The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1489 Volume 56 February 29, 2016 IN THIS ISSUE Elbasvir/Grazoprevir (Zepatier) for Hepatitis C p 25 Drugs for Tobacco Dependence p 27 Sonidegib (Odomzo) for Basal Cell Carcinoma p 31 Clarification: Half-Life of Heroin p 32 Olaparib (Lynparza) for Advanced Ovarian Cancer .online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1489 Volume 56 ▶ February 29, 2016 ALSO IN THIS ISSUE Drugs for Tobacco Dependence p 27 Sonidegib (Odomzo) for Basal Cell Carcinoma p 31 Clarification: Half-Life of Heroin p 32 Olaparib (Lynparza) for Advanced Ovarian Cancer .online only Elbasvir/Grazoprevir (Zepatier) for Hepatitis C Pronunciation Key Elbasvir : elb' as veer Zepatier : zep' ah teer Grazoprevir : graz oh' pre veer FIXED-DOSE COMBINATIONS — Zepatier is the third all-oral, interferon-free, fixed-dose combination to be approved for treatment of infections with HCV genotypes and The combination of ledipasvir/ sofosbuvir (Harvoni) was approved for HCV genotype infection in 20142 and for genotypes 4, 5, and in 2015.3 The fixed-dose combination of ombitasvir/ paritaprevir/ritonavir copackaged with dasabuvir (Viekira Pak) was approved for HCV genotype infection in 2014.4 Ombitasvir/paritaprevir/ritonavir (Technivie) coadministered with ribavirin was approved for genotype the following year.5 HCV GENOTYPES — Genotype is responsible for 70-80% of HCV infections in the US Genotype is uncommon in the US and Canada; it is the most prevalent strain of HCV in Central sub-Saharan Africa, North Africa, and the Middle East.1 TREATMENT OF HCV GENOTYPE — Current guidelines recommend that patients with chronic HCV genotype infection receive either Harvoni, Viekira Pak, sofosbuvir (Sovaldi) plus simeprevir (Olysio), or daclatasvir (Daklinza) plus sofosbuvir, all with or The FDA has approved Zepatier (Merck), a fixeddose combination of two direct-acting antiviral agents — elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor — for oral treatment of chronic hepatitis C virus (HCV) genotype or infection Table Oral Regimens for HCV Genotype Infection Brand Name Formulation Usual Dosage Number of Tablets Cost1 Harvoni (Gilead) 90/400 mg ledipasvir/sofosbuvir tabs tab once/day x 12 wks2,3 1/day4 $94,500 Sovaldi (Gilead) + Daklinza (BMS) 400 mg sofosbuvir tabs + 60 mg daclatasvir tabs sofosbuvir3 tab and daclatasvir tab once/day x 12 wks5 2/day4 147,000 Sovaldi (Gilead) + Olysio (Janssen) 400 mg sofosbuvir tabs + 150 mg simeprevir caps sofosbuvir3 tab and simeprevir6 cap once/day x 12 wks7 2/day4 150,360 Viekira Pak (Abbvie) 12.5/75/50 mg ombitasvir/paritaprevir/ritonavir tabs + 250 mg dasabuvir tabs ombitasvir/paritaprevir/ritonavir tabs qAM and dasabuvir tab bid x 12 wks8,9 4/day4 83,320 Zepatier (Merck) 50/100 mg elbasvir/grazoprevir tabs tab once/day x 12 wks9,10 1/day4 54,600 Approximate WAC for 12 weeks’ treatment WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy 24 weeks for treatment-experienced patients with compensated cirrhosis weeks may be considered for treatment-naive patients without cirrhosis with baseline HCV RNA 50 mL/min; 105 kg = 1400 mg/day) 25 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® without ribavirin.6 Harvoni has produced sustained virologic response (SVR) rates >90% in various patient populations, with minimal adverse effects Viekira Pak with or without ribavirin for 12 or 24 weeks appears to be similar in efficacy to Harvoni, but has a higher pill burden and has a greater potential for adverse drug interactions The level of evidence supporting use of simeprevir plus sofosbuvir is the same as that for Harvoni and Viekira Pak for treatment-naive patients, but lower for treatment-experienced patients Daclatasvir plus sofosbuvir was recently approved by the FDA for treatment of HCV genotype infection; the level of evidence supporting its use is lower than that for the other three regimens in both treatment-naive and treatment-experienced patients Harvoni, simeprevir plus sofosbuvir, and daclatasvir plus sofosbuvir are not recommended for patients with severe or end-stage renal disease because serum concentrations of sofosbuvir and its metabolite are significantly increased in these patients CLINICAL STUDIES — Approval of elbasvir/grazoprevir was based on the results of trials in both treatmentnaive and treatment-experienced patients infected with HCV genotype 1, 4, or In one double-blind trial (C-EDGE) in 306 treatmentnaive patients with HCV genotype or infection with or without cirrhosis, 95% of patients (273/288) with genotype and 100% (18/18) of those with genotype who were treated with elbasvir/grazoprevir achieved a sustained virologic response 12 weeks after stopping treatment (SVR12); there were no significant differences between cirrhotic and non-cirrhotic patients.7 In a single-arm trial in 218 treatment-naive patients co-infected with HCV and HIV (C-EDGE CO-INFECTION), 210 (96%), including all 35 patients with cirrhosis, achieved an SVR12.8 In an unpublished, 4-arm, open-label trial (C-EDGE TE), 420 patients with HCV genotype 1, 4, or infection that had previously failed to respond to peginterferon and ribavirin were randomized to receive elbasvir/grazoprevir for 12 or 16 weeks, with or without ribavirin Patients treated with ribavirin in addition to elbasvir/grazoprevir for 16 weeks had slightly higher SVR12 response rates (97%) than those treated with the combination alone for 12 or 16 weeks (92%) or with the combination plus ribavirin for only 12 weeks (94%).9 In an open-label trial in 79 patients with HCV genotype infection that did not respond to previous treatment 26 Vol 58 (1489) February 29, 2016 Table Results of Some Zepatier Clinical Trials Study Design SVR12 Rate Treatment-Naive Patients with or without Cirrhosis C-EDGE (double-blind; 316 patients with genotype 1, 4, or 6) Zepatier x 12 weeks 95% C-EDGE CO-INFECTION (open-label; 218 patients with genotype 1, 4, or and HIV) Zepatier x 12 weeks 96% Treatment-Experienced Patients with or without Cirrhosis C-EDGE TE (open-label; 420 patients with genotype 1, 4, or with or without HIV)1 Zepatier x 12 weeks 92% Zepatier x 16 weeks 92% Zepatier + ribavirin x 12 weeks 94% Zepatier + ribavirin x 16 weeks 97% C-SALVAGE (open-label; 79 patients with genotype 1)2 Zepatier + ribavirin x 12 weeks 96% Patients with Severe Renal Impairment including Hemodialysis3 C-SURFER (double-blind; 122 patients with genotype 1) Zepatier x 12 weeks 94% SVR12 = HCV RNA