MAVYRET, Glecaprevir-Pibrentasvir Form

Glecaprevir and pibrentasvir (Mavyret®) are a fixed-dose combination of glecaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor. ____ These criteria do NOT apply to California Commercial Exchange Plans. FDA Approved Indication(s) Mavyret is indicated for the treatment of adult and pediatric patients 3 years and older with: • Chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A); • HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor**, but not both. _

• In clinical trials, prior NS5A inhibitor experience included ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin. ** In clinical trials, prior NS3/4A protease inhibitor experience included regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin. 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 Mavyret 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 one of the following (a, b, c, or d); a. For treatment-naïve members: genotypes 1, 2, 3, 4, 5, or 6; b. For members treatment-experienced with interferon (IFN)/pegylated-interferon (pegIFN), ribavirin (RBV), and/or sofosbuvir only: genotypes 1, 2, 3, 4, 5, or 6; c. For members treatment-experienced with either an NS5A inhibitor or an NS3/4A protease inhibitor: genotype 1 (see Appendix D); d. For Vosevi-experienced members: genotype 1, 2, 3, 4, 5, or 6; *Chart note documentation and copies of lab results are required Page 1 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir

  3. 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);
  4. Age ≥ 3 years;
  5. If cirrhosis is present, confirmation of Child-Pugh A status;
  6. Member is not treatment-experienced with both NS3/4A protease inhibitor AND NS5A inhibitors, such as combination therapies including Technivie™, Viekira™, and Zepatier®;
  7. 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; b. For all other requests, member must use brand Epclusa or Vosevi®, unless clinically significant adverse effects are experienced or both are contraindicated; Coadministration with omeprazole up to 20 mg is not considered an acceptable medical justification for inability to use Epclusa
  8. Life expectancy ≥ 12 months with HCV treatment;
  9. Member agrees to participate in a medication adherence program including 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;
  10. Prescribed regimen is consistent with an FDA or AASLD-IDSA recommended regimen (see Section V for reference);
  11. Dose does not exceed one of the following (a, b, c, or d): a. Adult and pediatric members 12 years of age and older or with body weight ≥ 45 kg: glecaprevir 300 mg and pibrentasvir 120 mg (3 tablets) per day; b. Pediatric members 3 years to < 12 years of age with body weight < 20 kg: glecaprevir 150 mg and pibrentasvir 60 mg per day; c. Pediatric members 3 years to < 12 years of age with body weight 20 kg to < 30 kg: glecaprevir 200 mg and pibrentasvir 80 mg per day; d. Pediatric members 3 years to < 12 years of age with body weight 30 kg to < 45 kg: glecaprevir 250 mg and pibrentasvir 100 mg 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 all):
  12. Member must use brand Epclusa® or Vosevi®, if applicable for the requested indication, unless clinically significant adverse effects are experienced or both are contraindicated;
      Coadministration with omeprazole up to 20 mg is not considered an acceptable medical justification for inability to use Epclusa
  13. Must meet one of the following (a or b): a. 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 (i or ii): Page 2 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir i. 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 ii. 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 b. 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):

  1. 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 Mavyret for chronic HCV infection and has recently completed at least 40 days of treatment with Mavyret; ii. Confirmed HCV genotype is one of the following (1, 2, 3, or 4); 1) For treatment-naïve members: genotypes 1, 2, 3, 4, 5, or 6; 2) For members treatment-experienced with IFN/pegIFN, RBV, and/or sofosbuvir only: genotypes 1, 2, 3, 4, 5, or 6; 3) For members treatment-experienced with either an NS5A inhibitor or an NS3/4A protease inhibitor: genotype 1 (see Appendix E); 4) For Vosevi-experienced members: genotype 1, 2, 3, 4, 5, or 6;
  2. Member is not treatment-experienced with both NS3/4A protease inhibitor AND NS5A inhibitors, such as combination therapies including Technivie, Viekira, and Zepatier;
  3. Member is responding positively to therapy;
  4. Dose does not exceed one of the following (a, b, c, or d): a. Adult and pediatric members 12 years of age and older or with body weight ≥ 45 kg: glecaprevir 300 mg and pibrentasvir 120 mg (3 tablets) per day; b. Pediatric members 3 years to < 12 years of age with body weight < 20 kg: glecaprevir 150 mg and pibrentasvir 60 mg per day; c. Pediatric members 3 years to < 12 years of age with body weight 20 kg to < 30 kg: glecaprevir 200 mg and pibrentasvir 80 mg per day; d. Pediatric members 3 years to < 12 years of age with body weight 30 kg to < 45 kg: glecaprevir 250 mg and pibrentasvir 100 mg 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) Page 3 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir B. Other diagnoses/indications (must meet all):

  1. Member must use brand Epclusa® or Vosevi®, if applicable for the requested indication, unless clinically significant adverse effects are experienced or both are contraindicated;
     Coadministration with omeprazole up to 20 mg is not considered an acceptable medical justification for inability to use Epclusa
  2. Must meet one of the following (a or b): a. 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 (i or ii): i. 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 ii. 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 b. 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; B. Treatment-experienced members with both NS3/4A protease inhibitor AND NS5A inhibitors, such as combination therapies including: Technivie, Viekira, and Zepatier. 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. Page 4 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir Drug Name Dosing Regimen sofosbuvir/velpatasvir
  (Epclusa®) sofosbuvir/velpatasvir
  (Epclusa®) sofosbuvir/velpatasvir
  (Epclusa®)

• RBV Genotypes 1 through 6 Without cirrhosis or with compensated cirrhosis, treatment naïve or NS3/4A protease inhibitor and/or pegIFN/ RBV- experienced: One tablet PO QD for 12 weeks Genotypes 1 through 6 Treatment-naïve and treatment- experienced patients, post-liver transplant with compensated cirrhosis or without cirrhosis:
  One tablet PO QD for 12 weeks Genotype 3 with NS5A Y93H polymorphism
  Treatment-naïve with compensated cirrhosis or treatment-experienced without cirrhosis patient:
  sofosbuvir/velpatasvir 400 mg/100 mg + weight-based RBV for 12 weeksǂ Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir) Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir) Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir)

• RBV Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir) Genotype 1-6
  Treatment-experienced with NS5A inhibitor* with or without compensated cirrhosis:
  One tablet PO QD for 12 weeks Genotype 1a or 3 Treatment-experienced with a sofosbuvir-containing regimen without NS5A inhibitor with or without compensated cirrhosis:
  One tablet PO QD for 12 weeks Genotype 1-6
  Treatment-experienced with Vosevi with or without compensated cirrhosis:
  Vosevi one tablet PO QD with weight-based RBV for 24 weeksǂ Genotype 3 with NS5A Y93H polymorphism Treatment-naïve with compensated cirrhosis:
  One tablet PO QD for 12 weeksǂ Page 5 of 11 Dose Limit/ Maximum Dose sofosbuvir 400 mg/velpatasvir 100 mg (1 tablet) per day sofosbuvir 400 mg/ velpatasvir 100 mg (1 tablet) per day Varies One tablet (sofosbuvir 400 mg/ velpatasvir 100 mg/ voxilaprevir 100 mg) per day One tablet (sofosbuvir 400 mg/ velpatasvir 100 mg/ voxilaprevir 100 mg) per day Varies One tablet (sofosbuvir 400 mg/ velpatasvir 100 mg/ voxilaprevir 100 mg) per day

  CLINICAL POLICY Glecaprevir/Pibrentasvir 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. Treatment-experienced refers to previous treatment with NS3 protease inhibitor (telaprevir, boceprevir, or simeprevir) and/or peginterferon/RBV unless otherwise stated.

• In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir
  ǂ Off-label, AASLD-IDSA guideline-supported dosing regimen Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
  o Patients with severe hepatic impairment (Child-Pugh C) or those with any history of prior hepatic decompensation. o Co-administration with atazanavir or rifampin. • 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 NS5A Inhibitor Nucleotide Analog NS5B Polymerase Inhibitor Drug Class Non- Nucleoside NS5B Palm Polymerase Inhibitor Velpatasvir Sofosbuvir Ledipasvir Sofosbuvir Pibrentasvir NS3/4A Protease Inhibitor (PI) CYP3A Inhibitor Glecaprevir Ombitasvir Sofosbuvir Dasabuvir Paritaprevir Ritonavir Velpatasvir Sofosbuvir Elbasvir Voxilaprevir Grazoprevir Epclusa Harvoni Mavyret Sovaldi Viekira Pak Vosevi Zepatier *Combination drugs 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. • Unacceptable medical justification for inability to use Epclusa (preferred product): o Coadministration with omeprazole up to 20 mg is not considered an 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.” • Acceptable medical justification for inability to use Epclusa or Vosevi (preferred product): o In patients indicated for co-administration with amiodarone: serious symptomatic bradycardia in patients taking amiodarone, with cardiac monitoring recommended. Page 6 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir • 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. • Due to higher rates of virologic failure and treatment-emergent drug resistance, the data do not support labeling for treatment of HCV genotype 1 infected patients who are both NS3/4A PI and NS5A inhibitor-experienced. • 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 V. Dosage and Administration
  Indication Genotypes 1-6: Treatment-naive Dosing Regimen Without cirrhosis or with compensated cirrhosis:
  Three tablets PO QD for 8 weeks Maximum Dose Adults/Peds age ≥ 12 years or with body weight ≥ 45 kg: glecaprevir 300 Reference FDA- approved labeling Page 7 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir Indication Genotypes 1, 2, 4, 5, or 6:
  Treatment- experienced with IFN/pegIFN, RBV and/or sofosbuvir
  Genotype 3: Treatment- experienced with IFN/pegIFN, RBV and/or sofosbuvir Genotype 1:
  Treatment- experienced with NS5A inhibitor without prior NS3/4A protease inhibitor† Genotype 1: Treatment- experienced with NS3/4A protease inhibitor† without prior NS5A inhibitor Genotype 1-6: Treatment-naïve or treatment- experienced, post-liver or kidney transplantation without cirrhosis or with compensated cirrhosis Genotypes 1-6: Patients with prior sofosbuvir/velpatasvir/ voxilaprevir treatment failure Dosing Regimen Without cirrhosis: Three tablets PO QD for 8 weeks Maximum Dose mg/pibrentasvir 120 mg (3 tablets) per day; Reference Peds age 3 years to < 12 years of age with body weight < 20 kg: glecaprevir 150 mg/pibrentasvir 60 mg per day; Peds age 3 years to < 12 years of age with body weight 20 kg to < 30 kg: glecaprevir 200 mg/pibrentasvir 80 mg per day; Peds age 3 years to < 12 years of age with body weight 30 kg to < 45 kg: glecaprevir 250 mg/pibrentasvir 100 mg per day Three tablets (glecaprevir 300 mg/pibrentasvir 120 mg) per day AASLD- IDSA (updated March 2021) With compensated cirrhosis:
  Three tablets PO QD for 12 weeks Without cirrhosis or with compensated cirrhosis:
  Three tablets PO QD for 16 weeks Without cirrhosis or with compensated cirrhosis:
  Three tablets PO QD for 16 weeks Without cirrhosis or with compensated cirrhosis:
  Three tablets PO QD for 12 weeks Three tablets PO QD for 12 weeks (A 16-week treatment duration is recommended in genotype 1-infected patients who are NS5A inhibitor* experienced without prior treatment with an NS3/4A protease inhibitor† or in genotype 3-infected patients who are IFN/pegIFN, RBV and/or sofosbuvir treatment-experienced) With or without compensated cirrhosis: Mavyret 3 tablets PO QD

• Sovaldi 400 mg + Page 8 of 11

  CLINICAL POLICY Glecaprevir/Pibrentasvir Indication Dosing Regimen weight-based RBV for 16 weeks Maximum Dose Reference 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.

• In Mavyret clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with (peg)interferon and RBV † In Mavyret clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with (peg)interferon and RBV. VI. Product Availability
  • Tablet: glecaprevir 100 mg and pibrentasvir 40 mg • Oral pellet: glecaprevir 50 mg and pibrentasvir 20 mg VII.