HARVONI, Ledipasvir-Sofosbuvir Form

Ledipasvir/sofosbuvir (Harvoni®) is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor. ____ *These criteria do NOT apply to California Commercial Exchange Plans. FDA Approved Indication(s) Harvoni is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic HCV: • Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis • Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin (RBV)
• Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with RBV 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 Harvoni 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; *For treatment-naïve adult members without cirrhosis with genotype 1 and baseline viral load <6 million IU/mL, Harvoni will be approved for a maximum duration of 8 weeks (see Section V)
2. Confirmed HCV genotype is 1, 4, 5, or 6; *Chart note documentation and copies of lab results are required
3. Documentation of treatment status of the member (treatment-naïve or treatment- experienced);
4. Documentation of cirrhosis status of the member (no cirrhosis, compensated cirrhosis, or decompensated cirrhosis);
5. 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);

6. Age ≥ 3 years; Page 1 of 11

   CLINICAL POLICY Ledipasvir/Sofosbuvir

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, one of the following (i, ii, or iii): i. Member must use Epclusa (brand preferred) or Vosevi®, unless clinically significant adverse effects are experienced or both are contraindicated (see Appendix E);
   ii. If member has clinically significant adverse effects or contraindications to both Epclusa (brand preferred) and Vosevi, member must use authorized generic version of Harvoni®;
   iii. Member has clinically significant adverse effects or contraindications to Epclusa (brand preferred), Vosevi, and authorized generic version of Harvoni (clinical documentation required); Coadministration with omeprazole up to 20 mg is not considered 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;
9. Prescribed regimen is consistent with an FDA or AASLD-IDSA recommended regimen (see Section V Dosage and Administration for reference);
10. Dose does not exceed ledipasvir/sofosbuvir 90 mg/400 mg (1 tablet) per day. Approval duration: up to a total of 24 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. II. Continued Therapy A. Chronic Hepatitis C Infection (must meet all):

13. 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; Page 2 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir 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 Harvoni for chronic HCV infection and has recently completed at least 60 days of treatment with Harvoni; ii. Confirmed HCV genotype is 1, 4, 5, or 6;

14. Member is responding positively to therapy;
    3. Dose does not exceed ledipasvir/sofosbuvir 90 mg/400 mg (1 tablet) per day. Approval duration: up to a total of 24 weeks (Approved duration should be consistent with a regimen in Section V Dosage and Administration) B. Other diagnoses/indications (must meet 1 or 2):
15. 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

16. 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.
    Page 3 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir Drug Name Dosing Regimen sofosbuvir/
    velpatasvir
    (Epclusa®) sofosbuvir/
    velpatasvir
    (Epclusa®) Genotype 1 through 6:
    Without cirrhosis or with compensated cirrhosis, treatment-naïve or treatment- experienced patient
    One tablet PO QD for 12 weeks Genotype 1 through 6:
    With decompensated cirrhosis treatment- naïve or treatment-experienced patient
    Dose Limit/ Maximum Dose Adult/Peds ≥ 30 kg: sofosbuvir 400 mg /velpatasvir 100 mg (one tablet) per day;
    Peds 17 to < 30 kg: sofosbuvir 200 mg /velpatasvir 50 mg per day;
    Peds < 17 kg: sofosbuvir 150 mg /velpatasvir 37.5 mg per day
    sofosbuvir/
    velpatasvir
    (Epclusa®) sofosbuvir/
    velpatasvir
    (Epclusa®) sofosbuvir/
    velpatasvir
    (Epclusa®) Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir) One tablet PO QD with weight-based RBV for 12 weeks (GT 1, 4, 5, or 6 with decompensated cirrhosis and RBV-ineligible may use: one tablet PO QD for 24 weeks)ǂ Genotype 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 1 through 6:
    With decompensated cirrhosis in whom prior sofosbuvir- or NS5A-based treatment experienced failed
    One tablet (sofosbuvir 400 mg /velpatasvir 100 mg) per day One tablet PO QD with weight-based RBV for 24 weeksǂ Genotype 1 through 6:
    Treatment-naïve and treatment-experienced patients, post-liver transplant with decompensated cirrhosis One tablet PO QD with RBV (starting at 600 mg and increased as tolerated) for 12 weeks (treatment naïve) or 24 weeks (treatment experienced)ǂ Genotype 1-6 treatment-experienced with NS5A inhibitor with or without compensated cirrhosis: One tablet PO QD for 12 weeks One tablet (sofosbuvir 400 mg /velpatasvir 100 mg) per day One tablet (sofosbuvir 400 mg/ velpatasvir 100 mg/ voxilaprevir 100 mg) per day Page 4 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir Drug Name Dosing Regimen Vosevi® (sofosbuvir/ velpatasvir/ voxilaprevir) 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 Dose Limit/ Maximum Dose One tablet (sofosbuvir 400 mg/ velpatasvir 100 mg/ voxilaprevir 100 mg) per day 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 NS3/4A protease inhibitor (telaprevir, boceprevir, or simeprevir) and/or peginterferon/RBV unless otherwise stated
    ǂ Off-label, AASLD-IDSA guideline-supported dosing regimen Appendix C: Contraindications/Boxed Warnings • Contraindication(s): if used in combination with RBV, all contraindications to RBV also apply to Harvoni combination therapy. • 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 Non- Nucleoside NS5B Palm Polymerase Inhibitor Nucleotide Analog NS5B Polymerase Inhibitor Sofosbuvir Sofosbuvir Epclusa Harvoni Mavyret Sovaldi Viekira Pak Vosevi ZepatierCombination drugs Velpatasvir Ledipasvir Pibrentasvir Ombitasvir Velpatasvir Elbasvir 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. • 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 5 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir • 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. • 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 Genotype 1 chronic HCV infection: Dosing Regimen One tablet PO QD for: Treatment-naïve without cirrhosis, HIV- uninfected, AND HCV viral load < 6 million IU/mL: for 8 weeksǂ Maximum Dose Weight ≥ 35 kg: One tablet (sofosbuvir 400 mg / ledipasvir 90 mg) per day Weight ≥ 17 to < 35 kg: Reference 1) FDA- approved labeling 2) AASLD- IDSA (updated September 2021) Page 6 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir Indication Dosing Regimen Treatment-naïve without cirrhosis (not meeting the 8 week treatment indication requirements above) or with compensated cirrhosis: for 12 weeks Treatment-experienced without cirrhosis: for 12 weeks Treatment-experienced with compensated cirrhosis: Harvoni plus weight-based RBV for 12 weeks (or Harvoni for 24 weeks if RBV- intolerant) One tablet PO QD plus low initial dose of RBV (600 mg, increased as tolerated) for 12 weeks
    One tablet PO QD with low initial dose of RBV (600 mg, increased as tolerated) for 24 weeksǂ Without cirrhosis or with compensated cirrhosis: One tablet PO QD plus RBV for 12 weeks AASLD recommends patients without cirrhosis or with compensated cirrhosis receive one Genotype 1, 4ǂ, 5ǂ, or 6ǂ with decompensated cirrhosis Genotype 1, 4, 5, or 6 with decompensated cirrhosis: Adult patients in whom a previous sofosbuvir- containing regimen has failedǂ Genotype 1, 4, 5ǂ, or 6ǂ post-liver transplantation: Treatment-naive and treatment- experienced* patients without cirrhosis, with compensated cirrhosis, or with Reference Maximum Dose One tablet (sofosbuvir 200 mg / ledipasvir 45 mg) per day Weight < 17 kg: One packet of pellets (sofosbuvir 150 mg / ledipasvir 33.75 mg) per day 1) FDA- approved labeling 2) AASLD- IDSA (updated September 2021) AASLD-IDSA (updated September 2021) 1) FDA- approved labeling 2) AASLD- IDSA (updated September 2021) Page 7 of 11

    CLINICAL POLICY Ledipasvir/Sofosbuvir Indication decompensated cirrhosis Dosing Regimen tablet PO QD for 12 weeks (without RBV)ǂ Maximum Dose Reference With decompensated cirrhosis: One tablet PO QD with RBV for 12 weeks (treatment-naïve) or 24 weeks (treatment- experienced)ǂ One tablet PO QD for 12 weeks FDA-approved labeling Genotype 4, 5, or 6: Treatment-naïve and treatment- experienced patients without cirrhosis or with compensated cirrhosis 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.

    • Treatment-experienced refers to adult and pediatric subjects have failed a peginterferon alfa +/- RBV-based regimen with or without an HCV protease inhibitor unless otherwise stated
      ǂ Off-label, AASLD-IDSA guideline-supported dosing regimen VI. Product Availability
      • Tablets: 90 mg of ledipasvir and 400 mg of sofosbuvir; 45 mg of ledipasvir and 200 mg of sofosbuvir. • Oral pellets: 45 mg of ledipasvir and 200 mg of sofosbuvir; 33.75 mg of ledipasvir and 150 mg of sofosbuvir. VII.