The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Sofosbuvir (Sovaldi) for Chronic Hepatitis C .p Antiviral Drugs for Influenza 2013-2014 p In Brief: Ponatinib (Iclusig) Returns p Important Copyright Message The Medical Letter® publications are protected by US 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 US 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 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 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 Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 56 (Issue 1434) January 20, 2014 ALSO IN THIS ISSUE Antiviral Drugs for Influenza 2013-2014 .p In Brief: Ponatinib (Iclusig) Returns .p Sofosbuvir (Sovaldi) for Chronic Hepatitis C The FDA has approved the nucleotide polymerase inhibitor sofosbuvir (Sovaldi – Gilead) for use in combination with other antiviral drugs for treatment of chronic hepatitis C virus (HCV) infection www.medicalletter.org Take CME Exams with peginterferon and ribavirin for 24 weeks and those with genotype infection are treated with peginteferon and ribavirin for 48 weeks Interferon must be injected and is associated with a high incidence of adverse effects, including flu-like symptoms, fatigue, psychiatric disorders, hematologic abnormalities, and autoimmune disorders.2 CLINICAL STUDIES — Sustained virologic response (SVR) rates 12 weeks after stopping treatment with sofosbuvir are shown in table 2.3-5 Table Some Clinical Trials with Sofosbuvir Clinical Trial SVR12 Rates Patients with HCV genotype (or 4, 5, or 6) Table Pharmacology Class Route Formulation Tmax Metabolism Elimination Half-life (terminal) Nucleotide polymerase inhibitor Oral 400-mg tablets ~0.5-2 hrs (sofosbuvir) 2-4 hrs (inactive metabolite) Activated in liver by hydrolysis and phosphoramidate cleavage followed by phosphorylation; dephosphorylation results in formation of inactive metabolite Urine (~80%), feces (14%), expired air (2.5%) 0.4 hrs (sofosbuvir) 27 hrs (inactive metabolite) ACTIVITY — Sofosbuvir is a uridine nucleotide analog prodrug that is converted to an active metabolite in the liver It inhibits the HCV NS5B RNAdependent RNA polymerase, which is essential for viral replication In vitro, sofosbuvir has potent activity against all HCV genotypes (1-6), including strains resistant to protease inhibitors The prevalence of HCV genotypes in the US is 79% genotype 1, 13% genotype 2, 6% genotype 3, and 2% genotypes 4, 5, and combined STANDARD THERAPY — The current standard of care for patients with HCV genotype infection is peginterferon and ribavirin plus a protease inhibitor such as telaprevir (Incivek), boceprevir (Victrelis), or simeprevir (Olysio)1 for a total of 24-48 weeks Patients with HCV genotype or infection are treated NEUTRINO (open-label; 327 treatment-naive patients)1 Sofosbuvir + P + R x 12 wks 90% Historical control rate2 60% Patients with HCV genotype or GT2 GT3 FISSION (open-label; 496 treatment-naive patients)1 Sofosbuvir + R x 12 wks 97% P + R x 24 wks 78% 56% 63% POSITRON (double-blind; 278 patients intolerant, ineligible, or unwilling to take interferon)3 Sofosbuvir + R x 12 wks 93% 61% Placebo x 12 wks 0% 0% FUSION (double-blind; 195 treatment-experienced patients)3 Sofosbuvir + R x 12 wks 86% 30% Sofosbuvir + R x 16 wks 94% 62% Historical control rate4 overall 25% VALENCE (open-label; 323 treatment-naive and treatmentexperienced patients)5 Sofosbuvir + R x 12 wks 93% — Sofosbuvir + R x 24 wks — 84% GT = genotype; P = peginterferon; R = ribavirin; SVR12 = HCV RNA 5 yrs: inhalations (10 mg) once/d >7 yrs: inhalations (10 mg) bid x 5d 59.00 For post-exposure prophylaxis in households, a 10-day course is recommended For prophylaxis of exposures in institutions, the drug should be taken for at least weeks and continued for week after the end of the outbreak For prophylaxis during community outbreaks, oseltamivir has been shown to be effective and safe when taken for up to 42 days, and zanamivir for up to 28 days Some experts would use twice-daily therapeutic doses for post-exposure prophylaxis in highly immunocompromised persons Hospitalized, critically ill, or immunocompromised patients may require longer treatment Approximate wholesale acquisition cost (WAC) for days’ treatment at adult dosages Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) January 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher In patients with CrCl 10-30 mL/min, the dose should be 75 mg every other day or 30 mg once/d for prophylaxis and 75 mg once/d for treatment In adults with pneumonia or severe lower respiratory tract disease, some experts recommend 150 mg bid x 10 days for treatment (off-label) Dose for children >1 yr old: 40 kg: 75 mg (once daily for prophylaxis and twice daily for treatment) Although not FDA-approved for prophylaxis for children