Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.01.32 Subject: Harvoni Page: 1 of 9 Last Review Date: March 18, 2016 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). 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, 4, 5 and 6 infection in adults (2).
Subject: Harvoni Page: 2 of 9 Off Label Uses: In the SOLAR-1 study, a large multicenter, randomized controlled trial that included liver transplant recipients with HCV genotype 1 and 4 with a range of liver disease, including advanced liver disease and decompensated liver function, Harvoni and ribavirin for 12 weeks was found to be efficacious and well-tolerated, with SVR12 rates ranging from 60-98%. Harvoni was recommended per the AASLD/ IDSA guidelines for patients post liver transplant when used in combination with ribavirin (4-5). 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 (2). 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 (2-3). 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 Harvoni 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 (3). 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 (2). The use of Harvoni with other drugs containing sofosbuvir, including Sovaldi, is not recommended (2). Safety and effectiveness of Harvoni in children less than 18 years of age have not been established (2).
Subject: Harvoni Page: 3 of 9 Related policies Daklinza, Olysio, Sovaldi, Technivie, Viekira Pak, Zepatier 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; genotype 1: treatment-naïve patients with cirrhosis; genotype 4: treatment-naïve patients; genotype 1 and 4: treatment-experienced previously treated with Peg-Interferon and Ribavirin; genotype 1 and 4: treatmentexperienced previously treated with Sovaldi and/or Protease Inhibitor and moderate to severe fibrosis (F3-F4) confirmed by ONE of the following: liver biopsy confirming score of F3- F4 ( Metavir, Knodell, Batts-Ludwig, IASL, Scheuer, Laennec, or Ishak), transient elastography (Fibroscan) score greater than or equal to 9.5 kpa, FibroTest (FibroSURE) score of greater than or equal to 0.58 or APRI score greater than 1.5; genotype 1 and 4 post transplant and treatment naïve after transplant; genotype 5 and 6 with compensated liver disease; patient must have 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 (egfr less than 30ml/min/min/1.73m 2 ), or end stage renal disease (ESRD), or requiring hemodialysis, 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 all other indications. Prior-Approval Requirements Age 18 years of age or older
Subject: Harvoni Page: 4 of 9 Diagnosis Patient must have the following: Chronic Hepatitis C (Required documented viral load (HCV RNA) at least 6 months prior to request for treatment) AND ONE of the following: 1. Genotype 1: Treatment-naïve, without cirrhosis a. HCV RNA will be drawn at week 4 if initial load < 6 million IU/ml 2. Genotype 1: Treatment-naïve, with cirrhosis 3. Genotype 4: Treatment-naïve 4. Genotype 1 and 4: Treatment-experienced previously treated with Peg- Interferon and Ribavirin 5. Genotype 1 and 4: 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 6. Genotype 1 and 4: Post transplant and treatment naïve after transplant 7. Genotype 5 or 6 with compensated liver disease AND ALL of the following: 1. Presence of viral load (HCV RNA) in the serum prior to treatment 2. Absence of severe renal impairment (egfr less than 30 ml/min/1.73m 2 ) or end stage renal disease (ESRD) requiring hemodialysis
Subject: Harvoni Page: 5 of 9 3. 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 Prior Approval Renewal Requirements 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 Genotype 1 Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA < 6 million IU/ml: 8 weeks Harvoni (56 tablets per 56 days) Genotype 1 Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA > 6 million IU/ml:
Subject: Harvoni Page: 6 of 9 Genotype 1 Treatment-Naïve with cirrhosis: Genotype 4 Treatment-Naïve: Genotype 1 and 4 Treatment-Naïve with decompensated liver disease: / 12 weeks Ribavirin OR 24 weeks Harvoni (168 tablets per 168 days) Genotype 1 and 4 Treatment-experienced without cirrhosis previously treated with Peg-Interferon and Ribavirin: Genotype 1 and 4 Treatment-experienced with cirrhosis previously treated with Peg-Interferon and Ribavirin: / 12 weeks Ribavirin OR 24 weeks Harvoni (168 tablets per 168 days) Genotype 1 and 4 Treatment-experienced with decompensated liver disease previously treated with Peg-Interferon and Ribavirin: / 12 weeks Ribavirin OR 24 weeks Harvoni (168 tablets per 168 days) Genotype 1 and 4 Treatment-experienced without cirrhosis previously treated with Sovaldi and/or Protease Inhibitor: OR / 12 weeks Ribavirin Genotype 1 and 4 Treatment-experienced with cirrhosis previously treated with Sovaldi and/or Protease Inhibitor: 24 weeks Harvoni (168 tablets per 168 days) OR 24 weeks Harvoni (168 tablets per 168 days) / 24 weeks Ribavirin
Subject: Harvoni Page: 7 of 9 Genotype 1 and 4 Treatment-experienced with decompensated liver disease previously treated with Sovaldi and/or Protease Inhibitor: 24 weeks Harvoni (168 tablets per 168 days) / 24 weeks Ribavirin Genotype 1 and 4: Post Transplant and treatment naïve after transplant: / 12 weeks Ribavirin OR 24 weeks Harvoni (168 tablets per 168 days) Genotype 4, 5 or 6 Treatment-experienced or treatment-naïve: with compensated liver disease: Prior Approval Renewal Limits Rationale Treatment-Naïve, without cirrhosis, pre-treatment HCV RNA < 6 million IU/ml 4 weeks Harvoni (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, 4, 5 and 6 infections 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 treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/ml (2). 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 (2). Prior authorization is required to ensure the safe, clinically appropriate and cost effective use of Harvoni while maintaining optimal therapeutic outcomes. References
Subject: Harvoni Page: 8 of 9 1. FDA News Release. FDA approves first combination pill to treat hepatitis C. October 10, 2014. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm418365.htm?source= govdelivery&utm_medium=email&utm_source=govdelivery 2. Harvoni [package insert]. Foster City, CA. Gilead Sciences. November 2015. 3. AASLD and IDSA: Recommendations for Testing, Managing, and Treating Hepatitis C; October 2015. www.hcvguidelines.org 4. Abergel A, Loustaud-Ratti V, Metivier S et al. Ledipasvir/sofosbuvir for the treatment of patients with chronic genotype 4 or 5 HCV infection. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-26, 2015; Vienna, Italy 5. Gane EJ, Hyland RH, An D et al. High efficacy of LDV/SOF regimens for 12 weeks for patients with HCV genotype 3 or 6 infection. [Abstract LB11.] 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 7-11, 2014; Boston, MA. Policy History Date October 2014 October 2014 December 2014 March 2015 May 2015 August 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 Additions of genotypes 4, 5 and 6 per updated AASLD guidelines and the addition of post transplant duration limits.
Subject: Harvoni Page: 9 of 9 September 2015 December 2015 March 2016 Annual review Annual editorial review and reference update Addition of patients with cirrhosis for genotypes 4, 5 and 6 Annual editorial review and reference update Removal of the requirement of no decompensated liver disease Addition of therapies for decompensated patients and change in treatment duration of genotype 1 and 4 treatment-experienced, without cirrhosis previously treated with Sovaldi and/or Protease Inhibitor from 24 weeks to 12 weeks. Also addition of genotype 1and 4 treatment-experienced, with cirrhosis previously treated with Sovaldi and/or Protease Inhibitor: Policy change from 5.03.32 Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on March 18, 2016 and is effective on April 1, 2016. Deborah M. Smith, MD, MPH