See Important Reminder at the end of this policy for important regulatory and legal information.

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1 Clinical Policy: () Reference Number: CP.HNMC.178 Effective Date: Last Review Date: Line of Business: Medicaid Medi-Cal Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Sofosbuvir/ledipasvir ( ) is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor. FDA approved indication is indicated for the treatment of chronic hepatitis C virus (HCV) in: Adults with genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis Adults with genotype 1 infection with decompensated cirrhosis, in combination with ribavirin Adults with genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin Pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria It is the policy of health plans affiliated with Centene Corporation that 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 hepatitis C (CHC) confirmed by detectable serum HCV RNA by quantitative assay in the last 6 months; 2. Confirmed genotype is 1, 4, 5 or 6; 3. Documentation of baseline viral load by quantitative assay including genotype; 4. Age 18 years; 5. For members with no cirrhosis or compensated cirrhosis: Member must use Mavyret unless contraindicated or clinically significant adverse effects are experienced; 6. Any of the following clinical states to identify candidates for treatment: a. Evidence of Stage 2 or greater hepatic fibrosis including one of the following: i. Liver biopsy confirming a METAVIR score F2 or greater ii. Transient elastography (Fibroscan ), score greater than or equal to 7.5 kpa; iii. FibroSure (also known as FibroTest ) score of greater than or equal to 0.48; iv. APRI score greater than 0.7; v. FIB greater than 3.25; Page 1 of 11

2 vi. FibroMeter 0.34; b. Evidence of extra-hepatic manifestation of hepatitis C virus, such as type 2 or 3 essential mixed cryoglobulinemia with end- organ manifestations (e.g. vasculitis), or kidney disease (e.g. proteinuria, nephrotic syndrome or membranoproliferative glomerulonephritis); c. Persons with hepatocellular carcinoma with life expectancy greater than 12 months; d. Pre- and post-liver transplant, or other solid organ transplant; e. HIV-1 co-infection; f. Hepatitis B co-infection; g. Other coexistent liver disease (e.g. nonalcoholic steatohepatitis); h. Type 2 diabetes mellitus (insulin resistant); i. Porphyria cutanea tarda; j. Debilitating fatigue impacting quality of life (e.g., secondary to extra-hepatic manifestations and/or liver disease); k. Men who have sex with men with high-risk sexual practices; l. Active injection drug users; m. Persons on long-term hemodialysis; n. Women of childbearing age who wish to get pregnant; o. HCV-infected health care workers who perform exposure-prone procedures; 7. Member is hepatitis B virus (HBV) negative, or if positive, documentation that concurrent HBV infection is being treated (e.g., tenofovir alafenamide, adefovir, entecavir), unless contraindicated or clinically significant adverse effects are experienced (see Appendix B); 8. Dose does not exceed one tablet (90mg ledipasvir/400 mg sofosbuvir) daily. Approval duration: Up to 24 weeks based on section V (may be filled in quantities up to 28 days at a time) B. Other diagnoses/indications 1. Refer to CP.PHAR.57 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized). II. Continued Therapy A. Chronic Hepatitis C Infection (must meet all): 1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving for treatment of chronic HCV infection and has received this medication for at least 30 days; 2. Member is responding positively to therapy (e.g. decreased HCV RNA level, no unacceptable toxicity); 3. Evidence of lack of adherence may result in denial of treatment reauthorization; 4. Missed medical appointments related to the hepatitis C virus may result in denial of treatment authorization; 5. If request is for a dose increase, new dose does not exceed one tablet (90mg ledipasvir/400 mg sofosbuvir) daily. Approval duration: Up to a total of 24 weeks based on section V (may be filled in quantities up to 28 days at a time) Page 2 of 11

3 B. Other diagnoses/indications 1. Refer to CP.PHAR.57 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized). 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 CP.PHAR.57 or evidence of coverage documents; B. Dual therapy (+(Sovaldi, or Olysio). IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AASLD: American Association for the Study of Liver Diseases APRI: AST to platelet ratio ARFI: acoustic radiation force impulse CHC: chronic hepatitis C DHCS: Department of Health Care Services FIB-4: Fibrosis-4 index HCV: hepatitis C virus HIV: human immunodeficiency virus IDSA: Infectious Diseases Society of America MRE: magnetic resonance elastography RBV: ribavirin RNA: ribonucleic acid SWE: Shear Wave Elastography Appendix B: General Information Hepatitis B Reactivation is a Black Box Warning for all direct-acting antiviral drugs for the treatment of HCV. The provider must provide either 1, 2, or 3: 1. Documentation of absence of concurrent HBV infection as evidenced by laboratory values showing absence of hepatitis B virus envelope antigen (HBeAg) and HBV DNA; 2. Documentation that HBV co-infected patient may not be candidates for therapy as evidenced by a or b: a. Absence of HBeAg, HBV DNA less than 2,000 international units/ml, and alanine aminotransferase (ALT) level within 1 to 2 times the upper limit of normal; b. HBeAg-positive and HBV DNA greater than 1,000,000 international units/ml and ALT level within 1 to 2 times the upper limit of normal; 3. Documentation that concurrent HBV infection is being treated (e.g., tenofovir alafenamide, adefovir, entecavir), unless contraindicated or clinically significant adverse effects are experienced. Treatment-experienced patients have failed treatment with either peginterferon alfa + ribavirin or an HCV protease inhibitor + peginterferon alfa + ribavirin. Treatment-naive patients have no prior exposure to peginterferon alfa, ribavirin or an HCV protease inhibitor. METAVIR Fibrosis Scores: o F0 = No fibrosis o F1 = Portal fibrosis without septa Page 3 of 11

4 o F2 = Portal fibrosis with few septa o F3 = numerous septa without cirrhosis o F4 = Cirrhosis FibroSure (aka FibroTest) Scoring: o <0.21 = Stage F0 = No fibrosis o = Stage F0 - F1 o = Stage F1 = Portal fibrosis o = Stage F1 - F2 o = Stage 2 = Bridging fibrosis with few septa o = Stage F3 = Bridging fibrosis with many septa o = Stage F3 - F4 o >0.74 = Stage F4 = Cirrhosis Treatment with for 8 weeks can be considered in treatment-naive patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL. In the ION-3 trial, patients with a baseline HCV viral load of <6 million IU/mL and were treated with for 8 weeks achieved SVR-12 at a rate of 97% versus 96% of those treated with for 12 weeks. Based on information presented as abstracts at the 2014 American Association for Study of Liver Disease (AASLD), this organization had made recommendation for the use of outside of the approved indication. The AASLD treatment guideline include dosing recommendation for use in patients with decompensated cirrhosis, in patients with compensated cirrhosis who have relapsed following liver transplant and in patients who have failed previous treatment with a Sovaldi ) based therapy. There are currently neither published studies nor AASLD guidelines supporting the use of in patients with hepatocellular carcinoma (HCC). Sovaldi ) is currently approved by the FDA for patients with HCC. Serious symptomatic bradycardia may occur in patients taking with amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered : o Counsel patients about the risk of serious symptomatic bradycardia o Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients should be evaluated for readiness to initiate treatment. Patients selected for treatment shall be able and willing to strictly adhere to treatment protocols prescribed by their provider. Caution should be exercised with patients who have a history of treatment failure with prior hepatitis C treatment due to non-adherence with treatment regimen and appointments. Patients should be educated regarding potential risks and benefits of hepatitis C virus therapy, as well as the potential for resistance and failed therapy if medication is not taken as prescribed. Evidence of lack of adherence may result in denial of treatment reauthorization. Lost medications will not be replaced and may result in denial of treatment authorization. Replacement of stolen medications will require documentation and will be adjudicated on a case-by-case basis. Missed medical and lab appointments may result in denial of treatment authorization. Page 4 of 11

5 Retreatment may be considered where there is evidence that such retreatment will improve patient outcomes according to AASLD guidelines. HIV/HCV-coinfected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications. Investigational services are not covered except when it is clearly documented that all of the following apply: o Conventional therapy will not adequately treat the intended patient's condition; o Conventional therapy will not prevent progressive disability or premature death; o The provider of the proposed service has a record of safety and success with it equivalent or superior to that of other providers of the investigational service; o The investigational service is the lowest cost item or service that meets the patient's medical needs and is less costly than all conventional alternatives; o The service is not being performed as a part of a research study protocol; o There is a reasonable expectation that the investigational service will significantly prolong the intended patient's life or will maintain or restore a range of physical and social function suited to activities of daily living; o All investigational services require prior authorization. Payment will not be authorized for investigational services that do not meet the above criteria or for associated inpatient care when a beneficiary needs to be in the hospital primarily because she/he is receiving such non-approved investigational services. There is no dosing recommendation for patients with severe renal impairment (estimated glomerular filtration rate < 30mL/minute/1.73m 2 or with end stage renal disease due to higher exposures (up to 20 fold) of the predominant sofosbuvir metabolite. Pediatric patients age 12 years or total body weight 35 kg should be re-directed to California Children s Services. In August 2017, the Department of Health Care Services (DHCS) deemed Shear Wave Elastography (SWE) as a valid method of fibrosis scoring that is consistent with the DHCS hepatitis C treatment policy. The optimal cutoff values were determined to be 7.1 kpa (1.54 m/s) for significant fibrosis (METAVIR fibrosis score F2 or greater), 8.7 kpa (1.70 m/s) for advanced fibrosis (METAVIR fibrosis score of F3 or greater), and 10.4 kpa (1.86 m/s) for cirrhosis (METAVIR fibrosis score of F4). The Fee-For-Service Medi- Cal has adopted SWE as a valid method for staging liver fibrosis. Appendix C: Therapeutic Alternatives Drug Name Dosing Regimen Dose Limit/ Mavyret TM (glecaprevir /pibrentasvir) Treatment-naïve Chronic hepatitis C (CHC) infection: Genotypes 1, 4, 5, or 6 Without cirrhosis: 3 tablets PO QD for 8 weeks Maximum Dose Mavyret: Glecaprevir 300 mg/pibrentasvir 120 mg (3 tablets) per day Page 5 of 11

6 Drug Name Dosing Regimen Dose Limit/ Maximum Dose With compensated cirrhosis: 3 tablets PO QD for 12 weeks Mavyret TM (glecaprevir /pibrentasvir) Treatment-experienced with IFN/pegIFN + RBV +/- sofosbuvir CHC infection: Genotypes 1, 4, 5, or 6 Without cirrhosis: 3 tablets PO QD for 8 weeks Mavyret: Glecaprevir 300 mg/pibrentasvir 120 mg (3 tablets) per day Mavyret TM (glecaprevir /pibrentasvir) Mavyret TM (glecaprevir /pibrentasvir) With compensated cirrhosis: 3 tablets PO QD for 12 weeks Treatment-experienced with NS5A inhibitor without prior NS3/4A protease inhibitor CHC infection: Genotype 1 Without cirrhosis or with compensated cirrhosis: 3 tablets PO QD for 16 weeks Treatment-experienced with NS3/4A protease inhibitor without prior NS5A inhibitor CHC infection: Genotype 1 Mavyret: Glecaprevir 300 mg/pibrentasvir 120 mg (3 tablets) per day Mavyret: Glecaprevir 300 mg/pibrentasvir 120 mg (3 tablets) per day Without cirrhosis or with compensated cirrhosis: 3 tablets 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. V. Dosage and Administration Indication: Adult patients with chronic HCV infection Indication Dosing Regimen Maximum Dose Reference Genotype 1 CHC: 400 mg / 90 mg PO QD Treatment-naïve adult patients without cirrhosis AND whose HCV viral load is less than 6 million IU/mL: 8 weeks ǂ Treatment-naïve adult patients without cirrhosis AND whose Page 6 of 11

7 HCV viral load is greater than or equal to 6 million IU/mL: 12 weeks Treatment-naïve adult patients with compensated cirrhosis:12 weeks Treatment-experienced with peg-ifn/rbv adult patients without cirrhosis: 12 weeks Treatment-experienced with NS3 PI*/peg-IFN/RBV adult patient without cirrhosis: 12 weeks Treatment-experienced (with NS3 PI*/peg-IFN/RBV or peg- IFN/RBV ) adult patients with compensated cirrhosis: plus weight-based RBV for 12 weeks Or without RBV for 24 weeks ǂ if RBV ineligible Treatment-experienced with sofosbuvir/rbv with or without peg-ifn without cirrhosis: plus weight-based RBV for 12 weeksǂ Treatment-experienced with sofosbuvir/rbv with or without peg-ifn with compensated cirrhosis: plus weight-based RBV for 24 weeksǂ Genotype 1, 4ǂ, 5ǂ, or 6ǂ CHC with decompensated cirrhosis: Adult patients with who may or may not be candidates for liver transplantation, 400 mg/90 mg QD plus low initial dose of RBV (600mg, increased as tolerated) Or without RBV for 24 weeks if RBV ineligible Page 7 of 11

8 including those with hepatocellular carcinoma Genotype 1, 4ǂ, 5ǂ, or 6ǂ CHC with decompensated cirrhosis: Adult patients in whom a previous sofosbuvir-containing regimen has failedǂ Genotype 1 or 4 CHC and post-liver transplantation: Treatment-naive and treatment-experienced adult patients with or without compensated cirrhosis Genotype 1 or 4 CHC and post-liver transplantation, who are intolerant to RBV or RBV ineligible: 400 mg/90 mg PO QD with low initial dose of RBV (600mg, increased as tolerated) For 24 weeks 400 mg/90 mg PO QD plus RBV 400 mg/90 mg PO QD For 24 weeks ǂ AASLD-IDSA (updated April, 2017) ǂ AASLD-IDSA (updated April, 2017) Treatment-naïve adult patients with HCV in the allograft, including compensated cirrhosis Genotype 1 or 4 CHC and post-liver transplantation: Treatment-naive and treatment-experienced adult patients with decompensated cirrhosis Genotype 1, 4, 5 or 6 CHC with HIV coinfection: Treatment-naïve adult patients without cirrhosis Genotype 4, 5, or 6 CHC: 400 mg/90 mg PO QD plus low initial dose RBV (600mg, increased as tolerated) 400 mg / 90 mg PO QD 400 mg / 90 mg PO QD ǂ AASLD-IDSA (updated April, 2017) Page 8 of 11

9 Treatment-naive adult patients with or without compensated cirrhosis Genotype 4 CHC: Treatment-experienced adult patients without compensated cirrhosis Genotype 4 CHC: Treatment-experienced adult patients with compensated cirrhosis Genotype 5 or 6 CHC: Treatment-experienced adult patients with or without compensated cirrhosis 400 mg / 90 mg PO QD 400 mg / 90 mg PO QD plus weight-based RBV Or without RBV for 24 weeks if RBV ineligibleǂ 400 mg / 90 mg PO QD *NS3 PI refers to nonstructural protein 3 (NS3) protease inhibitor (telaprevir, boceprevir, or simeprevir). *Treatment-experienced refers to peg-ifn/rbv, unless otherwise indicated. *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. ǂ Off-label, AASLD-IDSA guideline-supported dosing regimen VI. Product Availability Tablet: 400 mg sofosbuvir with 90 mg ledipasvir VII. References 1. Prescribing Information. Foster City, CA: Gilead Sciences, Inc.; April Available at Accessed June 15, Afdhal N, Zeuzem S, Kwo N et al. Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection. NEJM May 15, ;19: Afdhal N, Reddy KR, Nelson DR et al. Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection. NEJM April 17, ;16: Kowdley KV, Gordon SV, Reddy KR et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. NEJM May 15, ;19: American Association for the Study of Liver Disease Recommendations for AASLD-IDSA. American Association for the Study of Liver Disease Recommendations for Testing,Managing, and Treating Hepatitis C; UpdatedApril Avaliable at: Accessed June 14, Wirth S, Gonzalez-Peralta R, Rosenthal P, et al. Sofosbuvir-Containing Regimens are Safe and Effective in Adolescents with Chronic hepatitis C Infection. The 26th Annual Meeting of the Asian pacific Association for the Study of the Liver (APASL) in February 15-19, 2017 in Shanghai, China. Page 9 of 11

10 7. Squires JE, Balisteri WF. Hepatitis C Virus Infection in Children and Adolescents. Hepatology Communications 2017; 1(2): Institute of Medicine of the National Academies. Beyond Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Redefining an Illness. Report Brief, February Available at portbrief.pdf, accessed June 15, Reviews, Revisions, and Approvals Date P&T Approval Date Policy converted from NATL docx and CP.CPA.XX Ledipasvir-Sofosbuvir () to new Centene template Annual Review Added requirement for cirrhosis status documentation. Added FibroMeter 0.34 for evidence of stage 2 fibrosis; deleted section II.B.1 other diagnoses/indications currently receiving medication via Centene. Added redirection to Mavyret for FDA-approved indications. Safety criteria were applied according to the safety guidance discussed at CPAC and endorsed by Centene Medical Affairs. Exception made to require Hep B screening for all patients prior to treatment to ensure that proper risk reduction measures are taking, though this is not specifically addressed in boxed warning. Removed redirection to Zepatier for GT1 and 4 (Mavyret is preferred); Updated redirection to Mavyret for members without cirrhosis or with compensated cirrhosis Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. Health Plan means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the Page 10 of 11

11 administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services. Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation. Page 11 of 11