Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: Zepatier Page: 1 of 6 Last Review Date: June 24, 2016 Zepatier Description Zepatier (elbasvir, grazoprevir) and Ribavirin 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). Zepatier is used in combination with or without ribavirin for the treatment of hepatitis C virus (HCV) genotype1 or 4 infections in patients without decompensated cirrhosis (1). Regulatory Status FDA-approved indications: Zepatier is a fixed-dose combination containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults (1). Zepatier is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to potential toxicity (1). If Zepatier is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. The primary toxicity of ribavirin is hemolytic anemia. The boxed warning
Subject: Zepatier Page: 2 of 6 explains that the anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin (2). There is a boxed warning stating that ribavirin may cause birth defects and fetal death. Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period (2). Hepatic laboratory testing on all patients during the first 8 weeks of treatment must be performed because elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) may occur with Zepatier with or without ribavirin. ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with Zepatier. Alternative methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during Zepatier therapy. Ethinyl estradiolcontaining medications can be restarted approximately 2 weeks following completion of treatment with Zepatier (1-2). Safety and effectiveness of Zepatier in children less than 18 years of age have not been established (1). Related policies Daklinza, Harvoni, Sovaldi, Technivie, Viekira Pak Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Zepatier may be considered medically necessary in patients 18 years of age or older with chronic Hepatitis C (Required documented viral load (HCV RNA) at least 6 months prior to request for treatment) genotype 1 or 4; patient s with genotype 1a must have been tested for the
Subject: Zepatier Page: 3 of 6 NS5A resistance-associated polymorphisms; intolerance, or contraindication to Harvoni therapy; with no history of alcohol and/or substance abuse in the past 6 months; no decompensated liver disease; no moderate or severe hepatic impairment (Child-Pugh Class B or C) and the patient has not had a liver transplant; 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. Zepatier 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 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 ALL of the following: 1. Genotype 1 or 4 2. Patient s with genotype 1a must have been tested for the NS5A resistanceassociated polymorphisms 3. Intolerance or contraindication to Harvoni therapy 4. NO history of alcohol and/or substance abuse in the past 6 months 5. NO decompensated liver disease 6. NO moderate or severe hepatic impairment (Child-Pugh Class B or C) 7. Patient has NOT had a liver transplant 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
Subject: Zepatier Page: 4 of 6 months after stopping ribavirin therapy Prior Approval Renewal Requirements None Policy Guidelines Pre - PA Allowance None Prior - Approval Limits Duration Genotype Naïve / Experienced No Cirrhosis Compensated Cirrhosis 1a 1b 1a Naïve: without NS5A Polymorphisms Naïve: with NS5A Polymorphisms Naïve Experienced: Peg-INF and Ribavirin without NS5A Polymorphisms Experienced: Peg-INF and Ribavirin with NS5A Polymorphisms 1b Experienced: Peg-INF and Ribavirin 1a & 1b Experienced: NS3 Protease Inh. & Peg-INF & Ribavirin without NS5A Polymorphisms Experienced: NS3 Protease Inh. & Peg-INF & Ribavirin with NS5A Polymorphisms Ribavirin 12 weeks Ribavirin 12 weeks
Subject: Zepatier Page: 5 of 6 Genotype Naïve / Experienced No Cirrhosis 4 Naïve Experienced (Relapsed): Peg-INF and Ribavirin Compensated Cirrhosis Experienced (Failure): Peg-INF and Ribavirin = (84 tablets per 84 days) = (112 tablets per 112 days) Prior Approval Renewal Limits None Rationale Summary Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Zepatier contains two new drugs - elbasvir and grazoprevir that work together to inhibit the growth of HCV. Zepatier can be used with or without ribavirin, but it is not recommended for patients whose liver is unable to function properly (decompensated liver disease). Safety and effectiveness of Zepatier in children less than 18 years of age have not been established (1-2). Prior authorization is required to ensure the safe, clinically appropriate and cost effective use of Zepatier while maintaining optimal therapeutic outcomes. References 1. Zepatier [package insert]. Whitehouse Station, NJ: Merck & CO. Inc; January 2016. 2. Rebetol capsules [package insert]. Whitehouse Station, NJ: Merck & CO. Inc; May 2015. 3. AASLD and IDSA: Recommendations for Testing, Managing, and Treating Hepatitis C; April 2016. www.hcvguidelines.org
Subject: Zepatier Page: 6 of 6 Policy History Date February 2016 March 2016 June 2016 Action Addition to PA Annual editorial review Removal of inadequate response per SME Annual editorial review and reference update Removal of must be prescribed by a board-certified gastroenterologist, hepatologist, oncologist, or infectious disease specialist Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on June 24, 2016 and is effective on July 1, 2016. Deborah M. Smith, MD, MPH