HIGHLIGHTS OF PRESCRIBING INFORMATION HCV/HIV-1 co ...

1 HIGHLIGHTS OF PRESCRIBING INFORMATIONT hese HIGHLIGHTS do not include all the INFORMATION needed to use ZEPATIER safely and effectively. See full PRESCRIBING INFORMATION for (elbasvir and grazoprevir) tablets, for oral useInitial Approval: 2016 WARNING: RISK OF HEPATITIS B VIRUS REACTIVATIONIN PATIENTS COINFECTED WITH HCV AND HBVSee full PRESCRIBING INFORMATION for complete boxed B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( )----------------------------INDICATIONS AND USAGE----------------------------ZEPATIE Ris a fixed-dose combination product containingelbasvir, a hepatitis C virus (HCV) NS5A inhibitor,and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicatedfor treatment of chronic HCVgenotype 1or 4 infection in adults. ZEPATIER is indicated for use with ribavirin in certain patient populations.

2 (1)-----------------------DOSAGE AND ADMINISTRATION----------------------- Testing Prior to Initiationof Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( ) Genotype 1a: Testing for the presence of virus with NS5A resistance-associated polymorphismsis recommended. ( ) Obtain hepatic laboratory testing. ( ) Recommended dosage: One tablet taken orally once daily with or without food. ( )Dosage Regimens and Durations for ZEPATIERin Patients with Genotype 1 or 4 HCV with or without CirrhosisPatient PopulationTreatmentDurationGenotype 1a: Treatment-na ve or PegIFN/RBV-experienced* withoutbaseline NS5A polymorphisms ZEPATIER12 weeksGenotype 1a: Treatment-na ve or PegIFN/RBV-experienced* with baseline NS5A polymorphisms ZEPATIER + ribavirin16 weeksGenotype 1b: Treatment-na ve or PegIFN/RBV-experienced*ZEPATIER12 weeksGenotype 1a or 1b: PegIFN/RBV/PI-experienced ZEPATIER + ribavirin12 weeksGenotype 4: Treatment-na veZEPATIER12 weeksGenotype 4: PegIFN/RBV-experienced*ZEPATIER + ribavirin16 weeks*Peginterferon alfa + ribavirin.

3 Polymorphisms at amino acid positions 28, 30, 31, or 93. Peginterferon alfa + ribavirin + HCV NS3/4A protease inhibitor. HCV/HIV-1 co-infection: Follow the dosage recommendations in the table above. ( ) Renal Impairment, including hemodialysis: No dosageadjustment of ZEPATIERis recommended. Refer to ribavirin PRESCRIBING INFORMATION for ribavirin dosing and dosage modifications. ( )---------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets: 50 mg elbasvir and 100 mg grazoprevir(3)-------------------------- -----CONTRAINDICATIONS------------------ ------------- Patients with moderate or severe hepatic impairment(Child-Pugh B or C). (4) OATP1B1/3 inhibitorsthat 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 (4)-----------------------WARNINGS AND PRECAUTIONS----------------------- Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( ) ALT elevations: Perform hepatic laboratory testing prior to therapy,at treatment week 8, andas clinically indicated. For patients receiving 16 weeks of therapy, perform additional hepatic laboratory testing at treatment week 12. For ALT elevations on ZEPATIER, follow recommendations in full PRESCRIBING INFORMATION .( ) Risk associated with ribavirin combination treatment: If ZEPATIERis administered with ribavirin, the warnings and precautions for ribavirinalso apply.

5 ( )------------------------------ADVERSE REACTIONS------------------------------I n subjects receiving ZEPATIERfor 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 reportedadverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache. ( )To report SUSPECTED ADVERSE REACTIONS, contactMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231or FDA at 1-800-FDA-1088or 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.

6 (7) Frequent monitoring of international normalized ratio (INR) values is recommended in patientsreceiving warfarin. ( ) Consult the full PRESCRIBING INFORMATION prior to and during treatment for potential drug interactions. (4, , 7, )See 17 for PATIENT COUNSELING INFORMATION andFDA-approved patient : 06/2018 FULL PRESCRIBING INFORMATION : CONTENTS*WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV1 INDICATIONS AND USAGE2 DOSAGE AND Prior to the Initiation of Recommended Dosage in Renal Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and Increased Risk of ALT Risks Associated with Risk of Adverse Reactions or Reduced Therapeutic Effect Due toDrug Interactions6 ADVERSE Experience7 DRUG for Drug and other Potentially SignificantDrug Drugs without Clinically Significant Interactions with ZEPATIER8 USE IN SPECIFIC and Males of Reproductive Renal Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL of , Mutagenesis.

7 Impairment of Fertility14 CLINICAL of Clinical Trials in Treatment-Na ve Subjects with Genotype 1 HCV (C-EDGE TN and C-EDGE COINFECTION) Trials in Treatment-Experienced Subjects with Genotype Clinical Trial in Subjects with Genotype 1 HCV and Severe Renal Impairment including Subjects on Hemodialysis(C-SURFER) Trials with Genotype 4 HCV16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full PRESCRIBING INFORMATION are not PRESCRIBING INFORMATIONWARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBVT estall patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with ZEPATIER. HBV reactivation has been reportedin HCV/HBVcoinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy.

8 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 ( )].1 INDICATIONS AND USAGEZEPATIER is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection in is indicated for use with ribavirin in certain patient populations[see Dosage and Administration ( )].2 DOSAGE AND Prior to the Initiation of Therapy Testing for HBV InfectionTest 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 andPrecautions ( )].NS5A Resistance Testing in HCV Genotype 1a-Infected PatientsTesting patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphismsis recommended prior to initiation of treatment with ZEPATIERto determine dosage regimen and duration[see Dosage and Administration ( )], Table 1.

9 In subjects receiving ZEPATIERfor 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 ( )], Table 11. Hepatic Laboratory TestingObtain hepatic laboratory testing prior to and during treatment with ZEPATIER[see Warnings and Precautions ( )]. Recommended Dosage in AdultsZEPATIERis a two-drug, fixed-dose combinationproductcontaining 50 mg of elbasvir and 100 mg of grazoprevirin a single tablet. The recommended dosage of ZEPATIERis one tablet taken orally once daily with or without food[see Clinical Pharmacology ( )]. ZEPATIERis used in combination with ribavirin in certain patient populations (see Table 1).When administered with ZEPATIER, therecommended dosage of ribavirin in patients without renal impairment is weight-based administered in two divided doses with food.

10 For further INFORMATION on ribavirin dosing and dosage modifications, refer to the ribavirin PRESCRIBING Regimen and Duration of TherapyRelapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups [see Clinical Studies (14)].Table 1below 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 cirrhosisand with or without renal impairment including patients receiving 1: Recommended Dosage Regimens and Durations for ZEPATIERfor Treatment of HCV Genotype 1 or 4in Patients with or without CirrhosisPatient PopulationTreatmentDurationGenotype 1a: Treatment-na ve or PegIFN/RBV-experienced*withoutbaseline NS5A polymorphisms ZEPATIER12 weeksGenotype 1a: Treatment-na ve or PegIFN/RBV-experienced*with baseline NS5A polymorphisms ZEPATIER + RBV 16 weeksGenotype 1b: Treatment-na ve or PegIFN/RBV-experienced*ZEPATIER12 weeksGenotype 1a or 1b: PegIFN/RBV/PI-experienced ZEPATIER + RBV 12 weeksGenotype 4: Treatment-Na veZEPATIER12 weeksGenotype 4.