Elbasvir And Grazoprevir

1 INDICATIONS AND USAGE ZEPATIER ® is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in adult and pediatric patients 12 years of age and older or weighing at least 30 kg. ZEPATIER is indicated for use with ribavirin in certain patient populations [see Dosage and Administration (2.2) ] . ZEPATIER is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated for treatment of chronic HCV genotype 1 or 4 infection in adult and pediatric patients 12 years of age and older or weighing at least 30 kg. ZEPATIER is indicated for use with ribavirin in certain patient populations. ( 1 )

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) ].

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) ]

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)