Antiviral EBR 20 mg once daily GZR 200 mg once daily 10 GZR 0.90 (0.63, 1.28) 0.87 (0.50, 1.52) 0.94 (0.77, 1.15) GZR 200 mg once daily EBR 20 mg once daily 10 EBR 1.01 (0.83, 1.24) 0.93 (0.76, 1.13) 1.02 (0.83, 1.24) HIV Protease Inhibitor Atazanavir/ ritonavir 300 mg/100 mg once daily EBR 50 mg once daily 10 EBR 4.76 (4.07, 5.56) 4.15 (3.46, 4.97) 6.45 (5.51, 7.54) 300 mg/100 mg once daily GZR 200 mg once daily 12 GZR 10.58 (7.78, 14.39) 6.24 (4.42, 8.81) 11.64 (7.96, 17.02) Darunavir/ ritonavir 600 mg/100 mg twice daily EBR 50 mg once daily 10 EBR 1.66 (1.35, 2.05) 1.67 (1.36, 2.05) 1.82 (1.39, 2.39) 600 mg/100 mg twice daily GZR 200 mg once daily 13 GZR 7.50 (5.92, 9.51) 5.27 (4.04, 6.86) 8.05 (6.33, 10.24) Lopinavir/ ritonavir 400 mg/100 mg twice daily EBR 50 mg once daily 10 EBR 3.71 (3.05, 4.53) 2.87 (2.29, 3.58) 4.58 (3.72, 5.64) 400 mg/100 mg twice daily GZR 200 mg once daily 13 GZR 12.86 (10.25, 16.13) 7.31 (5.65, 9.45) 21.70 (12.99, 36.25) Ritonavir Higher doses of ritonavir have not been tested in a drug interaction study with GZR. 100 mg twice daily GZR 200 mg single-dose 10 GZR 2.03 (1.60, 2.56) 1.15 (0.60, 2.18) 1.88 (1.65, 2.14) HIV Integrase Strand Transfer Inhibitor Dolutegravir 50 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 EBR 0.98 (0.93, 1.04) 0.97 (0.89, 1.05) 0.98 (0.93, 1.03) 50 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 GZR 0.81 (0.67, 0.97) 0.64 (0.44, 0.93) 0.86 (0.79, 0.93) Raltegravir 400 mg single-dose EBR 50 mg single-dose 10 EBR 0.81 (0.57, 1.17) 0.89 (0.61, 1.29) 0.80 (0.55, 1.16) 400 mg twice daily GZR 200 mg once daily 11 GZR 0.89 (0.72, 1.09) 0.85 (0.62, 1.16) 0.90 (0.82, 0.99) HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz 600 mg once daily EBR 50 mg once daily 10 EBR 0.46 (0.36, 0.59) 0.55 (0.41, 0.73) 0.41 (0.28, 0.59) 600 mg once daily GZR 200 mg once daily 12 GZR 0.17 (0.13, 0.24) 0.13 (0.09, 0.19) 0.31 (0.25, 0.38) Rilpivirine 25 mg once daily EBR 50 mg + GZR 200 mg once daily 19 EBR 1.07 (1.00, 1.15) 1.07 (0.99, 1.16) 1.04 (0.98, 1.11) 25 mg once daily EBR 50 mg + GZR 200 mg once daily 19 GZR 0.98 (0.89, 1.07) 0.97 (0.83, 1.14) 1.00 (0.93, 1.07) HIV Nucleotide Reverse Transcriptase Inhibitor Tenofovir disoproxil fumarate 300 mg once daily EBR 50 mg once daily 10 EBR 0.93 (0.82, 1.05) 0.88 (0.77, 1.00) 0.92 (0.81, 1.05) 300 mg once daily GZR 200 mg once daily 12 GZR 0.86 (0.65, 1.12) 0.78 (0.51, 1.18) 0.89 (0.78, 1.01) HIV Fixed-Dose Combination Regimen Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate 150 mg/ 150 mg/ 200 mg/ 300 mg once daily EBR 50 mg/ GZR 100 mg once daily 21 EBR 2.18 (2.02, 2.35) 1.91 (1.77, 2.05) 2.38 (2.19, 2.60) EBR 50 mg/ GZR 100 mg once daily 21 GZR 5.36 (4.48, 6.43) 4.59 (3.70, 5.69) 2.78 (2.48, 3.11) Immunosuppressant Cyclosporine 400 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.98 (1.84, 2.13) 1.95 (1.84, 2.07) 2.21 (1.98, 2.47) 400 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 15.21 (12.83, 18.04) 17.00 (12.94, 22.34) 3.39 (2.82, 4.09) Mycophenolate mofetil 1000 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.07 (1.00, 1.14) 1.07 (0.98, 1.16) 1.05 (0.97, 1.14) 1000 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 0.74 (0.60, 0.92) 0.58 (0.42, 0.82) 0.97 (0.89, 1.06) Prednisone 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.17 (1.11, 1.24) 1.25 (1.16, 1.35) 1.04 (0.97, 1.12) 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 1.09 (0.95, 1.25) 1.34 (1.10, 1.62) 0.93 (0.87, 1.00) Tacrolimus 2 mg single-dose EBR 50 mg + GZR 200 mg once daily 16 EBR 0.97 (0.90, 1.06) 0.99 (0.88, 1.10) 0.92 (0.83, 1.02) 2 mg single-dose EBR 50 mg + GZR 200 mg once daily 16 GZR 1.12 (0.97, 1.30) 1.07 (0.83, 1.37) 0.94 (0.87, 1.02) Opioid-Substitution Therapy Buprenorphine/naloxone 8 mg/2 mg single-dose EBR 50 mg single-dose 15 EBR 1.22 (0.98, 1.52) 1.13 (0.87, 1.46) 1.22 (0.99, 1.51) 8-24 mg/ 2-6 mg once daily GZR 200 mg once daily 12 The reference (EBR or GZR alone) for the analysis consisted of subjects pooled across Phase I studies. GZR 0.86 (0.63, 1.18) 0.80 (0.54, 1.20) 0.97 (0.77, 1.22) Methadone 20-120 mg once daily EBR 50 mg once daily 10 EBR 1.20 (0.94, 1.53) 1.23 (0.94, 1.62) 1.32 (1.03, 1.68) 20-150 mg once daily GZR 200 mg once daily 12 GZR 1.03 (0.76, 1.41) 0.89 (0.60, 1.32) 0.98 (0.79, 1.23) Acid-Reducing Agent Famotidine 20 mg single-dose EBR 50 mg/ GZR 100 mg single-dose 16 EBR 1.05 (0.92, 1.18) 1.11 (0.98, 1.26) 1.03 (0.91, 1.17) 20 mg single-dose EBR 50 mg/ GZR 100 mg single-dose 16 GZR 1.10 (0.95, 1.28) 0.89 (0.71, 1.11) 1.12 (0.97, 1.30) Pantoprazole 40 mg once daily EBR 50 mg/ GZR 100 mg single-dose 16 EBR 1.05 (0.93, 1.18) 1.02 (0.92, 1.14) 1.03 (0.92, 1.17) 40 mg once daily EBR 50 mg/ GZR 100 mg single-dose 16 GZR 1.12 (0.96, 1.30) 1.10 (0.89, 1.37) 1.17 (1.02, 1.34) Phosphate Binder Calcium acetate 2668 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 EBR 0.92 (0.75, 1.14) 0.86 (0.71, 1.04) 0.87 (0.70, 1.09) 2668 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 GZR 0.79 (0.68, 0.91) 0.57 (0.40, 0.83) 0.77 (0.61, 0.99) Sevelamer carbonate 2400 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 EBR 1.13 (0.94, 1.37) 1.07 (0.88, 1.29) 1.22 (1.02, 1.45) 2400 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 GZR 0.82 (0.68, 0.99) 0.53 (0.37, 0.76) 0.84 (0.71, 0.99) Statin Atorvastatin 20 mg single-dose GZR 200 mg once daily 9 GZR 1.26 (0.97, 1.64) 1.26 (0.83, 1.90) 1.11 (1.00, 1.23) Pitavastatin 1 mg single-dose GZR 200 mg once daily 9 GZR 0.81 (0.70, 0.95) 0.72 (0.57, 0.92) 0.91 (0.82, 1.01) Pravastatin 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 EBR 0.98 (0.93, 1.02) 0.97 (0.89, 1.05) 0.97 (0.92, 1.02) 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 GZR 1.24 (1.00, 1.53) 1.42 (1.00, 2.03) 1.07 (0.99, 1.16) Rosuvastatin 10 mg single-dose EBR 50 mg + GZR 200 mg single-dose 11 EBR 1.09 (0.98, 1.21) 1.11 (0.99, 1.26) 0.96 (0.86, 1.08) 10 mg single-dose GZR 200 mg once daily 11 GZR 1.16 (0.94, 1.44) 1.13 (0.77, 1.65) 0.93 (0.84, 1.03) 10 mg single-dose EBR 50 mg + GZR 200 mg once daily 11 GZR 1.01 (0.79, 1.28) 0.97 (0.63, 1.50) 0.95 (0.87, 1.04) Table 10: Drug Interactions: Changes in Pharmacokinetics for Co-Administered Drug in the Presence of Elbasvir, Grazoprevir, or Co-Administered Elbasvir and Grazoprevir Co-Administered Drug Regimen of Co-Administered Drug EBR or/and GZR Administration EBR or/and GZR Regimen N Geometric Mean Ratio [90% CI] of Co-Administered Drug PK with/without EBR or/and GZR (No Effect=1.00) AUC AUC 0-inf for single-dose administration; AUC 0-24 for once daily administration; AUC 0-12 for twice daily administration C max C trough C24 for once daily administration; C12 for twice daily administration. Abbreviations: EBR, elbasvir; GZR, grazoprevir; EBR + GZR, administration of EBR and GZR as separate tablets; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet P-gp Substrate Digoxin Digoxin 0.25 mg single-dose EBR 50 mg once daily 18 1.11 (1.02, 1.22) 1.47 (1.25, 1.73) -- CYP3A Substrate Midazolam Midazolam 2 mg single-dose GZR 200 mg once daily 11 1.34 (1.29, 1.39) 1.15 (1.01, 1.31) -- CYP2C8 Substrate Montelukast Montelukast 10 mg single-dose GZR 200 mg once daily 23 1.11 (1.01, 1.20) 0.92 (0.81, 1.06) 1.39 (1.25, 1.56) HCV Antiviral GS-331007 Sofosbuvir 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.13 (1.05, 1.21) 0.87 (0.78, 0.96) 1.53 (1.43, 1.63) Sofosbuvir Sofosbuvir 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 2.43 (2.12, 2.79) N=14 2.27 (1.72, 2.99) -- HIV Protease Inhibitor Atazanavir/ ritonavir Atazanavir 300 mg/ ritonavir 100 mg once daily EBR 50 mg once daily 8 1.07 (0.98, 1.17) 1.02 (0.96, 1.08) 1.15 (1.02, 1.29) Atazanavir 300 mg/ ritonavir 100 mg once daily GZR 200 mg once daily 11 1.43 (1.30, 1.57) 1.12 (1.01, 1.24) 1.23 (1.13, 1.34) Darunavir/ ritonavir Darunavir 600 mg/ ritonavir 100 mg twice daily EBR 50 mg once daily 8 0.95 (0.86, 1.06) 0.95 (0.85, 1.05) 0.94 (0.85, 1.05) Darunavir 600 mg/ ritonavir 100 mg twice daily GZR 200 mg once daily 13 1.11 (0.99, 1.24) 1.10 (0.96, 1.25) 1.00 (0.85, 1.18) Lopinavir/ ritonavir Lopinavir 400 mg/ ritonavir 100 mg twice daily EBR 50 mg once daily 9 1.02 (0.93, 1.13) 1.02 (0.92, 1.13) 1.07 (0.97, 1.18) Lopinavir 400 mg/ ritonavir 100 mg twice daily GZR 200 mg once daily 13 1.03 (0.96, 1.16) 0.97 (0.88, 1.08) 0.97 (0.81, 1.15) HIV Integrase Strand Transfer Inhibitor Dolutegravir Dolutegravir 50 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 1.16 (1.00, 1.34) 1.22 (1.05, 1.40) 1.14 (0.95, 1.36) Raltegravir Raltegravir 400 mg single-dose EBR 50 mg single-dose 10 1.02 (0.81, 1.27) 1.09 (0.83, 1.44) 0.99 (0.80, 1.22) C12 Raltegravir 400 mg twice daily GZR 200 mg once daily 11 1.43 (0.89, 2.30) 1.46 (0.78, 2.73) 1.47 (1.09, 2.00) HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Efavirenz 600 mg once daily EBR 50 mg once daily 7 0.82 (0.78, 0.86) 0.74 (0.67, 0.82) 0.91 (0.87, 0.96) Efavirenz 600 mg once daily GZR 200 mg once daily 11 1.00 (0.96, 1.05) 1.03 (0.99, 1.08) 0.93 (0.88, 0.98) Rilpivirine Rilpivirine 25 mg once daily EBR + GZR 50 mg + 200 mg once daily 19 1.13 (1.07, 1.20) 1.07 (0.97, 1.17) 1.16 (1.09, 1.23) HIV Nucleotide Reverse Transcriptase Inhibitor Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate 300 mg once daily EBR 50 mg once daily 10 1.34 (1.23, 1.47) 1.47 (1.32, 1.63) 1.29 (1.18, 1.41) Tenofovir disoproxil fumarate 300 mg once daily GZR 200 mg once daily 12 1.18 (1.09, 1.28) 1.14 (1.04, 1.25) 1.24 (1.10, 1.39) Tenofovir disoproxil fumarate 300 mg once daily EBR/GZR 50 mg + 100 mg once daily 13 1.27 (1.20, 1.35) 1.14 (0.95, 1.36) 1.23 (1.09, 1.40) HIV Fixed-Dose Combination Regimen Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate Elvitegravir 150 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.10 (1.00, 1.21) 1.02 (0.93, 1.11) 1.31 (1.11, 1.55) Cobicistat 150 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.49 (1.42, 1.57) 1.39 (1.29, 1.50) -- Emtricitabine 200 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.07 (1.03, 1.10) 0.96 (0.90, 1.02) 1.19 (1.13, 1.25) Tenofovir disoproxil fumarate 300 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.18 (1.13, 1.24) 1.25 (1.14, 1.37) 1.20 (1.15, 1.26) Immunosuppressant Cyclosporine Cyclosporine 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 0.96 (0.90, 1.02) 0.90 (0.85, 0.97) 1.00 (0.92, 1.08) Mycophenolic acid Mycophenolate mofetil 1000 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 0.95 (0.87, 1.03) 0.85 (0.67, 1.07) -- Prednisolone Prednisone 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 1.08 (1.01, 1.16) 1.04 (0.99, 1.09) -- Prednisone Prednisone 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 1.08 (1.00, 1.17) 1.05 (1.00, 1.10) -- Tacrolimus Tacrolimus 2 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.43 (1.24, 1.64) 0.60 (0.52, 0.69) 1.70 (1.49, 1.94) Oral Contraceptive Ethinyl estradiol (EE) 0.03 mg EE/ 0.15 mg LNG single-dose EBR 50 mg once daily 20 1.01 (0.97, 1.05) 1.10 (1.05, 1.16) -- GZR 200 mg once daily 20 1.10 (1.05, 1.14) 1.05 (0.98, 1.12) -- Levonorgestrel (LNG) EBR 50 mg once daily 20 1.14 (1.04, 1.24) 1.02 (0.95, 1.08) -- GZR 200 mg once daily 20 1.23 (1.15, 1.32) 0.93 (0.84, 1.03) -- Opioid Substitution Therapy Buprenorphine Buprenorphine 8 mg/Naloxone 2 mg single-dose EBR 50 mg once daily 15 0.98 (0.89, 1.08) 0.94 (0.82, 1.08) 0.98 (0.88, 1.09) Buprenorphine 8-24 mg/ Naloxone 2-6 mg once daily GZR 200 mg once daily 12 0.98 (0.81, 1.19) 0.90 (0.76, 1.07) -- R-Methadone Methadone 20-120 mg once daily EBR 50 mg once daily 10 1.03 (0.92, 1.15) 1.07 (0.95, 1.20) 1.10 (0.96, 1.26) Methadone 20-150 mg once daily GZR 200 mg once daily 12 1.09 (1.02, 1.17) 1.03 (0.96, 1.11) -- S-Methadone Methadone 20-120 mg once daily EBR 50 mg once daily 10 1.09 (0.94, 1.26) 1.09 (0.95, 1.25) 1.20 (0.98, 1.47) Methadone 20-150 mg once daily GZR 200 mg once daily 12 1.23 (1.12, 1.35) 1.15 (1.07, 1.25) -- Statin Atorvastatin Atorvastatin 10 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.94 (1.63, 2.33) 4.34 (3.10, 6.07) 0.21 (0.17, 0.26) Pitavastatin Pitavastatin 1 mg single-dose GZR 200 mg once daily 9 1.11 (0.91, 1.34) 1.27 (1.07, 1.52) -- Pravastatin Pravastatin 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 1.33 (1.09, 1.64) N=10 1.28 (1.05, 1.55) -- Rosuvastatin Rosuvastatin 10 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 2.26 (1.89, 2.69) N=8 5.49 (4.29, 7.04) 0.98 (0.84, 1.13) 12.4 Microbiology Mechanism of Action ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies. Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC 50 values of 7 pM, 4 pM, and 62 pM, respectively. Antiviral Activity In HCV replicon assays, the EC 50 values of elbasvir against full-length replicons from genotypes 1a, 1b, and 4, were 4 pM, 3 pM, and 0.3 pM, respectively. The median EC 50 values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 5 pM for genotype 1a (range 3-9 pM; N=5), 9 pM for genotype 1b (range 5-10 pM; N=4), 0.2 pM for genotype 4a (range 0.2-0.2 pM; N=2), 3,600 pM for genotype 4b (range 17 pM-34,000 pM; N=3), 0.45 pM for genotype 4d (range 0.4-0.5 pM; N=2), 1.9 pM for genotype 4f (N=1), 36.3 pM for genotype 4g (range 0.6-72 pM; N=2), 0.6 pM for genotype 4m (range 0.4-0.7 pM; N=2), 2.2 pM for genotype 4o (N=1), and 0.5 pM for genotype 4q (N=1). In HCV replicon assays, the EC 50 values of grazoprevir against full-length replicons from genotypes 1a, 1b, and 4, were 0.4 nM, 0.5 nM, and 0.3 nM, respectively. The median EC 50 values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nM for genotype 1a (range 0.4-5.1 nM; N=10), 0.3 nM for genotype 1b (range 0.2-5.9 nM; N=9), 0.3 nM for genotype 4a (N=1), 0.16 nM for genotype 4b (range 0.11-0.2 nM; N=2), and 0.24 nM for genotype 4g (range 0.15-0.33 nM; N=2). Combination Antiviral Activity Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b, and 4 which resulted in the emergence of resistance-associated amino acid substitutions in NS5A or NS3, respectively. The majority of amino acid substitutions in NS5A or NS3 selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a, 1b, or 4 replicons. For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions M28A/G/T, Q30D/E/H/K/R, L31M/V, H58D, and Y93C/H/N reduced elbasvir antiviral activity by 1.5- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L28M, L31F, and Y93H reduced elbasvir antiviral activity by 2- to 17-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity. For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y reduced grazoprevir antiviral activity by 2- to 81-fold; V36L/M, Q80K/R, or V107I single substitutions had no impact on grazoprevir antiviral activity in cell culture. In genotype 1b replicons, single NS3 substitutions F43S, Y56F, V107I, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 1.5- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity. In Clinical Studies In a pooled analysis of subjects treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials, resistance analyses of both drug targets were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on-treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects based on HCV genotypes and subtypes are shown in Table 11 . Treatment-emergent NS5A substitutions were detected in 30/37 (81%) genotype 1a-, 7/8 (88%) genotype 1b-, and 5/5 (100%) genotype 4-infected subjects. The most common treatment-emergent NS5A substitutions in genotype 1a were at position Q30 (n=22). Treatment-emergent NS3 substitutions were detected in 29/37 (78%) genotype 1a-, 2/8 (25%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects. The most common treatment-emergent NS3 substitutions in genotype 1a were at position D168 (n=18). Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62%) genotype 1a-, 1/8 (13%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects. Table 11: Treatment-Emergent Amino Acid Substitutions Among Virologic Failures in the Pooled Analysis of ZEPATIER with and without Ribavirin Regimens in Phase 2 and Phase 3 Clinical Trials Target Genotype 1a N = 37 Genotype 1b N = 8 Genotype 4 N = 5 NS5A M28A/G/T, Q30H/K/R/Y, L31F/M/V, H58D, Y93H/N/S L28M, L31F/V, Y93H L28S/T, M31I/V, P58D, Y93H NS3 V36L/M, Y56H, V107I, R155I/K, A156G/T/V, V158A, D168A/G/N/V/Y Y56F, V107I, A156T A156M/T/V, D168A/G, V170I Persistence of Resistance-Associated Substitutions The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in HCV genotype 1-infected subjects in Phase 2 and 3 trials whose virus had treatment-emergent resistance-associated substitutions in the drug target, and with available data through at least 24 weeks post-treatment using population nucleotide sequence analysis. Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than those with NS3 resistance-associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data. Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of subjects. Due to the limited number of genotype 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in this genotype could not be established. The lack of detection of a virus containing a resistance-associated substitution does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER-resistance-associated substitutions is unknown. Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response in Genotype 1-Infected Subjects Analyses using population nucleotide sequencing were conducted to explore the association between NS5A or NS3 amino acid polymorphisms and treatment response among treatment-naïve and treatment-experienced genotype 1-infected subjects. Baseline NS5A polymorphisms at resistance-associated positions (focusing on any change from subtype reference at NS5A amino acid positions 28, 30, 31, or 93) were evaluated. Baseline NS3 polymorphisms at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175 were evaluated. Analyses of SVR12 rates pooled data from subjects naïve to direct-acting antivirals and who received ZEPATIER with or without ribavirin in Phase 3 clinical trials, and censored subjects who did not achieve SVR12 for reasons unrelated to virologic failure. Genotype 1a In Clinical Studies In genotype 1a-infected subjects, the presence of one or more HCV NS5A amino acid polymorphisms at position M28, Q30, L31, or Y93 was associated with reduced efficacy of ZEPATIER for 12 weeks ( Table 12 ), regardless of prior treatment history or cirrhosis status. The prevalence of polymorphisms at any of these positions in genotype 1a-infected subjects was 11% (62/561) overall, and 12% (37/309) specifically for subjects in the U.S. across Phase 2 and Phase 3 clinical trials evaluating ZEPATIER for 12 weeks or ZEPATIER plus ribavirin for 16 weeks. The prevalence of polymorphisms at these positions in genotype 1a-infected subjects was 6% (35/561) at position M28, 2% (11/561) at position Q30, 3% (15/561) at position L31, and 2% (10/561) at position Y93. Polymorphisms at NS5A position H58 were common (10%) and were not associated with reduced ZEPATIER efficacy, except for a single virologic failure subject whose virus had baseline M28V and H58D polymorphisms. The SVR12 rates for subjects treated with ZEPATIER for 12 weeks were 88% (29/33) for subjects with M28V/T/L polymorphisms (n=29, 3, and 1, respectively), 40% (4/10) for subjects with Q30H/R/L polymorphisms (n=5, 3, and 2, respectively), 38% (5/13) for subjects with an L31M polymorphism, and 63% (5/8) for subjects with Y93C/H/N/S polymorphisms (n=3, 3, 1, and 1, respectively). Although clinical trial data are limited, among genotype 1a-infected subjects with these NS5A polymorphisms who received ZEPATIER plus ribavirin for 16 weeks, six out of six subjects achieved SVR12. The specific NS5A polymorphisms observed in subjects treated with ZEPATIER plus ribavirin for 16 weeks included M28V (n=2), Q30H (n=1), L31M (n=2), or Y93C/H (n=1 each). Table 12: Clinical Trial Data: SVR12 in HCV Genotype 1a-Infected Subjects without or with Baseline NS5A Polymorphisms NS5A Polymorphism Status ZEPATIER 12 Weeks SVR12 % (n/N) ZEPATIER + RBV 16 Weeks SVR12 % (n/N) Without baseline NS5A polymorphism (M28, Q30, L31, or Y93) 98% (441/450) 100% (49/49) With baseline NS5A polymorphism (M28 Any change from GT1a reference. , Q30 , L31 , or Y93 ) 70% (39/56) 100% (6/6) There are insufficient clinical trial data to determine the impact of HCV NS5A amino acid polymorphisms in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. In genotype 1a-infected subjects, the NS3 Q80K polymorphism did not impact treatment response. Polymorphisms at other NS3 resistance-associated positions were uncommon and were not associated with reduced treatment efficacy. In Postmarketing Observational Studies Effectiveness (SVR12 rates) in observational studies can be subject to certain biases and confounding factors that cannot be accounted for in the analyses, in part due to the nature of the study designs and populations under study. Protocol 095 In Protocol 095, a sub-study of a prospective, observational comparative study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 29 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 93% (27/29). 23 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 100% (14/14), 100% (1/1), 33% (1/3), and 100% (5/5), respectively. Six patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 100% (6/6). VA NS5A Cohort Study In a retrospective Veterans Administration (VA) NS5A cohort study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 93 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 81% (75/93). 65 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 94% (16/17), 100% (8/8), 84% (16/19), and 81% (17/21), respectively. 28 patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 64% (18/28). Genotype 1b In Clinical Studies In genotype 1b-infected subjects treated with ZEPATIER for 12 weeks, SVR12 rates (non-virologic failure-censored) were 94% (48/51) and 99% (247/248) for those with and without one or more NS5A polymorphisms at position 28, 30, 31, or 93. In genotype 1b-infected subjects, baseline NS3 polymorphisms did not impact treatment response. Effect of Baseline HCV Polymorphisms on Treatment Response in Genotype 4-Infected Subjects Phylogenetic analysis of HCV sequences from genotype 4-infected subjects (n=71) in the pooled analyses of subjects (non-virologic failure-censored) treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials identified 4 HCV genotype 4 subtypes (4a, 4d, 4k, 4o). Most subjects were infected with either subtype 4a (42%) or 4d (51%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Among subjects enrolled at U.S. study sites, 11/13 (85%) were infected with HCV subtype 4a. There were two subjects infected with HCV subtype 4d who experienced virologic failure with the regimen containing grazoprevir and elbasvir. In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS5A polymorphisms (any change from reference at NS5A amino acid positions 28, 30, 31, 58, and 93 by population nucleotide sequencing) were 100% (28/28) and for subjects without baseline NS5A polymorphisms were 95% (41/43). In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS3 polymorphisms (any change from reference at NS3 amino acid positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175 by population nucleotide sequencing) were 100% (18/18) and for subjects without baseline NS3 polymorphisms were 96% (51/53). Cross Resistance Cross resistance is possible among NS5A inhibitors and NS3/4A protease inhibitors by class. Elbasvir and grazoprevir are fully active against viral populations with substitutions conferring resistance to NS5B inhibitors. In the C-SALVAGE trial, subjects with genotype 1 infection who had failed prior treatment with boceprevir (n=28), simeprevir (n=8), or telaprevir (n=43) in combination with PegIFN + RBV received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. There are limited data to determine the impact of HCV NS3 resistance-associated substitutions detected at baseline in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. SVR was achieved in 88% (21/24) of genotype 1a and genotype 1b infected subjects with NS3 resistance-associated substitutions detected at baseline. Specific NS3 substitutions observed at baseline included one or more of the following: V36L/M (n=8), T54S (n=4), S122G/T (n=9), R155K/T (n=9), A156S/T (n=1), and D168E/N (n=3). SVR was 100% (55/55) in subjects without baseline NS3 resistance substitutions. The 3 virologic failure subjects had the following NS3 or NS5A substitutions/polymorphisms at baseline: NS3 R155T/D168N, NS3 R155K plus NS5A H58D, and NS3 T54S plus NS5A L31M. The efficacy of ZEPATIER has not been established in patients who have previously failed treatment with other regimens that included an NS5A inhibitor.

12.1 Mechanism of Action ZEPATIER is a fixed-dose combination of elbasvir and grazoprevir 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 elbasvir and grazoprevir. The effect of elbasvir 700 mg on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a concentration 3 to 4 times the therapeutic concentration, elbasvir does not prolong QTc to any clinically relevant extent. The effect of grazoprevir 1600 mg (16 times the approved dose) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a concentration 40 times the therapeutic concentration, grazoprevir does not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics The pharmacokinetic properties of elbasvir and grazoprevir have been evaluated in non-HCV-infected adult subjects and in HCV-infected adult subjects. Elbasvir pharmacokinetics were similar in healthy subjects and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects. Ribavirin co-administration with ZEPATIER had no clinically relevant impact on plasma AUC and C max of elbasvir and grazoprevir compared to administration of ZEPATIER alone. The geometric mean steady-state pharmacokinetic parameter values for elbasvir and grazoprevir in non-cirrhotic HCV-infected subjects are provided in Table 7 . Following once daily administration of ZEPATIER to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days. Table 7: Geometric Mean (90% Confidence Interval) for Elbasvir and Grazoprevir Steady State Pharmacokinetic Parameter Values in Non-Cirrhotic HCV-Infected Subjects Estimated Based on Population Pharmacokinetic Modeling Geometric Mean (90% Confidence Interval) AUC 0-24 (ng•hr/mL) C max (ng/mL) C 24 (ng/mL) Elbasvir 1920 (1880, 1960) 121 (118, 123) 48.4 (47.3, 49.6) Grazoprevir 1420 (1400, 1530) 165 (161, 176) 18.0 (17.8, 19.9) Absorption Following administration of ZEPATIER to HCV-infected subjects, elbasvir peak concentrations occur at a median T max of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median T max of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%. Effect of Food Relative to fasting conditions, the administration of a single dose of ZEPATIER with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC 0-inf and C max of approximately 11% and 15%, respectively, and increases in grazoprevir AUC 0-inf and C max of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food [see Dosage and Administration (2.2) ] . Distribution Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling. In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter. Elimination The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects. Metabolism Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma. Excretion The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Specific Populations Pediatric Population The pharmacokinetics of elbasvir and grazoprevir were evaluated in 22 pediatric subjects 12 years of age and older, with HCV genotype 1 or 4, who received a daily dose of ZEPATIER (50 mg elbasvir/100 mg grazoprevir). The pharmacokinetic properties of elbasvir and grazoprevir in pediatric subjects 12 years of age and older are provided in Table 8. Exposures in pediatric subjects were comparable to those observed in adults. Table 8: Geometric Mean (90% Confidence Interval) for Elbasvir and Grazoprevir Steady State Pharmacokinetic Parameter Values in Non-Cirrhotic HCV-Infected Pediatric Subjects Ages 12 to <18 Years PK Parameters AUC 0-24 and C max N=22; C trough N=21 Geometric Mean (90% Confidence Interval) AUC 0-24 (ng•hr/mL) C max (ng/mL) C 24 (ng/mL) Elbasvir 2120 (1800, 2510) 167 (140, 199) 50.3 (41.7, 60.6) Grazoprevir 1110 (871, 1410) 188 (140, 253) 11.7 (9.43, 14.5) Geriatric Population In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age compared to subjects less than 65 years of age. Gender In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. Weight/BMI In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53 kg subject compared to a 77 kg subject. This change is not clinically relevant for grazoprevir. Race/Ethnicity In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans. Renal Impairment In population pharmacokinetic analyses, elbasvir AUC was 25% higher in hemodialysis-dependent subjects and 46% higher in non-dialysis-dependent subjects with severe renal impairment compared to elbasvir AUC in subjects without severe renal impairment. In population pharmacokinetic analysis in HCV-infected subjects, grazoprevir AUC was 10% higher in hemodialysis-dependent subjects and 40% higher in non-dialysis-dependent subjects with severe renal impairment compared to grazoprevir AUC in subjects without severe renal impairment. Elbasvir and grazoprevir are not removed by hemodialysis. Elbasvir and grazoprevir are unlikely to be removed by peritoneal dialysis as both are highly protein bound. Overall, changes in exposure of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant [see Use in Specific Populations (8.8) ]. Hepatic Impairment The pharmacokinetics of elbasvir and grazoprevir were evaluated in non-HCV-infected subjects with mild hepatic impairment (Child-Pugh Category A [CP-A], score of 5-6), moderate hepatic impairment (Child-Pugh Category B [CP-B], score of 7-9) and severe hepatic impairment (Child-Pugh Category C [CP-C], score of 10-15). In addition, the pharmacokinetics of elbasvir and grazoprevir were also evaluated in HCV-infected subjects including CP-A subjects with compensated cirrhosis. Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. In population pharmacokinetic analyses, elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects. Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. In population pharmacokinetic analyses, grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects. Drug Interaction Studies Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co-administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. Table 9 summarizes the effects of co-administered drugs on the exposures of the individual components of ZEPATIER (elbasvir and grazoprevir). Table 10 summarizes the effects of the individual components of ZEPATIER on the exposures of the co-administered drugs. For information regarding clinical recommendations, [see Contraindications (4) , Warnings and Precautions (5) , and Drug Interactions (7) ]. Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations. Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations. Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see Tables 6 and 10 ). Elbasvir inhibited P-gp in vitro , but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see Table 10 ) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro . Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates. Clinically significant drug interactions with ZEPATIER as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data. Table 9: Drug Interactions: Changes in Pharmacokinetics of Elbasvir or Grazoprevir in the Presence of Co-Administered Drug Co-Administered Drug Regimen of Co-Administered Drug Regimen of EBR or/and GZR N Geometric Mean Ratio [90% CI] of EBR and GZR PK with/without Co-Administered Drug (No Effect=1.00) AUC AUC 0-inf for single-dose, AUC 0-24 for once daily. C max C24 Abbreviations: EBR, elbasvir; GZR, grazoprevir; IV, intravenous; PO, oral; EBR + GZR, administration of EBR and GZR as separate pills; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet. Antifungal Ketoconazole 400 mg once daily EBR 50 mg single-dose 7 EBR 1.80 (1.41, 2.29) 1.29 (1.00, 1.66) 1.89 (1.37, 2.60) 400 mg once daily GZR 100 mg single-dose 8 GZR 3.02 (2.42, 3.76) 1.13 (0.77, 1.67) 2.01 (1.49, 2.71) Antimycobacterial Rifampin 600 mg single-dose IV EBR 50 mg single-dose 14 EBR 1.22 (1.06, 1.40) 1.41 (1.18, 1.68) 1.31 (1.12, 1.53) 600 mg single-dose PO EBR 50 mg single-dose 14 EBR 1.17 (0.98, 1.39) 1.29 (1.06, 1.58) 1.21 (1.03, 1.43) 600 mg PO once daily GZR 200 mg once daily 12 GZR 0.93 (0.75, 1.17) 1.16 (0.82, 1.65) 0.10 (0.07, 0.13) 600 mg IV single-dose GZR 200 mg single-dose 12 GZR 10.21 (8.68, 12.00) 10.94 (8.92, 13.43) 1.77 (1.40, 2.24) 600 mg PO single-dose GZR 200 mg once daily 12 GZR 8.35 (7.38, 9.45) AUC 0-24 6.52 (5.16, 8.24) 1.62 (1.32, 1.98) HCV Antiviral EBR 20 mg once daily GZR 200 mg once daily 10 GZR 0.90 (0.63, 1.28) 0.87 (0.50, 1.52) 0.94 (0.77, 1.15) GZR 200 mg once daily EBR 20 mg once daily 10 EBR 1.01 (0.83, 1.24) 0.93 (0.76, 1.13) 1.02 (0.83, 1.24) HIV Protease Inhibitor Atazanavir/ ritonavir 300 mg/100 mg once daily EBR 50 mg once daily 10 EBR 4.76 (4.07, 5.56) 4.15 (3.46, 4.97) 6.45 (5.51, 7.54) 300 mg/100 mg once daily GZR 200 mg once daily 12 GZR 10.58 (7.78, 14.39) 6.24 (4.42, 8.81) 11.64 (7.96, 17.02) Darunavir/ ritonavir 600 mg/100 mg twice daily EBR 50 mg once daily 10 EBR 1.66 (1.35, 2.05) 1.67 (1.36, 2.05) 1.82 (1.39, 2.39) 600 mg/100 mg twice daily GZR 200 mg once daily 13 GZR 7.50 (5.92, 9.51) 5.27 (4.04, 6.86) 8.05 (6.33, 10.24) Lopinavir/ ritonavir 400 mg/100 mg twice daily EBR 50 mg once daily 10 EBR 3.71 (3.05, 4.53) 2.87 (2.29, 3.58) 4.58 (3.72, 5.64) 400 mg/100 mg twice daily GZR 200 mg once daily 13 GZR 12.86 (10.25, 16.13) 7.31 (5.65, 9.45) 21.70 (12.99, 36.25) Ritonavir Higher doses of ritonavir have not been tested in a drug interaction study with GZR. 100 mg twice daily GZR 200 mg single-dose 10 GZR 2.03 (1.60, 2.56) 1.15 (0.60, 2.18) 1.88 (1.65, 2.14) HIV Integrase Strand Transfer Inhibitor Dolutegravir 50 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 EBR 0.98 (0.93, 1.04) 0.97 (0.89, 1.05) 0.98 (0.93, 1.03) 50 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 GZR 0.81 (0.67, 0.97) 0.64 (0.44, 0.93) 0.86 (0.79, 0.93) Raltegravir 400 mg single-dose EBR 50 mg single-dose 10 EBR 0.81 (0.57, 1.17) 0.89 (0.61, 1.29) 0.80 (0.55, 1.16) 400 mg twice daily GZR 200 mg once daily 11 GZR 0.89 (0.72, 1.09) 0.85 (0.62, 1.16) 0.90 (0.82, 0.99) HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz 600 mg once daily EBR 50 mg once daily 10 EBR 0.46 (0.36, 0.59) 0.55 (0.41, 0.73) 0.41 (0.28, 0.59) 600 mg once daily GZR 200 mg once daily 12 GZR 0.17 (0.13, 0.24) 0.13 (0.09, 0.19) 0.31 (0.25, 0.38) Rilpivirine 25 mg once daily EBR 50 mg + GZR 200 mg once daily 19 EBR 1.07 (1.00, 1.15) 1.07 (0.99, 1.16) 1.04 (0.98, 1.11) 25 mg once daily EBR 50 mg + GZR 200 mg once daily 19 GZR 0.98 (0.89, 1.07) 0.97 (0.83, 1.14) 1.00 (0.93, 1.07) HIV Nucleotide Reverse Transcriptase Inhibitor Tenofovir disoproxil fumarate 300 mg once daily EBR 50 mg once daily 10 EBR 0.93 (0.82, 1.05) 0.88 (0.77, 1.00) 0.92 (0.81, 1.05) 300 mg once daily GZR 200 mg once daily 12 GZR 0.86 (0.65, 1.12) 0.78 (0.51, 1.18) 0.89 (0.78, 1.01) HIV Fixed-Dose Combination Regimen Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate 150 mg/ 150 mg/ 200 mg/ 300 mg once daily EBR 50 mg/ GZR 100 mg once daily 21 EBR 2.18 (2.02, 2.35) 1.91 (1.77, 2.05) 2.38 (2.19, 2.60) EBR 50 mg/ GZR 100 mg once daily 21 GZR 5.36 (4.48, 6.43) 4.59 (3.70, 5.69) 2.78 (2.48, 3.11) Immunosuppressant Cyclosporine 400 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.98 (1.84, 2.13) 1.95 (1.84, 2.07) 2.21 (1.98, 2.47) 400 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 15.21 (12.83, 18.04) 17.00 (12.94, 22.34) 3.39 (2.82, 4.09) Mycophenolate mofetil 1000 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.07 (1.00, 1.14) 1.07 (0.98, 1.16) 1.05 (0.97, 1.14) 1000 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 0.74 (0.60, 0.92) 0.58 (0.42, 0.82) 0.97 (0.89, 1.06) Prednisone 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 EBR 1.17 (1.11, 1.24) 1.25 (1.16, 1.35) 1.04 (0.97, 1.12) 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 14 GZR 1.09 (0.95, 1.25) 1.34 (1.10, 1.62) 0.93 (0.87, 1.00) Tacrolimus 2 mg single-dose EBR 50 mg + GZR 200 mg once daily 16 EBR 0.97 (0.90, 1.06) 0.99 (0.88, 1.10) 0.92 (0.83, 1.02) 2 mg single-dose EBR 50 mg + GZR 200 mg once daily 16 GZR 1.12 (0.97, 1.30) 1.07 (0.83, 1.37) 0.94 (0.87, 1.02) Opioid-Substitution Therapy Buprenorphine/naloxone 8 mg/2 mg single-dose EBR 50 mg single-dose 15 EBR 1.22 (0.98, 1.52) 1.13 (0.87, 1.46) 1.22 (0.99, 1.51) 8-24 mg/ 2-6 mg once daily GZR 200 mg once daily 12 The reference (EBR or GZR alone) for the analysis consisted of subjects pooled across Phase I studies. GZR 0.86 (0.63, 1.18) 0.80 (0.54, 1.20) 0.97 (0.77, 1.22) Methadone 20-120 mg once daily EBR 50 mg once daily 10 EBR 1.20 (0.94, 1.53) 1.23 (0.94, 1.62) 1.32 (1.03, 1.68) 20-150 mg once daily GZR 200 mg once daily 12 GZR 1.03 (0.76, 1.41) 0.89 (0.60, 1.32) 0.98 (0.79, 1.23) Acid-Reducing Agent Famotidine 20 mg single-dose EBR 50 mg/ GZR 100 mg single-dose 16 EBR 1.05 (0.92, 1.18) 1.11 (0.98, 1.26) 1.03 (0.91, 1.17) 20 mg single-dose EBR 50 mg/ GZR 100 mg single-dose 16 GZR 1.10 (0.95, 1.28) 0.89 (0.71, 1.11) 1.12 (0.97, 1.30) Pantoprazole 40 mg once daily EBR 50 mg/ GZR 100 mg single-dose 16 EBR 1.05 (0.93, 1.18) 1.02 (0.92, 1.14) 1.03 (0.92, 1.17) 40 mg once daily EBR 50 mg/ GZR 100 mg single-dose 16 GZR 1.12 (0.96, 1.30) 1.10 (0.89, 1.37) 1.17 (1.02, 1.34) Phosphate Binder Calcium acetate 2668 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 EBR 0.92 (0.75, 1.14) 0.86 (0.71, 1.04) 0.87 (0.70, 1.09) 2668 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 GZR 0.79 (0.68, 0.91) 0.57 (0.40, 0.83) 0.77 (0.61, 0.99) Sevelamer carbonate 2400 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 EBR 1.13 (0.94, 1.37) 1.07 (0.88, 1.29) 1.22 (1.02, 1.45) 2400 mg single-dose EBR 50 mg + GZR 100 mg single-dose 12 GZR 0.82 (0.68, 0.99) 0.53 (0.37, 0.76) 0.84 (0.71, 0.99) Statin Atorvastatin 20 mg single-dose GZR 200 mg once daily 9 GZR 1.26 (0.97, 1.64) 1.26 (0.83, 1.90) 1.11 (1.00, 1.23) Pitavastatin 1 mg single-dose GZR 200 mg once daily 9 GZR 0.81 (0.70, 0.95) 0.72 (0.57, 0.92) 0.91 (0.82, 1.01) Pravastatin 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 EBR 0.98 (0.93, 1.02) 0.97 (0.89, 1.05) 0.97 (0.92, 1.02) 40 mg single-dose EBR 50 mg + GZR 200 mg once daily 12 GZR 1.24 (1.00, 1.53) 1.42 (1.00, 2.03) 1.07 (0.99, 1.16) Rosuvastatin 10 mg single-dose EBR 50 mg + GZR 200 mg single-dose 11 EBR 1.09 (0.98, 1.21) 1.11 (0.99, 1.26) 0.96 (0.86, 1.08) 10 mg single-dose GZR 200 mg once daily 11 GZR 1.16 (0.94, 1.44) 1.13 (0.77, 1.65) 0.93 (0.84, 1.03) 10 mg single-dose EBR 50 mg + GZR 200 mg once daily 11 GZR 1.01 (0.79, 1.28) 0.97 (0.63, 1.50) 0.95 (0.87, 1.04) Table 10: Drug Interactions: Changes in Pharmacokinetics for Co-Administered Drug in the Presence of Elbasvir, Grazoprevir, or Co-Administered Elbasvir and Grazoprevir Co-Administered Drug Regimen of Co-Administered Drug EBR or/and GZR Administration EBR or/and GZR Regimen N Geometric Mean Ratio [90% CI] of Co-Administered Drug PK with/without EBR or/and GZR (No Effect=1.00) AUC AUC 0-inf for single-dose administration; AUC 0-24 for once daily administration; AUC 0-12 for twice daily administration C max C trough C24 for once daily administration; C12 for twice daily administration. Abbreviations: EBR, elbasvir; GZR, grazoprevir; EBR + GZR, administration of EBR and GZR as separate tablets; EBR/GZR, administration of EBR and GZR as a single fixed-dose combination tablet P-gp Substrate Digoxin Digoxin 0.25 mg single-dose EBR 50 mg once daily 18 1.11 (1.02, 1.22) 1.47 (1.25, 1.73) -- CYP3A Substrate Midazolam Midazolam 2 mg single-dose GZR 200 mg once daily 11 1.34 (1.29, 1.39) 1.15 (1.01, 1.31) -- CYP2C8 Substrate Montelukast Montelukast 10 mg single-dose GZR 200 mg once daily 23 1.11 (1.01, 1.20) 0.92 (0.81, 1.06) 1.39 (1.25, 1.56) HCV Antiviral GS-331007 Sofosbuvir 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.13 (1.05, 1.21) 0.87 (0.78, 0.96) 1.53 (1.43, 1.63) Sofosbuvir Sofosbuvir 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 2.43 (2.12, 2.79) N=14 2.27 (1.72, 2.99) -- HIV Protease Inhibitor Atazanavir/ ritonavir Atazanavir 300 mg/ ritonavir 100 mg once daily EBR 50 mg once daily 8 1.07 (0.98, 1.17) 1.02 (0.96, 1.08) 1.15 (1.02, 1.29) Atazanavir 300 mg/ ritonavir 100 mg once daily GZR 200 mg once daily 11 1.43 (1.30, 1.57) 1.12 (1.01, 1.24) 1.23 (1.13, 1.34) Darunavir/ ritonavir Darunavir 600 mg/ ritonavir 100 mg twice daily EBR 50 mg once daily 8 0.95 (0.86, 1.06) 0.95 (0.85, 1.05) 0.94 (0.85, 1.05) Darunavir 600 mg/ ritonavir 100 mg twice daily GZR 200 mg once daily 13 1.11 (0.99, 1.24) 1.10 (0.96, 1.25) 1.00 (0.85, 1.18) Lopinavir/ ritonavir Lopinavir 400 mg/ ritonavir 100 mg twice daily EBR 50 mg once daily 9 1.02 (0.93, 1.13) 1.02 (0.92, 1.13) 1.07 (0.97, 1.18) Lopinavir 400 mg/ ritonavir 100 mg twice daily GZR 200 mg once daily 13 1.03 (0.96, 1.16) 0.97 (0.88, 1.08) 0.97 (0.81, 1.15) HIV Integrase Strand Transfer Inhibitor Dolutegravir Dolutegravir 50 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 1.16 (1.00, 1.34) 1.22 (1.05, 1.40) 1.14 (0.95, 1.36) Raltegravir Raltegravir 400 mg single-dose EBR 50 mg single-dose 10 1.02 (0.81, 1.27) 1.09 (0.83, 1.44) 0.99 (0.80, 1.22) C12 Raltegravir 400 mg twice daily GZR 200 mg once daily 11 1.43 (0.89, 2.30) 1.46 (0.78, 2.73) 1.47 (1.09, 2.00) HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Efavirenz 600 mg once daily EBR 50 mg once daily 7 0.82 (0.78, 0.86) 0.74 (0.67, 0.82) 0.91 (0.87, 0.96) Efavirenz 600 mg once daily GZR 200 mg once daily 11 1.00 (0.96, 1.05) 1.03 (0.99, 1.08) 0.93 (0.88, 0.98) Rilpivirine Rilpivirine 25 mg once daily EBR + GZR 50 mg + 200 mg once daily 19 1.13 (1.07, 1.20) 1.07 (0.97, 1.17) 1.16 (1.09, 1.23) HIV Nucleotide Reverse Transcriptase Inhibitor Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate 300 mg once daily EBR 50 mg once daily 10 1.34 (1.23, 1.47) 1.47 (1.32, 1.63) 1.29 (1.18, 1.41) Tenofovir disoproxil fumarate 300 mg once daily GZR 200 mg once daily 12 1.18 (1.09, 1.28) 1.14 (1.04, 1.25) 1.24 (1.10, 1.39) Tenofovir disoproxil fumarate 300 mg once daily EBR/GZR 50 mg + 100 mg once daily 13 1.27 (1.20, 1.35) 1.14 (0.95, 1.36) 1.23 (1.09, 1.40) HIV Fixed-Dose Combination Regimen Elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate Elvitegravir 150 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.10 (1.00, 1.21) 1.02 (0.93, 1.11) 1.31 (1.11, 1.55) Cobicistat 150 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.49 (1.42, 1.57) 1.39 (1.29, 1.50) -- Emtricitabine 200 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.07 (1.03, 1.10) 0.96 (0.90, 1.02) 1.19 (1.13, 1.25) Tenofovir disoproxil fumarate 300 mg once daily EBR/GZR 50 mg / 100 mg once daily 22 1.18 (1.13, 1.24) 1.25 (1.14, 1.37) 1.20 (1.15, 1.26) Immunosuppressant Cyclosporine Cyclosporine 400 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 0.96 (0.90, 1.02) 0.90 (0.85, 0.97) 1.00 (0.92, 1.08) Mycophenolic acid Mycophenolate mofetil 1000 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 0.95 (0.87, 1.03) 0.85 (0.67, 1.07) -- Prednisolone Prednisone 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 1.08 (1.01, 1.16) 1.04 (0.99, 1.09) -- Prednisone Prednisone 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 14 1.08 (1.00, 1.17) 1.05 (1.00, 1.10) -- Tacrolimus Tacrolimus 2 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.43 (1.24, 1.64) 0.60 (0.52, 0.69) 1.70 (1.49, 1.94) Oral Contraceptive Ethinyl estradiol (EE) 0.03 mg EE/ 0.15 mg LNG single-dose EBR 50 mg once daily 20 1.01 (0.97, 1.05) 1.10 (1.05, 1.16) -- GZR 200 mg once daily 20 1.10 (1.05, 1.14) 1.05 (0.98, 1.12) -- Levonorgestrel (LNG) EBR 50 mg once daily 20 1.14 (1.04, 1.24) 1.02 (0.95, 1.08) -- GZR 200 mg once daily 20 1.23 (1.15, 1.32) 0.93 (0.84, 1.03) -- Opioid Substitution Therapy Buprenorphine Buprenorphine 8 mg/Naloxone 2 mg single-dose EBR 50 mg once daily 15 0.98 (0.89, 1.08) 0.94 (0.82, 1.08) 0.98 (0.88, 1.09) Buprenorphine 8-24 mg/ Naloxone 2-6 mg once daily GZR 200 mg once daily 12 0.98 (0.81, 1.19) 0.90 (0.76, 1.07) -- R-Methadone Methadone 20-120 mg once daily EBR 50 mg once daily 10 1.03 (0.92, 1.15) 1.07 (0.95, 1.20) 1.10 (0.96, 1.26) Methadone 20-150 mg once daily GZR 200 mg once daily 12 1.09 (1.02, 1.17) 1.03 (0.96, 1.11) -- S-Methadone Methadone 20-120 mg once daily EBR 50 mg once daily 10 1.09 (0.94, 1.26) 1.09 (0.95, 1.25) 1.20 (0.98, 1.47) Methadone 20-150 mg once daily GZR 200 mg once daily 12 1.23 (1.12, 1.35) 1.15 (1.07, 1.25) -- Statin Atorvastatin Atorvastatin 10 mg single-dose EBR + GZR 50 mg + 200 mg once daily 16 1.94 (1.63, 2.33) 4.34 (3.10, 6.07) 0.21 (0.17, 0.26) Pitavastatin Pitavastatin 1 mg single-dose GZR 200 mg once daily 9 1.11 (0.91, 1.34) 1.27 (1.07, 1.52) -- Pravastatin Pravastatin 40 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 1.33 (1.09, 1.64) N=10 1.28 (1.05, 1.55) -- Rosuvastatin Rosuvastatin 10 mg single-dose EBR + GZR 50 mg + 200 mg once daily 12 2.26 (1.89, 2.69) N=8 5.49 (4.29, 7.04) 0.98 (0.84, 1.13)

20240705

20

3 DOSAGE FORMS AND STRENGTHS ZEPATIER is available as a beige-colored, oval-shaped, film-coated tablet debossed with "770" on one side and plain on the other. Each tablet contains 50 mg elbasvir and 100 mg grazoprevir. Tablets: 50 mg elbasvir and 100 mg grazoprevir ( 3 )

ZEPATIER elbasvir and grazoprevir ELBASVIR ELBASVIR GRAZOPREVIR ANHYDROUS GRAZOPREVIR ANHYDROUS SILICON DIOXIDE COPOVIDONE K25-31 CROSCARMELLOSE SODIUM HYPROMELLOSE 2910 (3 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM CHLORIDE SODIUM LAURYL SULFATE TOCOPHERSOLAN CARNAUBA WAX FERROSOFERRIC OXIDE HYPROMELLOSE 2910 (15 MPA.S) FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE TRIACETIN Beige 770

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays. Carcinogenicity studies with elbasvir or grazoprevir have not been conducted. If ZEPATIER is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen. Refer to the ribavirin prescribing information for information on carcinogenesis and mutagenesis. Impairment of Fertility No effects on mating, female or male fertility, or early embryonic development were observed in rats at up to the highest dose tested. Systemic exposures (AUC) to elbasvir and grazoprevir were approximately 8 and 114 times, respectively, the exposure in humans at the recommended human dose. If ZEPATIER is administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. Refer to the ribavirin prescribing information for information on impairment of fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays. Carcinogenicity studies with elbasvir or grazoprevir have not been conducted. If ZEPATIER is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen. Refer to the ribavirin prescribing information for information on carcinogenesis and mutagenesis. Impairment of Fertility No effects on mating, female or male fertility, or early embryonic development were observed in rats at up to the highest dose tested. Systemic exposures (AUC) to elbasvir and grazoprevir were approximately 8 and 114 times, respectively, the exposure in humans at the recommended human dose. If ZEPATIER is administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. Refer to the ribavirin prescribing information for information on impairment of fertility.

NDA208261

ZEPATIER

elbasvir and grazoprevir

0006-3074

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Mechanism of Action ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies. Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC 50 values of 7 pM, 4 pM, and 62 pM, respectively. Antiviral Activity In HCV replicon assays, the EC 50 values of elbasvir against full-length replicons from genotypes 1a, 1b, and 4, were 4 pM, 3 pM, and 0.3 pM, respectively. The median EC 50 values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 5 pM for genotype 1a (range 3-9 pM; N=5), 9 pM for genotype 1b (range 5-10 pM; N=4), 0.2 pM for genotype 4a (range 0.2-0.2 pM; N=2), 3,600 pM for genotype 4b (range 17 pM-34,000 pM; N=3), 0.45 pM for genotype 4d (range 0.4-0.5 pM; N=2), 1.9 pM for genotype 4f (N=1), 36.3 pM for genotype 4g (range 0.6-72 pM; N=2), 0.6 pM for genotype 4m (range 0.4-0.7 pM; N=2), 2.2 pM for genotype 4o (N=1), and 0.5 pM for genotype 4q (N=1). In HCV replicon assays, the EC 50 values of grazoprevir against full-length replicons from genotypes 1a, 1b, and 4, were 0.4 nM, 0.5 nM, and 0.3 nM, respectively. The median EC 50 values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nM for genotype 1a (range 0.4-5.1 nM; N=10), 0.3 nM for genotype 1b (range 0.2-5.9 nM; N=9), 0.3 nM for genotype 4a (N=1), 0.16 nM for genotype 4b (range 0.11-0.2 nM; N=2), and 0.24 nM for genotype 4g (range 0.15-0.33 nM; N=2). Combination Antiviral Activity Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b, and 4 which resulted in the emergence of resistance-associated amino acid substitutions in NS5A or NS3, respectively. The majority of amino acid substitutions in NS5A or NS3 selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a, 1b, or 4 replicons. For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions M28A/G/T, Q30D/E/H/K/R, L31M/V, H58D, and Y93C/H/N reduced elbasvir antiviral activity by 1.5- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L28M, L31F, and Y93H reduced elbasvir antiviral activity by 2- to 17-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity. For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions Y56H, R155K, A156G/T/V, and D168A/E/G/N/S/V/Y reduced grazoprevir antiviral activity by 2- to 81-fold; V36L/M, Q80K/R, or V107I single substitutions had no impact on grazoprevir antiviral activity in cell culture. In genotype 1b replicons, single NS3 substitutions F43S, Y56F, V107I, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 1.5- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b, or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity. In Clinical Studies In a pooled analysis of subjects treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials, resistance analyses of both drug targets were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on-treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects based on HCV genotypes and subtypes are shown in Table 11 . Treatment-emergent NS5A substitutions were detected in 30/37 (81%) genotype 1a-, 7/8 (88%) genotype 1b-, and 5/5 (100%) genotype 4-infected subjects. The most common treatment-emergent NS5A substitutions in genotype 1a were at position Q30 (n=22). Treatment-emergent NS3 substitutions were detected in 29/37 (78%) genotype 1a-, 2/8 (25%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects. The most common treatment-emergent NS3 substitutions in genotype 1a were at position D168 (n=18). Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62%) genotype 1a-, 1/8 (13%) genotype 1b-, and 2/5 (40%) genotype 4-infected subjects. Table 11: Treatment-Emergent Amino Acid Substitutions Among Virologic Failures in the Pooled Analysis of ZEPATIER with and without Ribavirin Regimens in Phase 2 and Phase 3 Clinical Trials Target Genotype 1a N = 37 Genotype 1b N = 8 Genotype 4 N = 5 NS5A M28A/G/T, Q30H/K/R/Y, L31F/M/V, H58D, Y93H/N/S L28M, L31F/V, Y93H L28S/T, M31I/V, P58D, Y93H NS3 V36L/M, Y56H, V107I, R155I/K, A156G/T/V, V158A, D168A/G/N/V/Y Y56F, V107I, A156T A156M/T/V, D168A/G, V170I Persistence of Resistance-Associated Substitutions The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in HCV genotype 1-infected subjects in Phase 2 and 3 trials whose virus had treatment-emergent resistance-associated substitutions in the drug target, and with available data through at least 24 weeks post-treatment using population nucleotide sequence analysis. Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than those with NS3 resistance-associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data. Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of subjects. Due to the limited number of genotype 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in this genotype could not be established. The lack of detection of a virus containing a resistance-associated substitution does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER-resistance-associated substitutions is unknown. Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response in Genotype 1-Infected Subjects Analyses using population nucleotide sequencing were conducted to explore the association between NS5A or NS3 amino acid polymorphisms and treatment response among treatment-naïve and treatment-experienced genotype 1-infected subjects. Baseline NS5A polymorphisms at resistance-associated positions (focusing on any change from subtype reference at NS5A amino acid positions 28, 30, 31, or 93) were evaluated. Baseline NS3 polymorphisms at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175 were evaluated. Analyses of SVR12 rates pooled data from subjects naïve to direct-acting antivirals and who received ZEPATIER with or without ribavirin in Phase 3 clinical trials, and censored subjects who did not achieve SVR12 for reasons unrelated to virologic failure. Genotype 1a In Clinical Studies In genotype 1a-infected subjects, the presence of one or more HCV NS5A amino acid polymorphisms at position M28, Q30, L31, or Y93 was associated with reduced efficacy of ZEPATIER for 12 weeks ( Table 12 ), regardless of prior treatment history or cirrhosis status. The prevalence of polymorphisms at any of these positions in genotype 1a-infected subjects was 11% (62/561) overall, and 12% (37/309) specifically for subjects in the U.S. across Phase 2 and Phase 3 clinical trials evaluating ZEPATIER for 12 weeks or ZEPATIER plus ribavirin for 16 weeks. The prevalence of polymorphisms at these positions in genotype 1a-infected subjects was 6% (35/561) at position M28, 2% (11/561) at position Q30, 3% (15/561) at position L31, and 2% (10/561) at position Y93. Polymorphisms at NS5A position H58 were common (10%) and were not associated with reduced ZEPATIER efficacy, except for a single virologic failure subject whose virus had baseline M28V and H58D polymorphisms. The SVR12 rates for subjects treated with ZEPATIER for 12 weeks were 88% (29/33) for subjects with M28V/T/L polymorphisms (n=29, 3, and 1, respectively), 40% (4/10) for subjects with Q30H/R/L polymorphisms (n=5, 3, and 2, respectively), 38% (5/13) for subjects with an L31M polymorphism, and 63% (5/8) for subjects with Y93C/H/N/S polymorphisms (n=3, 3, 1, and 1, respectively). Although clinical trial data are limited, among genotype 1a-infected subjects with these NS5A polymorphisms who received ZEPATIER plus ribavirin for 16 weeks, six out of six subjects achieved SVR12. The specific NS5A polymorphisms observed in subjects treated with ZEPATIER plus ribavirin for 16 weeks included M28V (n=2), Q30H (n=1), L31M (n=2), or Y93C/H (n=1 each). Table 12: Clinical Trial Data: SVR12 in HCV Genotype 1a-Infected Subjects without or with Baseline NS5A Polymorphisms NS5A Polymorphism Status ZEPATIER 12 Weeks SVR12 % (n/N) ZEPATIER + RBV 16 Weeks SVR12 % (n/N) Without baseline NS5A polymorphism (M28, Q30, L31, or Y93) 98% (441/450) 100% (49/49) With baseline NS5A polymorphism (M28 Any change from GT1a reference. , Q30 , L31 , or Y93 ) 70% (39/56) 100% (6/6) There are insufficient clinical trial data to determine the impact of HCV NS5A amino acid polymorphisms in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. In genotype 1a-infected subjects, the NS3 Q80K polymorphism did not impact treatment response. Polymorphisms at other NS3 resistance-associated positions were uncommon and were not associated with reduced treatment efficacy. In Postmarketing Observational Studies Effectiveness (SVR12 rates) in observational studies can be subject to certain biases and confounding factors that cannot be accounted for in the analyses, in part due to the nature of the study designs and populations under study. Protocol 095 In Protocol 095, a sub-study of a prospective, observational comparative study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 29 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 93% (27/29). 23 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 100% (14/14), 100% (1/1), 33% (1/3), and 100% (5/5), respectively. Six patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 100% (6/6). VA NS5A Cohort Study In a retrospective Veterans Administration (VA) NS5A cohort study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 93 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 81% (75/93). 65 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 94% (16/17), 100% (8/8), 84% (16/19), and 81% (17/21), respectively. 28 patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 64% (18/28). Genotype 1b In Clinical Studies In genotype 1b-infected subjects treated with ZEPATIER for 12 weeks, SVR12 rates (non-virologic failure-censored) were 94% (48/51) and 99% (247/248) for those with and without one or more NS5A polymorphisms at position 28, 30, 31, or 93. In genotype 1b-infected subjects, baseline NS3 polymorphisms did not impact treatment response. Effect of Baseline HCV Polymorphisms on Treatment Response in Genotype 4-Infected Subjects Phylogenetic analysis of HCV sequences from genotype 4-infected subjects (n=71) in the pooled analyses of subjects (non-virologic failure-censored) treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials identified 4 HCV genotype 4 subtypes (4a, 4d, 4k, 4o). Most subjects were infected with either subtype 4a (42%) or 4d (51%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Among subjects enrolled at U.S. study sites, 11/13 (85%) were infected with HCV subtype 4a. There were two subjects infected with HCV subtype 4d who experienced virologic failure with the regimen containing grazoprevir and elbasvir. In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS5A polymorphisms (any change from reference at NS5A amino acid positions 28, 30, 31, 58, and 93 by population nucleotide sequencing) were 100% (28/28) and for subjects without baseline NS5A polymorphisms were 95% (41/43). In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS3 polymorphisms (any change from reference at NS3 amino acid positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175 by population nucleotide sequencing) were 100% (18/18) and for subjects without baseline NS3 polymorphisms were 96% (51/53). Cross Resistance Cross resistance is possible among NS5A inhibitors and NS3/4A protease inhibitors by class. Elbasvir and grazoprevir are fully active against viral populations with substitutions conferring resistance to NS5B inhibitors. In the C-SALVAGE trial, subjects with genotype 1 infection who had failed prior treatment with boceprevir (n=28), simeprevir (n=8), or telaprevir (n=43) in combination with PegIFN + RBV received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. There are limited data to determine the impact of HCV NS3 resistance-associated substitutions detected at baseline in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. SVR was achieved in 88% (21/24) of genotype 1a and genotype 1b infected subjects with NS3 resistance-associated substitutions detected at baseline. Specific NS3 substitutions observed at baseline included one or more of the following: V36L/M (n=8), T54S (n=4), S122G/T (n=9), R155K/T (n=9), A156S/T (n=1), and D168E/N (n=3). SVR was 100% (55/55) in subjects without baseline NS3 resistance substitutions. The 3 virologic failure subjects had the following NS3 or NS5A substitutions/polymorphisms at baseline: NS3 R155T/D168N, NS3 R155K plus NS5A H58D, and NS3 T54S plus NS5A L31M. The efficacy of ZEPATIER has not been established in patients who have previously failed treatment with other regimens that included an NS5A inhibitor.

PRINCIPAL DISPLAY PANEL - 50 mg/100 mg Tablet Dose Pack Carton NDC 0006-3074-02 Zepatier ® (elbasvir and grazoprevir) tablets 50 mg/100 mg Rx only 28 Tablets This carton contains a total of 28 tablets packaged within 2 dose packs. Each dose pack contains 14 blister units with one tablet per blister unit. PRINCIPAL DISPLAY PANEL - 50 mg/100 mg Tablet Dose Pack Carton

Indications and Usage ( 1 ) 12/2021 Dosage and Administration, Recommended Dosage in Adult and Pediatric Patients 12 Years of Age and Older or Weighing at Least 30 kg ( 2.2 ) 12/2021

Manufactured for: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent Copyright © 2016-2022 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk5172a-t-2205r008

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). For patients receiving ZEPATIER with ribavirin, advise patients to read the FDA-approved patient labeling (Medication Guide) for ribavirin [see Warnings and Precautions (5.4) ] . 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 hepatitis B virus infection [see Warnings and Precautions (5.1) ]. Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease Advise patients to seek medical evaluation immediately for symptoms of worsening liver problems such as nausea, tiredness, yellowing of the skin or white part of the eyes, bleeding or bruising more easily than normal, confusion, loss of appetite, diarrhea, dark or brown urine, dark or bloody stool, swelling of the stomach area (abdomen) or pain in the upper right side of the stomach area, sleepiness, or vomiting of blood [see Warnings and Precautions (5.3) ]. Risk of ALT Elevations Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to consult their healthcare professional without delay if such symptoms occur [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . Pregnancy Advise patients taking ZEPATIER with ribavirin to avoid pregnancy during treatment and within 6 months of stopping ribavirin and to notify their healthcare provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1) ] . Drug Interactions Inform patients that ZEPATIER may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider [see Contraindications (4) , Warnings and Precautions (5.5) , and Drug Interactions (7) ] . Storage Advise patients to store ZEPATIER in the original package until use to protect from moisture [see How Supplied/Storage and Handling (16) ] . Administration Advise patients to take ZEPATIER 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 ZEPATIER for the duration that is recommended by the healthcare provider.

14 CLINICAL STUDIES 14.1 Overview of Clinical Trials The efficacy of ZEPATIER was assessed in 2 placebo-controlled trials and 4 uncontrolled Phase 2 and 3 clinical trials in 1401 subjects with genotype (GT) 1, 4, or 6 and in 1 clinical trial in 22 pediatric subjects with GT 1 or 4 chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis). An overview of the 6 trials (n=1373) contributing to the assessment of efficacy in genotype 1 or 4 is provided in Table 13 . C-EDGE TN, C-EDGE COINFECTION, C-SCAPE, and C-EDGE TE also included subjects with genotype 6 HCV infection (n=28). Because ZEPATIER is not indicated for genotype 6 infection, results in patients with genotype 6 infection are not included in Clinical Studies (14). Table 13: Trials Conducted with ZEPATIER Trial Population Study Groups and Duration (Number of Subjects Treated) GT = Genotype TN = Treatment-Naïve TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [PegIFN] with or without ribavirin [RBV] or were intolerant to prior therapy). C-EDGE TN (double-blind) GT 1, 4 TN with or without cirrhosis ZEPATIER for 12 weeks (N=306) Placebo for 12 weeks (N=102) C-EDGE COINFECTION (open-label) GT 1, 4 TN with or without cirrhosis HCV/HIV-1 co-infection ZEPATIER for 12 weeks (N=217) C-SURFER (double-blind) GT 1 TN or TE with or without cirrhosis Severe Renal Impairment including Hemodialysis EBR EBR = elbasvir 50 mg; GZR = grazoprevir 100 mg; EBR + GZR = co-administered as single agents. + GZR for 12 weeks (N=122) Placebo for 12 weeks (N=113) C-SCAPE (open-label) GT 4 TN without cirrhosis EBR + GZR for 12 weeks (N=10) EBR + GZR + RBV for 12 weeks (N=10) C-EDGE TE (open-label) GT 1, 4 TE with or without cirrhosis with or without HCV/HIV-1 co-infection ZEPATIER for 12 or 16 weeks (N=105 and 101, respectively) ZEPATIER + RBV for 12 or 16 weeks (N=104 and 104, respectively) C-SALVAGE (open-label) GT 1 TE with HCV protease inhibitor regimen Failed prior treatment with boceprevir, telaprevir, or simeprevir in combination with PegIFN + RBV. with or without cirrhosis EBR + GZR + RBV for 12 weeks (N=79) MK-5172-079 (open-label) GT 1, 4 TN or TE pediatric subjects ZEPATIER for 12 weeks (N=22; 12 years to less than 18 years) ZEPATIER was administered once daily by mouth in these trials. For subjects who received ribavirin (RBV), the RBV dosage was weight-based (less than 66 kg = 800 mg per day, 66 to 80 kg = 1000 mg per day, 81 to 105 kg = 1200 mg per day, greater than 105 kg = 1400 mg per day) administered by mouth in two divided doses with food. Sustained virologic response (SVR) was the primary endpoint in all trials and was defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12). Serum HCV RNA values were measured during these clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with an LLOQ of 15 HCV RNA IU per mL, with the exception of C-SCAPE where the assay had an LLOQ of 25 HCV RNA IU per mL. 14.2 Clinical Trials in Treatment-Naïve Subjects with Genotype 1 HCV (C-EDGE TN and C-EDGE COINFECTION) The efficacy of ZEPATIER in treatment-naïve subjects with genotype 1 chronic hepatitis C virus infection with or without cirrhosis was demonstrated in the C-EDGE TN and C-EDGE COINFECTION trials. C-EDGE TN was a randomized, double-blind, placebo-controlled trial in treatment-naïve subjects with genotype 1 or 4 infection with or without cirrhosis. Subjects were randomized in a 3:1 ratio to: ZEPATIER for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with ZEPATIER for 12 weeks (deferred treatment group). Among subjects with genotype 1 infection randomized to the immediate treatment group, the median age was 55 years (range: 20 to 78); 56% of the subjects were male; 61% were White; 20% were Black or African American; 8% were Hispanic or Latino; mean body mass index was 26 kg/m 2 ; 72% had baseline HCV RNA levels greater than 800,000 IU per mL; 24% had cirrhosis; 67% had non-C/C IL28B alleles (CT or TT); and 55% had genotype 1a and 45% had genotype 1b chronic HCV infection. C-EDGE COINFECTION was an open-label, single-arm trial in treatment-naïve HCV/HIV-1 co-infected subjects with genotype 1 or 4 infection with or without cirrhosis. Subjects received ZEPATIER for 12 weeks. Among subjects with genotype 1 infection, the median age was 50 years (range: 21 to 71); 85% of the subjects were male; 75% were White; 19% were Black or African American; 6% were Hispanic or Latino; mean body mass index was 25 kg/m 2 ; 59% had baseline HCV RNA levels greater than 800,000 IU per mL; 16% had cirrhosis; 65% had non-C/C IL28B alleles (CT or TT); and 76% had genotype 1a, 23% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection. Table 14 presents treatment outcomes for ZEPATIER in treatment-naïve subjects with genotype 1 infection from C-EDGE TN (immediate treatment group) and C-EDGE COINFECTION. For treatment outcomes for ZEPATIER in genotype 4 infection, [see Clinical Studies (14.5) ] . Table 14: C-EDGE TN and C-EDGE COINFECTION: SVR12 in Treatment-Naïve Subjects with or without Cirrhosis with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks Trial C-EDGE TN (Immediate Treatment Group) C-EDGE COINFECTION (HCV/HIV-1 Co-Infection) Regimen ZEPATIER 12 Weeks N=288 ZEPATIER 12 Weeks N=189 SVR in Genotype 1 95% (273/288) 95% (179/189) Outcome for subjects without SVR On-treatment Virologic Failure Includes subjects with virologic breakthrough. <1% (1/288) 0% (0/189) Relapse 3% (10/288) 3% (6/189) Other Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. 1% (4/288) 2% (4/189) SVR by Genotype 1 Subtypes GT 1a For the impact of baseline NS5A polymorphisms on SVR12, [see Microbiology (12.4) , Table 12 ] . 92% (144/157) 94% (136/144) GT 1b Includes genotype 1 subtypes other than 1a or 1b. 98% (129/131) 96% (43/45) SVR by Cirrhosis status Non-cirrhotic 94% (207/220) 94% (148/158) Cirrhotic 97% (66/68) 100% (31/31) 14.3 Clinical Trials in Treatment-Experienced Subjects with Genotype 1 HCV Treatment-Experienced Subjects who Failed Prior PegIFN with RBV Therapy (C-EDGE TE) C-EDGE TE was a randomized, open-label comparative trial in subjects with genotype 1 or 4 infection, with or without cirrhosis, with or without HCV/HIV-1 co-infection, who had failed prior therapy with PegIFN + RBV therapy. Subjects were randomized in a 1:1:1:1 ratio to one of the following treatment groups: ZEPATIER for 12 weeks, ZEPATIER + RBV for 12 weeks, ZEPATIER for 16 weeks, or ZEPATIER + RBV for 16 weeks. Among subjects with genotype 1 infection, the median age was 57 years (range: 19 to 77); 64% of the subjects were male; 67% were White; 18% were Black or African American; 9% were Hispanic or Latino; mean body mass index was 28 kg/m 2 ; 78% had baseline HCV RNA levels greater than 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); and 60% had genotype 1a, 39% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection. Treatment outcomes in genotype 1 subjects treated with ZEPATIER for 12 weeks or ZEPATIER with RBV for 16 weeks are presented in Table 15 . Treatment outcomes with ZEPATIER with RBV for 12 weeks or without RBV for 16 weeks are not shown because these regimens are not recommended in PegIFN/RBV-experienced genotype 1 patients. For treatment outcomes for ZEPATIER in genotype 4 infection, [see Clinical Studies (14.5) ] . Table 15: C-EDGE TE: SVR12 in Treatment-Experienced Subjects who Failed Prior PegIFN with RBV with or without Cirrhosis, with or without HCV/HIV-1 Co-infection with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks or ZEPATIER with Ribavirin for 16 Weeks Regimen ZEPATIER 12 weeks N=96 ZEPATIER + RBV 16 weeks N=96 SVR in Genotype 1 94% (90/96) 97% (93/96) Outcome for subjects without SVR On-treatment Virologic Failure Includes subjects with virologic breakthrough or rebound. 0% (0/96) 0% (0/96) Relapse 5% (5/96) 0% (0/96) Other Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. 1% (1/96) 3% (3/96) SVR by Genotype 1 Subtypes GT 1a For the impact of baseline NS5A polymorphisms on SVR, [see Microbiology (12.4) , Table 12 ] . 90% (55/61) 95% (55/58) GT 1b Includes genotype 1 subtypes other than 1a or 1b. 100% (35/35) 100% (38/38) SVR by Cirrhosis status Non-cirrhotic 94% (61/65) 95% (61/64) Cirrhotic 94% (29/31) 100% (32/32) SVR by Response to Prior HCV Therapy On-treatment Virologic Failure Includes prior null responders and partial responders. 90% (57/63) 95% (58/61) Relapser 100% (33/33) 100% (35/35) Treatment-Experienced Subjects who Failed Prior PegIFN + RBV + HCV Protease Inhibitor Therapy (C-SALVAGE) C-SALVAGE was an open-label single-arm trial in subjects with genotype 1 infection, with or without cirrhosis, who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with PegIFN + RBV. Subjects received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. Subjects had a median age of 55 years (range: 23 to 75); 58% of the subjects were male; 97% were White; 3% were Black or African American; 15% were Hispanic or Latino; mean body mass index was 28 kg/m 2 ; 63% had baseline HCV RNA levels greater than 800,000 IU/mL; 43% had cirrhosis; and 97% had non-C/C IL28B alleles (CT or TT); 46% had baseline NS3 resistance-associated substitutions. Overall SVR was achieved in 96% (76/79) of subjects receiving EBR + GZR + RBV for 12 weeks. Four percent (3/79) of subjects did not achieve SVR due to relapse. Treatment outcomes were consistent in genotype 1a and genotype 1b subjects, in subjects with different response to previous HCV therapy, and in subjects with or without cirrhosis. Treatment outcomes were generally consistent in subjects with or without NS3 resistance-associated substitutions at baseline, although limited data are available for subjects with specific NS3 resistance-associated substitutions [see Microbiology (12.4) ] . 14.4 Clinical Trial in Subjects with Genotype 1 HCV and Severe Renal Impairment including Subjects on Hemodialysis (C-SURFER) C-SURFER was a randomized, double-blind, placebo-controlled trial in subjects with genotype 1 infection, with or without cirrhosis, with chronic kidney disease (CKD) Stage 4 (eGFR 15-29 mL/min/1.73 m 2 ) or CKD Stage 5 (eGFR <15 mL/min/1.73 m 2 ), including subjects on hemodialysis, who were treatment-naïve or who had failed prior therapy with IFN or PegIFN ± RBV therapy. Subjects were randomized in a 1:1 ratio to one of the following treatment groups: EBR 50 mg once daily + GZR 100 mg once daily for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by open-label treatment with EBR + GZR for 12 weeks (deferred treatment group). In addition, 11 subjects received open-label EBR + GZR for 12 weeks (intensive pharmacokinetic [PK] group). Subjects randomized to the immediate treatment group and intensive PK group had a median age of 58 years (range: 31 to 76); 75% of the subjects were male; 50% were White; 45% were Black or African American; 11% were Hispanic or Latino; 57% had baseline HCV RNA levels greater than 800,000 IU/mL; 6% had cirrhosis; and 72% had non-C/C IL28B alleles (CT or TT). Treatment outcomes in subjects treated with ZEPATIER for 12 weeks in the pooled immediate treatment group and intensive PK group are presented in Table 16 . Table 16: C-SURFER: SVR12 in Subjects with Severe Renal Impairment including Subjects on Hemodialysis who were Treatment-Naïve or had Failed Prior IFN or PegIFN ± RBV, with or without Cirrhosis, with Genotype 1 HCV Treated with ZEPATIER for 12 Weeks Regimen EBR + GZR 12 weeks (Immediate Treatment Group) N=122 Includes subjects (n=11) in the intensive PK group. Overall SVR 94% (115/122) SVR was achieved in 99% (115/116) of subjects in the pre-specified primary analysis population, which excluded subjects not receiving at least one dose of study treatment and those with missing data due to death or early study discontinuation for reasons unrelated to treatment response. Outcome for subjects without SVR On-treatment Virologic Failure 0% (0/122) Relapse <1% (1/122) Other Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. 5% (6/122) SVR by Genotype GT 1a 97% (61/63) GT 1b Includes genotype 1 subtypes other than 1a or 1b. 92% (54/59) SVR by Cirrhosis status No 95% (109/115) Yes 86% (6/7) SVR by Prior HCV Treatment Status Treatment-naïve 95% (96/101) Treatment-experienced 90% (19/21) SVR by Dialysis Status No 97% (29/30) Yes 93% (86/92) SVR by Chronic Kidney Disease Stage Stage 4 100% (22/22) Stage 5 93% (93/100) 14.5 Clinical Trials with Genotype 4 HCV The efficacy of ZEPATIER in subjects with genotype 4 chronic HCV infection was demonstrated in C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, and C-SCAPE. C-SCAPE was a randomized, open-label trial which included treatment-naïve subjects with genotype 4 infection without cirrhosis. Subjects were randomized in a 1:1 ratio to EBR 50 mg once daily + GZR 100 mg once daily for 12 weeks or EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. In these combined studies in subjects with genotype 4 infection, 64% were treatment-naïve; 66% of the subjects were male; 87% were White; 10% were Black or African American; 22% had cirrhosis; and 30% had HCV/HIV-1 co-infection. In C-SCAPE, C-EDGE TN, and C-EDGE COINFECTION trials combined, a total of 66 genotype 4 treatment-naïve subjects received ZEPATIER or EBR + GZR for 12 weeks. In these combined trials, SVR12 among subjects treated with ZEPATIER or EBR + GZR for 12 weeks was 97% (64/66). In C-EDGE TE, a total of 37 genotype 4 treatment-experienced subjects received a 12- or 16-week ZEPATIER with or without RBV regimen. SVR12 among randomized subjects treated with ZEPATIER + RBV for 16 weeks was 100% (8/8). 14.6 Clinical Trial in Pediatric Subjects with Genotype 1 or 4 Chronic Hepatitis C Infection The efficacy of ZEPATIER was evaluated in an open-label study (MK-5172-079, NCT03379506) that evaluated pediatric subjects 12 years to less than 18 years of age who received ZEPATIER for 12 weeks. HCV GT1a infected subjects with one or more baseline NS5A RAS were excluded from study participation. In the MK-5172-079 study, 22 treatment-naïve or treatment-experienced subjects 12 years to less than 18 years of age with genotype 1 (n=21) or 4 CHC (n=1), without cirrhosis, were treated with ZEPATIER for 12 weeks. The median age was 13.5 years (range: 12 to 17); 50% were female; 95% were White; the weight range was 28.1 kg to 96.5 kg; 95.5% had genotype 1 and 4.5% had genotype 4; 64% were treatment-naïve, 36% were treatment-experienced; 46% had baseline HCV RNA levels greater than 800,000 IU/mL. The overall SVR12 rate was 100% (22/22).

8.5 Geriatric Use Clinical trials of ZEPATIER with or without ribavirin included 187 subjects aged 65 years and over. Higher elbasvir and grazoprevir plasma concentrations were observed in subjects aged 65 years and over. A higher rate of late ALT elevations was observed in subjects aged 65 years and over in clinical trials [see Warnings and Precautions (5.2) ] . However, no dosage adjustment of ZEPATIER is recommended in geriatric patients [see Clinical Pharmacology (12.3) ] .

8.4 Pediatric Use The safety, efficacy, and pharmacokinetics of ZEPATIER was evaluated in an open-label clinical trial (MK-5172-079), which included 22 subjects (n=21, genotype 1; n=1, genotype 4) 12 years of age and older who received ZEPATIER for 12 weeks. The safety, pharmacokinetics, and efficacy observed in this trial were comparable to those observed in adults [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.6) ] . Safety and effectiveness of ZEPATIER have not been established in pediatric patients younger than 12 years of age who weigh less than 30 kg.

8.1 Pregnancy Risk Summary No adequate human data are available to establish whether or not ZEPATIER poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of ZEPATIER (elbasvir or grazoprevir) 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) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD. In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 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. If ZEPATIER 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 use in pregnancy. Data Animal Data Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD. In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20. Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to grazoprevir were ≥78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal plasma concentrations of up to 7% (rabbits) and 89% (rats) that of maternal concentrations observed on gestation day 20.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary No adequate human data are available to establish whether or not ZEPATIER poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of ZEPATIER (elbasvir or grazoprevir) 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) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD. In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 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. If ZEPATIER 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 use in pregnancy. Data Animal Data Elbasvir: Elbasvir was administered orally at up to 1000 mg/kg/day to pregnant rats and rabbits on gestation days 6 to 20 and 7 to 20, respectively, and also to rats on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to elbasvir were approximately 10 (rats) and 18 (rabbits) times the exposure in humans at the RHD. In both species, elbasvir has been shown to cross the placenta, with fetal plasma concentrations of up to 0.8% (rabbits) and 2.2% (rats) that of maternal concentrations observed on gestation day 20. Grazoprevir: Grazoprevir was administered to pregnant rats (oral doses up to 400 mg/kg/day) and rabbits (intravenous doses up to 100 mg/kg/day) on gestation days 6 to 20 and 7 to 20, respectively, and also to rats (oral doses up to 400 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. Systemic exposures (AUC) to grazoprevir were ≥78 (rats) and 41 (rabbits) times the exposure in humans at the RHD. In both species, grazoprevir has been shown to cross the placenta, with fetal plasma concentrations of up to 7% (rabbits) and 89% (rats) that of maternal concentrations observed on gestation day 20. 8.2 Lactation Risk Summary It is not known whether ZEPATIER is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, the components of ZEPATIER (elbasvir and grazoprevir) were present in milk, without effects on growth and development observed in nursing pups (see Data ) . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEPATIER and any potential adverse effects on the breastfed child from ZEPATIER or from the underlying maternal condition. If ZEPATIER is administered with ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for information on use during lactation. Data Elbasvir: No effects of elbasvir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to elbasvir was approximately 10 times the exposure in humans at the RHD. Elbasvir was excreted into the milk of lactating rats following oral administration (1000 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 4 times that of maternal plasma concentrations observed 2 hours post-dose on lactation day 14. Grazoprevir: No effects of grazoprevir on growth and postnatal development were observed in nursing pups at up to the highest dose tested. Maternal systemic exposure (AUC) to grazoprevir was approximately 78 times the exposure in humans at the RHD. Grazoprevir was excreted into the milk of lactating rats following oral administration (up to 400 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations of 54 and 87% that of maternal plasma concentrations observed 2 and 8 hours post-dose, respectively, on lactation day 14. 8.3 Females and Males of Reproductive Potential If ZEPATIER 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, efficacy, and pharmacokinetics of ZEPATIER was evaluated in an open-label clinical trial (MK-5172-079), which included 22 subjects (n=21, genotype 1; n=1, genotype 4) 12 years of age and older who received ZEPATIER for 12 weeks. The safety, pharmacokinetics, and efficacy observed in this trial were comparable to those observed in adults [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.6) ] . Safety and effectiveness of ZEPATIER have not been established in pediatric patients younger than 12 years of age who weigh less than 30 kg. 8.5 Geriatric Use Clinical trials of ZEPATIER with or without ribavirin included 187 subjects aged 65 years and over. Higher elbasvir and grazoprevir plasma concentrations were observed in subjects aged 65 years and over. A higher rate of late ALT elevations was observed in subjects aged 65 years and over in clinical trials [see Warnings and Precautions (5.2) ] . However, no dosage adjustment of ZEPATIER is recommended in geriatric patients [see Clinical Pharmacology (12.3) ] . 8.6 Gender Higher elbasvir and grazoprevir plasma concentrations were observed in females compared to males. Females experienced a higher rate of late ALT elevations in clinical trials [see Warnings and Precautions (5.2) ] . However, no dose adjustment of ZEPATIER is recommended based on gender [see Clinical Pharmacology (12.3) ] . 8.7 Race Higher elbasvir and grazoprevir plasma concentrations were observed in Asians compared to Caucasians. Asians experienced a higher rate of late ALT elevations in clinical trials [see Warnings and Precautions (5.2) ] . However, no dose adjustment of ZEPATIER is recommended based on race/ethnicity [see Clinical Pharmacology (12.3) ] . 8.8 Renal Impairment No dosage adjustment of ZEPATIER is recommended in patients with any degree of renal impairment including patients receiving hemodialysis [see Clinical Pharmacology (12.3) ] . Administer ZEPATIER with or without ribavirin according to recommendations in Table 1 [see Dosage and Administration (2.2 , 2.3) ]. Refer to the prescribing information for ribavirin tablets for renal dosage adjustment of ribavirin in patients with CrCl less than or equal to 50 mL per minute. 8.9 Hepatic Impairment No dosage adjustment of ZEPATIER is recommended in patients with mild hepatic impairment (Child-Pugh A). ZEPATIER is contraindicated in patients with moderate hepatic impairment (Child-Pugh B) due to the lack of clinical safety and efficacy experience in HCV-infected Child-Pugh B patients, and in patients with severe hepatic impairment (Child-Pugh C) due to a 12-fold increase in grazoprevir exposure in non-HCV infected Child-Pugh C subjects. In addition, postmarketing cases of hepatic decompensation/failure have been reported in patients with advanced liver disease [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.3) , and Clinical Pharmacology (12.3) ]. The safety and efficacy of ZEPATIER have not been established in patients awaiting liver transplant or in liver transplant recipients.

16 HOW SUPPLIED/STORAGE AND HANDLING Each ZEPATIER tablet contains 50 mg elbasvir and 100 mg grazoprevir, is beige, oval-shaped, film-coated, debossed with "770" on one side and plain on the other. The tablets are packaged into a carton (NDC 0006-3074-02) containing two (2) 14-count child-resistant dose packs for a total of 28 tablets. Store ZEPATIER in the original blister package until use to protect from moisture. Store ZEPATIER at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (between 59°F to 86°F) [see USP Controlled Room Temperature].

Store ZEPATIER in the original blister package until use to protect from moisture. Store ZEPATIER at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (between 59°F to 86°F) [see USP Controlled Room Temperature].

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 ZEPATIER. 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 )