Clinical Alert DECEMBER 2014 Hot Topic: Hepatitis C Spotlight The Food and Drug Administration (FDA) has approved Janssen’s simeprevir (Olysio®) to be used in combination with Gilead’s sofosbuvir (Sovaldi®) as an all oral, interferonand ribavirin-free option for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection in adults. Simeprevir, a NS3/4A protease inhibitor, was originally FDA approved in November 2013 for use in combination with peginterferon alfa and ribavirin for the treatment of chronic HCV genotype 1 infection. Sofosbuvir, a NS5B polymerase inhibitor, was FDA approved in December 2013 for the treatment of chronic HCV genotype 1 in combination with peginterferon alfa and/or ribavirin, in genotype 4 with peginterferon and ribavirin, and genotypes 2 and 3 in combination with ribavirin. Simeprevir’s expanded indication is supported by data from the COmbination of SiMeprevir and sOfoSbuvir in HCV-infected patients (COSMOS) trial. In addition, the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) recommends use of this combination, based on the COSMOS study. COSMOS was a phase II, open-label trial in patients with chronic HCV genotype 1 and compensated liver disease. It included patients with no to moderate liver fibrosis (Metavir F0-F2) who were previous non-responders to peginterferon alfa and ribavirin and patients with severe liver fibrosis (Metavir F3-F4) who were either treatment-naïve or previous non-responders to peginterferon alfa and ribavirin. Patients received simeprevir plus sofosbuvir, with or without ribavirin, for 12 or 24 weeks. Cure, or sustained virologic response (SVR), was defined as HCV RNA level less than 25 IU/mL or HCV RNA not detected 12 weeks after stopping treatment. COSMOS reported an overall SVR rate of 93 and 97 percent after 12 and 24 weeks of therapy, respectively. In patients with cirrhosis, simeprevir plus sofosbuvir resulted in an SVR rate of 86 and 100 percent after 12 and 24 weeks, respectively. Overall, viral relapse occurred in seven percent and zero percent of patients after 12 or 24 weeks of therapy, respectively. Use of ribavirin or prior HCV antiviral therapy did not impact SVR. The most common adverse events were fatigue (31 percent), headache (20 percent), and nausea (16 percent). Results of the COSMOS study were published in the November 15, 2014 issue of The Lancet. The recommended dosage for combination use is simeprevir 150 mg and sofosbuvir 400 mg daily for 12 weeks in treatment-naïve or treatment-experienced patients without cirrhosis and for 24 weeks in treatment-naïve or treatment-experienced patients with cirrhosis. Simeprevir should be taken with food. Simeprevir is not recommended for use as monotherapy or for use in patients who have previously failed therapy with a treatment regimen that included simeprevir or other HCV protease inhibitors. Unlike combination therapy with simeprevir plus peginterferon alfa and ribavirin, screening for the presence of viral NS3 Q80K polymorphism in patients with HCV genotype 1a is not strongly recommended with simeprevir/sofosbuvir use; however, it may be considered. In October 2014, the FDA approved Gilead’s fixed-dose combination ledipasvir, a NS5A inhibitor, and sofosbuvir for treatment of HCV genotype 1 infection. Ledipasvir/sofosbuvir (Harvoni®) is taken as one tablet daily, with or without food. The usual recommended length of therapy is 12 weeks for treatment-naïve patients (with or without cirrhosis), 12 weeks for treatment-experienced patients without cirrhosis, and 24 weeks for treatmentexperienced patients with cirrhosis. However, for treatment-naïve patients without Drug Information Highlights •Merck’s IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT) study evaluated the safety and efficacy of ezetimibe 10 mg/simvastatin 40 mg (Vytorin®) fixed-dose combination compared to simvastatin 40 mg (Zocor®) alone in reducing CV events in 18,144 patients with recent acute coronary syndrome (ACS). The study reported reductions in low density lipoprotein cholesterol (LDL-C) as early as one month and reductions in triglyceride and increases in high density lipoprotein cholesterol (HDL-C) at one year. The average reduction in LDL-C with the addition of ezetimibe was 17 mg/dL. The primary composite endpoint of CV death, myocardial infarction (MI), unstable angina, stroke, and coronary revascularization beyond 30 days of randomization was significantly lower in the ezetimibe/simvastatin group compared with the simvastatin group (32.7 versus 34.7 percent, respectively; p=0.016) during the seven year follow-up period, with reports of significant reduction for all endpoint components. This translates to a reduction of two ACS events for every 100 patients treated with combination therapy. Both treatment arms reported similar rates of CV and all-cause mortality and revascularization. Diabetic patients appeared to have a greater benefit with combination therapy. Incidence of cancer was similar in both groups (10.2 percent). These findings were presented at the 2014 AHA Scientific Sessions. •A retrospective study conducted by the FDA compared the use of dabigatran (Pradaxa®) and warfarin in 134,414 Medicare patients with NVAF. Dabigatran use was associated with reduced risk of ischemic stroke (Hazard Ratio [HR] 0.80), intracranial hemorrhage (HR 0.34), and death (HR 0.86) and an increased risk of major gastrointestinal (GI) bleeding (HR 1.28), as compared to warfarin. There was no difference in risk of major bleeding or MI. These findings are similar to those from the RE-LY trial, which supported the FDA approval of dabigatran, with the exception that RE-LY reported a greater risk of MI associated with dabigatran. This FDA study was published online in Circulation on October 30, 2014. In contrast, a study published online on November 30, 2014 in the JAMA Internal Medicine reported that the use of dabigatran was associated with a higher risk of GI and Editorial Staff Maryam Tabatabai, PharmD Editor in Chief 1December Contact Carole Kerzic, RPh Executive Editor Leslie Pittman, PharmD Deputy Editor Barbara Dowd, RPh Deputy Editor Raquel Holmes, RPh Deputy Editor Dona Jones Executive Assistant [email protected] cirrhosis and a pre-treatment HCV RNA value of less than 6 million IU/mL, a total of eight weeks of therapy can be considered. In clinical studies, the use of ledipasvir/sofosbuvir resulted in SVR rates of 93 to 100 percent depending on presence of cirrhosis, previous HCV therapy, and duration of therapy. Use of ribavirin did not alter clinical response. Common adverse effects reported were fatigue and headache. The phase III trial, Optimal Treatment with a simeprevir and Sofosbuvir Therapy (OPTIMIST) trial, is currently underway and includes shorter therapy duration of eight weeks for combination of simeprevir/sofosbuvir in patients with HCV genotype 1 infection. Additional direct-acting antivirals for the treatment of HCV are currently in the pipeline, including competitors from Abbvie, Bristol-Myers-Squibb, Merck, and Boehringer-Ingelheim. AASLD/IDSA Statement on Treating Chronic HCV In September 2014, the AASLD/IDSA updated their guidelines for the treatment of chronic HCV infection to include the new section When and in Whom to Initiate HCV Therapy, which provides guidance to identify patients with chronic HCV infection in immediate need of treatment and those who can safely wait for drugs in the pipeline to become available. In this section, they recommend that, when resource limitations exist, treatment may be prioritized for those patients who will gain the most benefit or who will have the most impact on reducing HCV transmission with the highest risk of severe complications; namely those patients with advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4), liver transplant, type 2 or 3 mixed cryoglobulinemia with end-organ manifestations, and patients with proteinuria, membranoproliferative glomerulonephritis, or nephrotic syndrome. Recently, the AASLD/IDSA released a position statement affirming that, although they proposed that the sickest patients be treated first, the decision should be left to the clinician and the patient on when to treat and that patients should not be denied therapy with the newest medications. The AASLD reiterates that treatment will benefit almost all patients in all stages of chronic HCV and that immediate initiation of therapy is needed in patients with certain conditions. AASLD/IDSA is expected to release the final section of the guidelines, Management of HCV Infection, in the coming weeks at which time the guidance will be complete, and will be updated regularly. American Heart Association (AHA) Primary Prevention of Stroke Guidelines major bleeding compared to warfarin in 9,400 patients with NVAF. Results in the latter study were propensity weighted to account for demographic and clinical factors. •The Centers for Disease Control and Prevention (CDC) reported that, based on data from the U.S. Flu Vaccine Effectiveness Network, the live attenuated influenza vaccine (LAIV; FluMist®) was not effective against influenza A H1N1 virus in children ages two through eight years during the 2013-2014 flu season. The same H1N1 virus that was in the 2013-2014 vaccine is included in the 2014-2015 vaccine. However, since surveillance shows that, to date, there is significantly more circulating H3N2 and B virus strains and very little H1N1, LAIV is expected to provide protection and should be used in healthy children two through eight years of age, unless contraindicated. Pipeline News: Upcoming Prescription Drug User Fee Acts (PDUFA) Dates •Dec 5: Jakafi®; oral kinase inhibitor ruxolitinib; polycythaemia vera; Incyte. •Dec 7: Abilify Maintena®; aripiprazole intramuscular; acute agitation in schizophrenic patients; Bristol-Myers Squibb/Otsuka. •4th Quarter 2014: oral ABT-450/ritonavir, ombitasvir + dasabuvir; 3 DAA regimen; chronic HCV genotype 1; ABT-450/ritonavir, ombitasvir combination once daily; dasabuvir twice daily; Abbvie. •4th Quarter 2014: Savaysa; oral edoxaban; atrial fibrillation and venous thromboembolism; Daiichi Sankyo. •4th Quarter 2014: Carbella™; intravenous carbamazepine; epilepsy; Lundbeck/Ligand. •4th Quarter 2014: Rizaport®; oral rizatriptan film; migraine headaches; IntelGenX/RedHill. Stroke ranks as the fourth-leading cause of death in the United States and the leading cause of functional impairment. The AHA has released new guidelines for the primary prevention of stroke as an update to their 2011 guidance. This updated guidance is consistent with several other current AHA statements regarding cardiovascular (CV) risk assessment and reduction, lifestyle and weight management, and dyslipidemia management and supports an individualized approach to primary prevention. AHA recommends a Mediterranean diet to lower stroke risk. AHA supports the use of the American College of Cardiology (ACC)/AHA CV risk calculator to identify individuals who could benefit from therapeutic intervention. Guidance on the management of dyslipidemia now follows the 2013 ACC/AHA blood cholesterol guidelines, rather than those from the National Cholesterol Education Program (NCEP), in which they recommend statin therapy in patients with a high 10-year risk of a CV event. Blood pressure (BP) screening should be performed in patients with pre-hypertension. Hypertension therapy should be individualized and focus on successful reduction of blood pressure rather than the choice of a specific agent. Self-monitoring of BP should be promoted. In patients with valvular atrial fibrillation (AF) and at high risk for stroke (CHA2DS2-VAS score ≥ 2) and low risk for bleeding, anticoagulation therapy with warfarin is recommended. For patients with non-valvular AF (NVAF), warfarin, apixaban (Eliquis®), dabigatran (Pradaxa®), and rivaroxaban (Xarelto®) are all acceptable choices. Anticoagulant or antiplatelet therapy is reasonable for patients with heart failure who do not have AF or a previous thrombotic event. These guidelines also offer guidance for the use of anticoagulants for stroke prevention in those with valvular conditions, such as mitral stenosis and valvular prosthetics. The use of aspirin for overall CV prophylaxis is reasonable in people at high risk (10-year risk > 10 percent). Aspirin may be considered for primary prevention in people with chronic kidney disease (glomerular filtration rate between 30 and 45 mL/min/1.73 m2). Cilostazol (Pletal®) may be used in those with peripheral arterial disease. 2 December 2014 Recent FDA Approvals Generic Name Trade Name sotalol Description Applicant FDA Status SotylizeTM Sotalol (Sotylize) is an antiarrhythmic now available as a 5 mg/mL oral solution indicated for the treatment of life-threatening ventricular arrhythmias and maintenance of normal sinus rhythm in individuals with highly symptomatic atrial fibrillation/flutter. Patients should be hospitalized when starting therapy. The recommended initial dose is 80 mg once or twice daily based on creatinine clearance (CrCL) and titrated to a maximum of 160 mg or 320 mg for treatment of atrial fibrillation/flutter or ventricular arrhythmias, respectively. Sotalol is not recommended if CrCL is less than 40 mL/min. For pediatric patients, dosage is based on age. Sotylize will be available the in early 2015. Arbor FDA NDA approval 10/22/2014 dapagliflozin/ metformin XigduoTM XR Dapagliflozin/metformin extended-release (Xigduo XR) is a combination hypoglycemic product containing a sodium glucose cotransporter 2 (SGLT2) inhibitor and metformin ER. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate. It is dosed once daily and is available as 5 mg/500 mg, 5 mg/1,000 mg, 10 mg/500 mg, and 10 mg/1,000 mg tablets. AstraZeneca FDA NDA approval 10/29/2014 meningococcal Group B vaccine, recombinant Trumenba® Meningococcal Group B vaccine, recombinant (Trumenba), is the first vaccine licensed in the U.S. for active immunization against Neisseria meningitidis serogroup B in individuals 10 to 25 years of age. It is available as a suspension for intramuscular (IM) injection in a 0.5 mL single-dose prefilled syringe. It should be given as three 0.5 mL IM doses, according to a 0-, 2-, and 6-month schedule. N. meningitidis is the leading cause of bacterial meningitis. Wyeth FDA BLA approval 10/29/2014 paliperidone palmitate Invega® Sustenna® The FDA has granted an expanded indication for the long-acting atypical antipsychotic agent paliperidone palmitate (Invega Sustenna) for the treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants. It is given IM by a healthcare professional. Starting dosage is 234 mg on day 1 and 156 mg on day 8, then 78 mg to 234 mg once monthly thereafter. Paliperidone palmitate is also indicated for the treatment of schizophrenia. Janssen FDA NDA approval 11/12/2014 alemtuzumab LemtradaTM Alemtuzumab (Lemtrada) is a humanized monoclonal antibody that is FDA approved for the treatment of relapsing forms of multiple sclerosis (MS). Due to the safety profile of the drug, it should be reserved for patients who have had an inadequate response to two or more treatments for MS. Warnings include the potential for serious, sometimes fatal, autoimmune conditions, such as immune thrombocytopenia and anti-glomerular basement membrane disease, serious and life-threatening infusion reactions and increased risk of malignancies. Alemtuzumab is administered as 12 mg/day by intravenous infusion for five consecutive days initially and for three consecutive days one year later (two treatment courses one year apart). Genzyme FDA BLA approval 11/14/2014 hydrocodone bitartrate extendedrelease Hysingla™ ER The FDA has approved the second single-entity hydrocodone bitartrate extended-release product, Hysingla ER, for the treatment of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The tablet has properties to help reduce abuse via chewing, snorting, or injecting. Although, overdose can occur by taking too much of the drug. Recommended dosing is one tablet every 24 hours. Zohydro® ER is also a single-entity hydrocodone ER product; but is dosed every 12 hours and is not approved with abuse-deterrent properties. Hysingla ER will be available as 20 mg, 30 mg, 40 mg, 80 mg, and 120 mg tablets. Purdue FDA NDA approval 11/20/2014 References https://www.magellanmedicaid.com/news/clinicalalerts.asp © 2014, Magellan Health, All Rights Reserved. 3 December 2014 www.aasld.org www.cdc.gov www.fda.gov www.medscape.com www.heart.org www.pubmed.gov