The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1461 Volume 56 February 2, 2015 IN THIS ISSUE A 4-Drug Combination (Viekira Pak) for Hepatitis C p 15 Peramivir (Rapivab): An IV Neuraminidase Inhibitor for Treatment of Influenza p 17 Bunavail: Another Buprenorphine/Naloxone Formulation for Opioid Dependence p 19 In Brief: A New Formulation of Posaconazole (Noxafil) p 20 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 Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1461 Volume 56 ▶ February 2, 2015 Take CME Exams ALSO IN THIS ISSUE Peramivir (Rapivab): An IV Neuraminidase Inhibitor for Treatment of Influenza p 17 Bunavail: Another Buprenorphine/Naloxone Formulation for Opioid Dependence p 19 In Brief: A New Formulation of Posaconazole (Noxafil) p 20 A 4-Drug Combination (Viekira Pak) for Hepatitis C The FDA has approved Viekira Pak (Abbvie), a fixeddose combination of two new direct-acting antiviral agents (ombitasvir, paritaprevir) with the pharmacologic enhancer ritonavir in one tablet, co-packaged with a third new direct-acting antiviral agent (dasabuvir) in a second tablet, for oral treatment of chronic hepatitis C virus (HCV) genotype infection Genotype is responsible for 70-80% of HCV infections in the US Viekira Pak is the second all-oral, interferon-free, fixed-dose combination for treatment of chronic HCV genotype infection to be approved in the US; it will compete with the fixed-dose combination of sofosbuvir and ledipasvir (Harvoni) for inclusion in the formularies of third-party payers Neither Harvoni nor Viekira Pak is approved for treatment of infections caused by HCV genotypes 2-6 Pronunciation Key Ombitasvir: om bit' as veer Paritaprevir : par" i ta' pre veer Ritonavir : ri toe' na veer Dasabuvir: da sa' bue veer Viekira Pak: vee kee' rah pak DRUGS FOR HCV GENOTYPE INFECTION — Harvoni has produced sustained virologic response (SVR) rates exceeding 90% in various patient populations with minimal adverse effects.1 Sofosbuvir (Sovaldi) plus simeprevir (Olysio) is an alternative, but double-blind trials documenting the efficacy of this combination are lacking.2 Current guidelines recommend that patients with chronic HCV genotype infection receive either Harvoni, sofosbuvir plus simeprevir with or without ribavirin, or Viekira Pak with or without ribavirin The level of evidence supporting these recommendations is lower for sofosbuvir plus simeprevir than for either Harvoni or Viekira Pak.3 MECHANISM OF ACTION — Each of the three directacting antiviral drugs in Viekira Pak inhibits an HCV protein that is essential for viral replication Ombitasvir, like ledipasvir, inhibits the HCV NS5A protein Dasabuvir is a non-nucleoside inhibitor of the HCV NS5B RNAdependent RNA polymerase, the same enzyme that sofosbuvir inhibits Paritaprevir, like telaprevir (Incivek), boceprevir (Victrelis), and simeprevir,4,5 inhibits the HCV NS3/4A protease Ritonavir, a CYP3A4 inhibitor, is included in the regimen to increase exposure to paritaprevir, a CYP3A4 substrate Table Some Clinical Trials with Viekira Pak in HCV Study Design SVR12 Rates Treatment-Naive Patients without Cirrhosis SAPPHIRE-I (double-blind; 631 pts with GT1a or GT1b)6 Viekira Pak + Rbv x 12 wks 96% PEARL-III (double-blind; 419 pts with GT1b)7 Viekira Pak + Rbv x 12 wks Viekira Pak + placebo x 12 wks 100% 99% PEARL-IV (double-blind; 305 pts with GT1a)7 Viekira Pak + Rbv x 12 wks Viekira Pak + placebo x 12 wks 97% 90% Treatment-Experienced Patients without Cirrhosis SAPPHIRE-II (double-blind; 394 pts with GT1a or GT1b)8 Viekira Pak + Rbv x 12 wks 96% PEARL-II (open-label; 179 pts with GT1b)9 Viekira Pak + Rbv x 12 wks Viekira Pak + placebo x 12 wks 97% 100% Treatment-Naive or -Experienced Patients with Cirrhosis TURQUOISE-II (open-label; 380 pts with GT1a or GT1b)10 Viekira Pak + Rbv x 12 wks 92% Viekira Pak + Rbv x 24 wks 96% Treatment-Naive or -Experienced Patients with HIV TURQUOISE-I (open-label; 63 pts with GT1a or GT1b)11 Viekira Pak + Rbv x 12 wks Viekira Pak + Rbv x 24 wks 94% 91% Patients with Prior Liver Transplant CORAL-I (single-arm; 34 pts with GT1a or GT1b)12 Viekira Pak + Rbv x 24 wks 97% SVR12 = HCV RNA 75 kg) in two divided doses is unclear ADVERSE EFFECTS — The most common adverse effects observed in patients taking Viekira Pak and ribavirin have been fatigue, nausea, pruritus, skin reactions, insomnia, and asthenia Without ribavirin, adverse effects occur less frequently, but still include nausea, pruritus, and insomnia Serum alanine aminotransferase (ALT) elevations occurred in 1-4% of patients taking Viekira Pak in clinical trials and sometimes required early discontinuation; the labeling for Viekira Pak recommends ALT monitoring for the first weeks of treatment The rate of permanent discontinuation due to adverse effects with Viekira Pak was 75 kg) Viekira Pak is not recommended for patients who have a history of treatment failure with an HCV protease inhibitor (telaprevir, boceprevir, simeprevir) CONCLUSION — The fixed-dose combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak) taken orally with or without ribavirin for 12 or 24 weeks appears to be similar in efficacy to the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni), which does not require addition of ribavirin, for treatment of chronic hepatitis C genotype infection Use of Viekira Pak requires taking more tablets per day and has a greater potential for causing adverse drug interactions ■ A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C Med Lett Drugs Ther 2014; 56:111 E Lawitz et al Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study Lancet 2014; 384:1756 American Association for the Study of Liver Diseases/ Infectious Disease Society of America/International Antiviral Society–USA Recommendations for testing, managing, and treating hepatitis C December 19, 2014 Available at www.hcvguidelines.org Accessed January 22, 2015 Telaprevir (Incivek) and boceprevir (Victrelis) for chronic hepatitis C Med Lett Drugs Ther 2011; 53:57 Simeprevir (Olysio) for chronic hepatitis C Med Lett Drugs Ther 2014; 56:1 JJ Feld et al Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin N Engl J Med 2014; 370:1594 P Ferenci et al ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV N Engl J Med 2014; 370:1983 S Zeuzem et al Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin N Engl J Med 2014; 370:1604 P Andreone et al ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection Gastroenterology 2014; 147:359 10 F Poordad et al ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis N Engl J Med 2014; 370:1973 11 D Wyles et al TURQUOISE-I: 94% SVR12 in HCV/HIV-1 coinfected patients treated with ABT-450/r/ombitasvir and dasabuvir and ribavirin Presented at 65th annual meeting of the American Association for the Study of Liver Diseases, Boston, MA November 7-11, 2014 Available at www.natap.org/2014/ AASLD/AASLD_28.htm 12 PY Kwo et al An interferon-free antiviral regimen for HCV after liver transplantation N Engl J Med 2014; 371:2375 13 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Vol 57 (1461) ▶ February 2, 2015 Peramivir (Rapivab): An IV Neuraminidase Inhibitor for Treatment of Influenza The FDA has approved peramivir (Rapivab – BioCryst), an IV neuraminidase inhibitor administered as a single dose, for treatment of acute uncomplicated influenza in patients ≥18 years old who have had symptoms for no more than days Peramivir was available temporarily in the US during the 2009-2010 influenza season under an emergency use authorization for treatment of hospitalized patients It has been available in some Asian countries since 2010 Peramivir is the third neuraminidase inhibitor to be approved in the US Oseltamivir (Tamiflu), which is taken orally, and zanamivir (Relenza), which is inhaled, are approved for prophylaxis and treatment of influenza in children and adults.1 Pronunciation Key Peramivir: per am' i veer Rapivab: rap' i vab TREATMENT OF INFLUENZA — Neuraminidase inhibitors are currently the drugs of choice for treatment of patients with influenza; almost all of the influenza A and B viruses tested by the CDC this year have been susceptible to these drugs Neuraminidase inhibitors are most effective when started within 48 hours after symptom onset, but the results of some observational studies in hospitalized patients suggest that treatment within 4-5 days after symptoms appear may still provide some benefit Although approved by the FDA only for treatment of uncomplicated influenza, as an IV drug peramivir may also be used off-label to treat hospitalized patients No neuraminidase inhibitor is approved for use in hospitalized or critically ill patients For such patients, the CDC recommends administering oseltamivir orally or by nasogastric tube and considering use of IV peramivir or investigational IV zanamivir for those who cannot take oseltamivir.2 Table Pharmacology Drug class Neuraminidase inhibitor Route IV Formulation 200 mg/20 mL single-use vials Tmax 30 minutes Metabolism Not significantly metabolized Half-life ~20 hours Elimination Unchanged in urine (90%) CLINICAL STUDIES — Uncomplicated Influenza – In a 14-day, double-blind trial in Japan, 296 previously healthy adults with uncomplicated seasonal influenza were randomized to receive a single IV dose of peramivir (300 or 600 mg) or placebo Almost all 17 The Medical Letter ® February 2, 2015 Vol 57 (1461) Table Antiviral Drugs for Treatment of Seasonal Influenza Drug Formulations Usual Adult Dosage Cost1 Oseltamivir – Tamiflu (Genentech) Peramivir – Rapivab (BioCryst) Zanamivir – Relenza7 (GSK) 30, 45, 75 mg caps; mg/mL oral susp 200 mg/20 mL single-use vials mg/blister for inhalation8 75 mg PO bid x 5d 600 mg IV once2,5 inhalations bid x 5d2 $120.60 950.006 59.00 2-4 Approximate WAC for days’ 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 January 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Hospitalized, critically ill, or immunocompromised patients are sometimes treated longer Dosage for patients with CrCl >30-60 mL/min: 30 mg bid; CrCl >10-30 mL/min: 30 mg once daily; end-stage renal disease on hemodialysis (HD): 30 mg after every HD; continuous ambulatory peritoneal dialysis (CAPD): 30 mg immediately following exchange In adults with pneumonia or severe lower respiratory tract disease, some expert clinicians recommend 150 mg bid x 10 days (off-label) The dose should be reduced to 200 mg for patients with a CrCl 30-49 mL/min and to 100 mg for a CrCl 10-29 mL/min In patients on hemodialysis, the dose should be based on renal function and should be given after dialysis Approximate WAC for single-use vials Not recommended for use in patients with underlying respiratory disease such as asthma or COPD Available in a carton containing rotadisks (each rotadisk contains four 5-mg blisters of the active drug in a lactose carrier) and a Diskhaler inhalation device Zanamivir should not be used in a nebulizer IV zanamivir is available under an emergency investigational new drug (EIND) request to the manufacturer (1-877-626-8019) for hospitalized patients with severe influenza of the patients had confirmed influenza A infection and treatment was started within 48 hours after the onset of symptoms Peramivir significantly reduced the median time to self-assessment of influenza symptoms as absent or mild, the primary endpoint, from 81.8 hours with placebo to 59.1 and 59.9 hours with 300 and 600 mg of peramivir The median time to resolution of fever was 12 hours shorter with peramivir 600 mg than with placebo.3 A randomized, double-blind trial compared IV peramivir (300 or 600 mg in a single dose) with oral oseltamivir (75 mg twice daily for days) in 1091 adults with confirmed seasonal influenza Both doses of peramivir were noninferior to oseltamivir in reducing the time to self-assessment of influenza symptoms as absent or mild; the median duration of symptoms was 78 and 81 hours with peramivir 300 and 600 mg and 81.8 hours with oseltamivir The trial was conducted in Japan, South Korea, and Taiwan during the 2008-2009 influenza season, a season in which the predominant circulating influenza strain was A/H1N1 with an H275Y substitution This substitution resulted in reduced influenza susceptibility to oseltamivir and peramivir.4 Hospitalized Patients – A randomized, double-blind trial in 338 hospitalized patients with influenza who had been symptomatic for