ZEPATIER, Elbasvir-Grazoprevir Form

Grazoprevir/elbasvir (Zepatier®) is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. ____ *These criteria do NOT apply to California Commercial Exchange Plans. FDA Approved Indication(s) Zepatier 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 (RBV) in certain patient populations. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Zepatier is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Chronic Hepatitis C Infection (must meet all):

1. Diagnosis of chronic HCV infection as evidenced by detectable serum HCV RNA levels by quantitative assay in the last 6 months;
2. Confirmed HCV genotype is 1 or 4;
   *Chart note documentation and copies of lab results are required
3. For genotype 1a, laboratory testing for the presence or absence of virus with NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93;
   4. Documentation of the treatment status of the patient (treatment-naive or treatment- experienced);

4. If cirrhosis is present, confirmation of Child-Pugh A status;

   6. Prescribed by or in consultation with a gastroenterologist, hepatologist, infectious disease specialist, or provider who has expertise in treating HCV based on a certified training program (see Appendix F);
   7. Age ≥ 12 years or weight ≥ 30 kg;
   8. One of the following (a or b): a. If request is from Florida, member must use Epclusa authorized generic, unless contraindicated or clinically significant adverse effects are experienced; Page 1 of 9

   CLINICAL POLICY
   Elbasvir/Grazoprevir b. For all other requests, member must use Epclusa® (brand preferred), unless contraindicated or clinically significant adverse effects are experienced (see Appendix E);*

   • Coadministration with omeprazole up to 20 mg is not considered acceptable medical justification for inability to use Epclusa
5. Life expectancy ≥ 12 months with HCV treatment; 10. Member agrees to participate in a medication adherence program meeting both of the following components (a and b): a. Medication adherence monitored by pharmacy claims data or member report; b. Member’s risk for non-adherence identified by adherence program or member/prescribing physician follow-up at least every 4 weeks;
6. Prescribed regimen is consistent with an FDA or AASLD-IDSA recommended regimen (see Section V Dosage and Administration for reference);
7. Dose does not exceed elbasvir/grazoprevir 50 mg/100 mg (1 tablet) per day.
   Approval duration: up to a total of 16 weeks (Approved duration should be consistent with a regimen in Section V Dosage and Administration) B. Other diagnoses/indications (must meet 1 or 2):
8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace; or
9. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace. II. Continued Therapy A. Chronic Hepatitis C Infection (must meet all):

10. Member meets one of the following (a, b, or c): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B); c. Must meet both of the following (i and ii): i. Documentation supports that member is currently receiving Zepatier for chronic HCV infection and has recently completed at least at least 60 days of treatment with Zepatier; ii. Confirmed HCV genotype is 1 or 4;

    2. Member is responding positively to therapy;
    3. Dose does not exceed elbasvir/grazoprevir 50 mg/100 mg (1 tablet) per day. Page 2 of 9

    CLINICAL POLICY
    Elbasvir/Grazoprevir Approval duration: up to a total of 16 weeks (Approved duration should be consistent with a regimen in Section V Dosage and Administration) B. Other diagnoses/indications (must meet 1 or 2):

11. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace; or

12. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace. III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off-label use policy – HIM.PA.154 for health insurance marketplace, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AASLD: American Association for the Study of Liver Diseases FDA: Food and Drug Administration
    HBV: hepatitis B virus HCV: hepatitis C virus HIV: human immunodeficiency virus IDSA: Infectious Diseases Society of America NS3/4A, NS5A/B: nonstructural protein PegIFN: pegylated interferon RBV: ribavirin RNA: ribonucleic acid Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization. Drug Name Dosing Regimen sofosbuvir/
    velpatasvir
    (Epclusa®) Without cirrhosis or with compensated cirrhosis, treatment naïve or treatment-experienced* patient: Genotypes 1 through 6 Dose Limit/ Maximum sofosbuvir 400 mg/ velpatasvir 100 mg (1 tablet) per day One tablet PO QD for 12 weeks Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Page 3 of 9

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    Elbasvir/Grazoprevir From clinical trials, treatment-experienced refers to previous treatment with NS3/4A protease inhibitor (telaprevir, boceprevir, or simeprevir) and/or peginterferon/RBV unless otherwise stated Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o 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 or those with any history of hepatic decompensation due to the risk of hepatic decompensation. o With inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations, strong CYP3A inducers, and efavirenz. o If Zepatier is administered with RBV, the contraindications to RBV also apply. • Boxed warning(s): risk of hepatitis B virus (HBV) reactivation in patients coinfected with HCV and HBV Appendix D: Direct-Acting Antivirals for Treatment of HCV Infection Brand Name Drug Class NS5A Inhibitor NS3/4A Protease Inhibitor (PI) CYP3A Inhibitor Nucleotide Analog NS5B Polymerase Inhibitor Sofosbuvir Non- Nucleoside NS5B Palm Polymerase Inhibitor Epclusa Velpatasvir Harvoni Mavyret Sovaldi Viekira Pak Vosevi ZepatierCombination drugs Ledipasvir Pibrentasvir Ombitasvir Velpatasvir Elbasvir Sofosbuvir Sofosbuvir Sofosbuvir Glecaprevir Dasabuvir Paritaprevir Ritonavir Voxilaprevir Grazoprevir Appendix E: General Information • Acceptable medical justification for inability to use Epclusa (preferred product): o In patients indicated for co-administration of Epclusa with ribavirin: contraindications to ribavirin. o In patients indicated for co-administration with amiodarone: serious symptomatic bradycardia in patients taking amiodarone, with cardiac monitoring recommended. • Unacceptable medical justification for inability to use Epclusa (preferred product): o Coadministration with omeprazole up to 20 mg is not considered acceptable medical justification for inability to use Epclusa.
     Per the Epclusa Prescribing Information: “If it is considered medically necessary to coadminister, Epclusa should be administered with food and taken 4 hours before omeprazole 20 mg.” Page 4 of 9

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    Elbasvir/Grazoprevir • HBV reactivation is a Black Box Warning for all direct-acting antiviral drugs for the treatment of HCV. HBV reactivation has been reported when treating HCV for patients co-infected with HBV, leading to fulminant hepatitis, hepatic failure, and death, in some cases. Patients should be monitored for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up, with treatment of HBV infection as clinically indicated. • For patients infected with HCV Genotype 1a: Testing for the presence of virus with NS5A resistance-associated polymorphisms is recommended. Clinical trial results show decreased efficacy of Zepatier in HCV genotype 1a with presence of NS5A polymorphisms. If baseline NS5A polymorphisms are present for genotype 1a, refer to Section VI on the longer recommended duration of therapy. • Child-Pugh Score: Bilirubin Albumin INR Ascites 1 Point Less than 2 mg/dL Less than 34 umol/L Over 3.5 g/dL Over 35 g/L Less than 1.7 None Encephalopathy None 2 Points 2-3 mg/dL 34-50 umol/L 2.8-3.5 g/dL 28-35 g/L 1.7 - 2.2 Mild / medically controlled Mild / medically controlled Grade I-II 3 Points Over 3 mg/dL Over 50 umol/L Less than 2.8 g/dL Less than 28 g/L Over 2.2 Moderate-severe / poorly controlled Moderate-severe / poorly controlled. Grade III-IV Child-Pugh class is determined by the total number of points: A = 5-6 points; B = 7-9 points; C = 10-15 points. Appendix F: Healthcare Provider HCV Training Acceptable HCV training programs and/or online courses include, but are not limited to the following: • Hepatitis C online course (https://www.hepatitisc.uw.edu/): University of Washington is funded by the Division of Viral Hepatitis to develop a comprehensive, online self-study course for medical providers on diagnosis, monitoring, and management of hepatitis C virus infection. Free CME and CNE credit available. • Fundamentals of Liver Disease (https://liverlearning.aasld.org/fundamentals-of-liver- disease): The AASLD, in collaboration with ECHO, the American College of Physicians (ACP), CDC, and the Department of Veterans Affairs, has developed Fundamentals of Liver Disease, a free, online CME course to improve providers’ knowledge and clinical skills in hepatology. • Clinical Care Options: http://www.clinicaloptions.com/hepatitis.aspx • CDC training resources: https://www.cdc.gov/hepatitis/resources/professionals/trainingresources.htm Page 5 of 9

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    Elbasvir/Grazoprevir V. Dosage and Administration Indication Dosing Regimen Maximum Reference Genotype 1a: Treatment-naïve or pegIFN/RBV-experienced with or without compensated cirrhosis and without baseline NS5A polymorphisms at amino acid positions 28, 30, 31, or 93 Genotype 1a:
    Treatment-naïve or PegIFN/RBV experienced with or without compensated cirrhosis and with baseline NS5A polymorphisms at amino acid positions 28, 30, 31, or 93 Genotype 1b: Treatment-naïve or PegIFN/RBV experienced with or without compensated cirrhosis Genotype 1a or 1b: pegIFN/RBV/NS3/4A PI* - experienced with or without compensated cirrhosis, (for genotype 1a: without baseline NS5A polymorphisms at amino acid positions 28, 30, 31, or 93) Genotype 4: Treatment-naïve with or without compensated cirrhosis One tablet PO QD for 12 weeks One tablet PO QD plus weight-based RBV for 16 weeks One tablet PO QD for 12 weeks An 8-week regimen can be considered in those with genotype 1b infection and mild fibrosis (F0-F2)ǂ One tablet PO QD plus weight-based RBV for 12 weeks One tablet PO QD for 12 weeks Genotype 4: PegIFN/RBV-experienced with or without compensated cirrhosis
    One tablet PO QD plus weight-based RBV for 16 weeks Dose One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day FDA-approved labeling FDA-approved labeling One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day 1) FDA- approved labeling 2) AASLD- IDSA (updated September 2021) FDA-approved labeling FDA-approved labeling FDA-approved labeling One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day One tablet (grazoprevir 100 mg/ elbasvir 50 mg) per day Page 6 of 9

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    Elbasvir/Grazoprevir AASLD/IDSA treatment guidelines for chronic hepatitis C infection are updated at irregular intervals; refer to the most updated AASLD/IDSA guideline for most accurate treatment regimen.

    • NS3/4A protease inhibitor = telaprevir, boceprevir, or simeprevir
      ǂ Off-label, AASLD-IDSA guideline-supported dosing regimen VI. Product Availability Tablet: grazoprevir 100 mg with elbasvir 50 mg VII.