Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: Harvoni Page: 1 of 7 Last Review Date: June 19, 2015 Harvoni Description Harvoni (ledipasvir & sofosbuvir) Background Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with hepatitis C virus (HCV) have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer (1). Harvoni is a combination pill to treat chronic HCV genotype 1 infection that does not require administration with peg-interferon or ribavirin. Both drugs in Harvoni, ledipasvir (an NS5A inhibitor) and sofosbuvir (an NS5B-inhibitor), interfere with the enzymes needed by HCV to multiply. Sofosbuvir is a previously approved HCV drug marketed under the brand name Sovaldi (2,3). Regulatory Status FDA-approved indications: Harvoni is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults (3).
Subject: Harvoni Page: 2 of 7 Harvoni is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of Harvoni is one tablet taken orally once daily with or without food (3). Harvoni treatment durations for treatment-naïve (with or without cirrhosis) and treatmentexperienced (without cirrhosis) patients is 12 weeks. The treatment duration for treatmentexperienced patients with cirrhosis is 24 weeks. Treatment-experienced is defined as patients who have failed treatment with either peg-interferon alfa + ribavirin or treatment with the combination of an HCV protease inhibitor + peg-interferon alfa + ribavirin. Harvoni for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/ml (3,4). Based on data from the SIRIUS study, patients with cirrhosis in whom a prior PEG-IFN and RBV, with or without HCV protease inhibitors containing regimen failed may also receive ledipasvir/sofosbuvir plus weight-based RBV for 12 weeks (4). In patients who require retreatment more urgently, based on emerging data and the expected pattern of HCV drug resistance, patients in whom simeprevir plus sofosbuvir does not result in a cure may be treated with ledipasvir/sofosbuvir with or without RBV for 24 weeks (4). No dose recommendation of Harvoni can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [egfr] <30 ml/min/1.73m 2 ) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite (3). The use of Harvoni with other drugs containing sofosbuvir, including Sovaldi, is not recommended (3). Safety and effectiveness of Harvoni in children less than 18 years of age have not been established (3). Related policies Olysio, Sovaldi, Viekira Pak
Subject: Harvoni Page: 3 of 7 Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Harvoni may be considered medically necessary in patients 18 years of age or older with chronic Hepatitis C genotype 1 (Required documented viral load (HCV RNA) at least 6 months prior to request for treatment) in treatment-naïve patients with no cirrhosis, HCV RNA will be drawn at week 4 if initial load is less than 6 million IU/ml; treatment-experienced previously treated with Peg-Interferon and Ribavirin and not previously with Protease Inhibitors; treatmentexperienced previously treated with Sovaldi and/or Protease Inhibitor and are cirrhotic; have compensated liver disease, presence of viral load (HCV RNA) in the serum prior to treatment, no concurrent therapy with other drugs containing Sovaldi; absence of severe renal impairment (CrCl less than 30ml/min, end stage renal disease (ESRD), or requires dialysis, with no history of alcohol and/or substance abuse in the past 6 months; when combined with ribavirin then absence of significant or unstable cardiac disease, neither the patient nor the partner of the patient is pregnant, and if patient or their partner are of child bearing age, the patient has been or will be instructed to practice effective contraception during therapy and for 6 months after stopping ribavirin therapy. Harvoni is considered investigational for patients that are under 18 years of age and for patients that do not meet the criteria for medical necessity. Prior-Approval Requirements Age 18 years of age or older Diagnosis Patient must have the following: Chronic Hepatitis C Genotype 1 (Required documented viral load (HCV RNA) at least 6 months prior to request for treatment.) AND ONE of the following: 1. Treatment-naïve, without cirrhosis a. HCV RNA will be drawn at week 4 if initial load is less than 6 million
Subject: Harvoni Page: 4 of 7 IU/ml 2. Treatment-naïve, with cirrhosis 3. Treatment-experienced, without cirrhosis previously treated with Peg- Interferon and Ribavirin a. NOT previously treated with Protease Inhibitors 4. Treatment-experienced, with cirrhosis - previously treated with Peg-Interferon and Ribavirin a. NOT previously treated with Protease Inhibitors 5. Treatment-experienced previously treated with Sovaldi and/or Protease Inhibitor a. Moderate to severe fibrosis (F3-F4) confirmed by ONE of the following: i. Liver biopsy confirming score of F3-F4 ( Metavir, Knodell, Batts-Ludwig, IASL, Scheuer, Laennec, or Ishak) ii. Transient elastography (Fibroscan) score greater than or equal to 9.5 kpa iii. FibroTest (FibroSURE) score of greater than or equal to 0.58 iv. APRI score greater than 1.5 AND ALL of the following: 1. NO decompensated liver disease 2. Presence of viral load (HCV RNA) in the serum prior to treatment 3. Absence of severe renal impairment (egfr less than 30 ml/min/1.73m 2 ) or end stage renal disease (ESRD) requiring hemodialysis 4. NO history of alcohol and/or substance abuse in the past 6 months AND ALL of the following if combined with ribavirin therapy: 1. Absence of significant or unstable cardiac disease 2. Neither the patient nor the partner of the patient is pregnant 3. If patient or their partner are of child bearing age, the patient has been or will be instructed to practice effective contraception during therapy and for 6 months after stopping ribavirin therapy
Subject: Harvoni Page: 5 of 7 Prior Approval Renewal Requirements Age 18 years of age or older Diagnosis Patient must have the following: Chronic Hepatitis C Genotype 1 AND ALL of the following: Policy Guidelines 1. Continuation of therapy for treatment-naïve patients, without cirrhosis, pretreatment HCV RNA < 6 million IU/ml: a. Evaluation of patient at 4 weeks to determine that the viral load was not met within the 8 weeks of treatment Pre - PA Allowance None Prior - Approval Limits Duration Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA < 6 million IU/ml: 8 weeks (56 tablets per 56 days) Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA > 6 million IU/ml: 12 weeks (84 tablets per 84 days) Treatment-Naïve with cirrhosis: 12 weeks (84 tablets per 84 days) Treatment-experienced, without cirrhosis previously treated with Peg- Interferon and Ribavirin: 12 weeks (84 tablets per 84 days)
Subject: Harvoni Page: 6 of 7 Treatment-experienced, with cirrhosis previously treated with Peg-Interferon and Ribavirin: 24 weeks (168 tablets per 168 days) OR 12 weeks Harvoni (84 tablets per 84 days) / 12 weeks Ribavirin Treatment-experienced previously treated with Sovaldi and/or Protease Inhibitor : 24 weeks (168 tablets per 168 days) OR 24 weeks Harvoni (84 tablets per 84 days) / 24 weeks Ribavirin Prior Approval Renewal Limits Rationale Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA < 6 million IU/ml 4 weeks (28 tablets per 28 days) Summary Harvoni is a fixed-dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. Harvoni treatment durations for treatment-naïve (with or without cirrhosis) and treatment-experienced (without cirrhosis) patients is 12 weeks. However, Harvoni for 8 weeks can be considered in treatmentnaïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/ml (3). The use of Harvoni with other drugs containing sofosbuvir, including Sovaldi, is not recommended. Safety and effectiveness of Harvoni in children less than 18 years of age have not been established (3). Prior authorization is required to ensure the safe, clinically appropriate and cost effective use of Harvoni while maintaining optimal therapeutic outcomes. References 1. FDA Newspress Announcement. FDA approves Sovaldi for chronic Hepatitis C. December 6, 2013. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm377888.htm 2. FDA News Release. FDA approves first combination pill to treat hepatitis C. October 10,
Subject: Harvoni Page: 7 of 7 2014. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm418365.htm?source= govdelivery&utm_medium=email&utm_source=govdelivery 3. Harvoni [package insert]. Foster City, CA. Gilead Sciences. October 2014. 4. AASLD and IDSA: Recommendations for Testing, Managing, and Treating Hepatitis C; 2015. www.hcvguidelines.org Policy History Date October 2014 October 2014 December 2014 March 2015 May 2015 June 2015 Action New addition to PA Addition of relapsed patients to criteria and changed nonresponder to treatment failure, compensated liver disease, fibrosis testing scores and the absence of end-stage renal disease. Changed SVR to viral load (HCV RNA) per SME Annual review and reference update. Addition of HCV RNA will be drawn at week 4 if initial load is less than 6 million IU/ml for treatment naïve without cirrhosis, more acceptable fibrosis staging scoring methods, compensated liver disease, absence of end stage renal disease (ESRD), changing requirement to 4 weeks on the continuation of therapy and defining chronic hepatitis with documentation of 6 months of viral load Annual editorial review and reference update. Addition of severe renal disease and dialysis; and treatment experienced with peg-interferon and ribavirin Addition of Ribavirin to therapy and no history of alcohol and/or substance abuse in the past 6 months Annual editorial review and reference update. Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on June 19, 2015 and is effective July 1, 2015. Deborah M. Smith, MD, MPH