The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1503 Volume 56 September 12, 2016 IN THIS ISSUE Byvalson – A Beta Blocker/ARB Combination for Hypertension p 115 Daclizumab (Zinbryta) for Multiple Sclerosis p 117 In Brief: Defibrotide (Defitelio) for Hepatic Veno-Occlusive Disease p 120 In Brief: Repatha Pushtronex – A New Evolocumab Injection Device p 120 In Brief: Epinephrine Auto-Injectors for Anaphylaxis 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 September 12, 2016 Take CME Exams ISSUE ISSUE No 1433 1503 Volume 56 ▶ ALSO IN THIS ISSUE Daclizumab (Zinbryta) for Multiple Sclerosis p 117 In Brief: Defibrotide (Defitelio) for Hepatic Veno-Occlusive Disease p 120 In Brief: Repatha Pushtronex – A New Evolocumab Injection Device p 120 In Brief: Epinephrine Auto-Injectors for Anaphylaxis online only Byvalson – A Beta Blocker/ARB Combination for Hypertension The FDA has approved Byvalson (Allergan), a fixeddose combination of the beta blocker nebivolol (Bystolic) and the angiotensin receptor blocker (ARB) valsartan (Diovan, and generics), for treatment of hypertension It is the only combination product that contains nebivolol, and the first to combine a beta blocker with an ARB Pronunciation Key Nebivolol: ne biv’ oh lol Byvalson: bye val' son Valsartan: val sar’ tan STANDARD TREATMENT — Most recent guidelines recommend a thiazide-type diuretic (chlorthalidone is preferred), a calcium channel blocker, an angiotensin-converting enzyme (ACE) inhibitor, or an ARB as initial therapy for hypertension in nonblack patients A thiazide-type diuretic or a calcium channel blocker is preferred for initial treatment of black patients, except those with chronic kidney disease or heart failure, who should receive an ACE inhibitor or an ARB Beta blockers generally are no longer recommended as initial therapy, except in patients with a comorbidity such as coronary heart disease or left ventricular dysfunction.1 Table Initial Treatment of Hypertension1,2 General Population Non-black Thiazide-type diuretic,3 CCB, ACE inhibitor, or ARB Thiazide-type diuretic3 or CCB Black Chronic Kidney Disease Non-black Black ACE inhibitor or ARB ACE inhibitor or ARB Diabetes Non-black Black ACE inhibitor or ARB Thiazide-type diuretic3 or CCB4 ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker PA James et al JAMA 2014; 311:507 When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin this treatment with two drugs Chlorthalidone is preferred Black patients with both diabetes and chronic kidney disease should receive an ACE inhibitor or an ARB Many patients with hypertension need more than one drug to control their blood pressure If monotherapy does not achieve blood pressure goals, adding a second drug with a different mechanism of action is generally more effective than increasing the dose of the first drug and often allows for use of lower, bettertolerated doses of both drugs If an ACE inhibitor or an ARB was used initially, it would be reasonable to add a thiazide-type diuretic or a calcium channel blocker When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin treatment with two drugs Table Byvalson and Components Drug Formulations Usual Adult Dosage Cost1 Nebivolol/valsartan – Byvalson (Allergan) 5/80 mg tabs 5/80 mg once/d2 $1315.20 Nebivolol – Bystolic (Allergan) 2.5, 5, 10, 20 mg tabs 5-40 mg once/d 1315.20 Valsartan – generic Diovan (Novartis) 40, 80, 160, 320 mg tabs 80-320 mg once/d 309.60 2041.20 Approximate WAC for year's treatment at the lowest usual adult dosage 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 August 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Higher doses not appear to offer additional benefit 115 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 58 (1503) ® Table Some Other Combinations for Hypertension Drug Formulations Cost1 ARBs and Diuretics Azilsartan/chlorthalidone 40/12.5, 40/25 mg tabs Edarbyclor (Arbor) $1934.20 Candesartan/HCTZ 16/12.5, 32/12.5, generic 32/25 mg tabs Atacand HCT (AstraZeneca) 1269.90 1575.10 Irbesartan/HCTZ generic Avalide (Sanofi) 150/12.5, 300/12.5 mg tabs 272.00 2477.70 Losartan/HCTZ generic Hyzaar (Merck) 50/12.5, 100/12.5, 100/25 mg tabs Olmesartan/HCTZ Benicar HCT (Daiichi Sankyo) 20/12.5, 40/12.5, 40/25 mg tabs Telmisartan/HCTZ generic Micardis HCT (Boehringer Ingelheim) 40/12.5, 80/12.5, 80/25 mg tabs Valsartan/HCTZ generic Diovan HCT (Novartis) 80/12.5, 160/12.5, 160/25, 320/12.5, 320/25 mg tabs 79.10 1393.20 2095.20 1542.90 2133.70 408.40 2522.40 ARBs and CCBs Amlodipine/telmisartan 5/40, 5/80, 10/40, 10/80 mg tabs generic Twynsta (Boehringer Ingelheim) 1515.80 2295.80 Amlodipine/valsartan generic Exforge (Novartis) 5/160, 5/320, 10/160, 10/320 mg tabs 572.90 2630.40 Amlodipine/olmesartan Azor (Daiichi Sankyo) 5/20, 5/40, 10/20, 10/40 mg tabs 2613.60 ARBs, CCBs, and Diuretics Valsartan/amlodipine/HCTZ 160/5/12.5, 160/5/25, 160/10/12.5, generic Exforge HCT (Novartis) 160/10/25, 320/10/25 mg tabs 1340.40 2630.40 Olmesartan/amlodipine/HCTZ 20/5/12.5, 40/5/12.5, Tribenzor (Daiichi Sankyo) 40/5/25, 40/10/12.5, 40/10/25 mg tabs 2613.60 Beta-Adrenergic Blockers and Diuretics Atenolol/chlorthalidone generic Tenoretic (Almatica) 50/25, 100/25 mg tabs Bisoprolol/HCTZ generic Ziac (Duramed/Barr) 2.5/6.25, 5/6.25, 10/6.25 mg tabs Metoprolol/HCTZ generic Lopressor HCT (Validus) 50/25, 100/25, 100/50 mg tabs 50/25 mg tabs Nadolol/bendroflumethiazide generic Corzide (Pfizer) 40/5, 80/5 mg tabs 197.20 4320.00 96.70 1869.40 331.00 745.40 1341.40 2185.80 ARB = angiotensin receptor blocker; CCB = calcium channel blocker; HCTZ = hydrochlorothiazide Approximate WAC for year’s treatment at the lowest available dosage 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 August 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy 116 September 12, 2016 MECHANISM OF ACTION — At doses ≤10 mg/ day, nebivolol selectively inhibits beta1-adrenergic receptors and acts as an agonist at beta3-adrenergic receptors Beta1 inhibition decreases heart rate, myocardial contractility, and renin activity Beta3 activation induces vasodilation through endothelial release of nitric oxide Valsartan blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II by preventing it from binding to the AT1 receptor CLINICAL STUDIES — Approval of the new combination was based on the results of an 8-week, double-blind trial in 4161 adults with hypertension (BP 100 mg/m2, myelosuppression, acute and chronic myeloid leukemia Fingolimod – Gilenya (Novartis) ~55%10 0.5 mg PO once/d Transaminase elevations, bradycardia, AV block, macular edema, mild hypertension, lymphopenia, decreased pulmonary function, hypersensitivity reactions, malignancies, serious viral and fungal infections, PML 82,044.70 Teriflunomide – Aubagio (Sanofi-Aventis) ~30%11 or 14 mg PO once/d Diarrhea, nausea, alopecia, transaminase elevations, neutropenia, leukopenia, peripheral neuropathy, hyperkalemia, hypophosphatemia, hypertension, hepatic failure, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis 74,379.70 Dimethyl fumarate – Tecfidera (Biogen-Idec) ~50%12 240 mg PO bid Flushing, abdominal pain, nausea, vomiting, diarrhea, lymphopenia, anaphylaxis, angioedema, PML 76,832.50 1330.409 Oral PML = progressive multifocal leukoencephalopathy Approximate WAC for year’s treatment at the usual maintenance dosage 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 August 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Peginterferon beta-1a (Plegridy) for multiple sclerosis Med Lett Drugs Ther 2015; 57:67 CH Polman et al A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl J Med 2006; 354:899 Compared to interferon beta-1a (JA Cohen et al Lancet 2012; 380:1819; AJ Coles et al Lancet 2012; 380:1829) Cost for second year of treatment; cost for first year’s treatment is $101,218.80 Compared to interferon beta-1a (L Kappos et al N Engl J Med 2015; 373:1418) R Gold et al Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial Lancet 2013; 381:2167 HP Hartung et al Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial Lancet 2002; 360:2018 Cost for treatment of a patient with a body surface area of 1.7 m2 using 12.5-mL multi-dose vials containing 25 mg (2 mg/mL) 10 Oral fingolimod (Gilenya) for multiple sclerosis Med Lett Drugs Ther 2010; 52:98 11 New drugs for multiple sclerosis Med Lett Drugs Ther 2012; 54:89 12 Dimethyl fumarate (Tecfidera) for multiple sclerosis Med Lett Drugs Ther 2013; 55:45 118 The Medical Letter ® in NK cells appears to be a biomarker for reductions in brain inflammatory activity in MS patients treated with daclizumab.3 CLINICAL STUDIES — Approval of daclizumab was based on the results of two randomized, double-blind trials in patients with relapsing-remitting MS The SELECT trial compared daclizumab 150 mg SC every weeks with placebo in 412 adults who had had at least one relapse in the previous 12 months or one new brain lesion in the previous weeks The annualized relapse rate was significantly lower in patients treated with daclizumab (0.21 vs 0.46 with placebo) Patients treated with daclizumab also had significantly fewer new or newly-enlarging brain lesions seen on MRI scans The percentage of patients with confirmed disability progression at week 52 (KaplanMeier estimate) was 6% with daclizumab versus 13% with placebo.4 Extensions of this trial found that clinical efficacy was maintained for three years among patients receiving continuous treatment with daclizumab.5,6 The DECIDE trial compared daclizumab 150 mg SC every weeks with interferon beta-1a (Avonex) 30 mcg IM once a week for up to 144 weeks in 1841 adults who had had or more relapses during the previous years or at least one relapse and one new brain lesion during the previous years (one of these events had to have occurred within 12 months before randomization) The annualized relapse rate was significantly lower with daclizumab (0.22 vs 0.39 with interferon beta-1a) The number of new or newly-enlarged T2 brain lesions seen on MRI scans was also significantly lower with daclizumab The estimated percentage of patients with confirmed disability progression at week 144 was 16% with daclizumab compared to 20% with interferon beta-1a, a nonsignificant difference.7 ADVERSE EFFECTS — The daclizumab package insert includes a boxed warning about the risk of severe hepatic injury, including liver failure and autoimmune hepatitis, and other immune-mediated disorders such as skin reactions, lymphadenopathy, and noninfectious colitis In the SELECT trial, hepatic transaminase elevations >5 times the upper limit of normal occurred in 4% of patients treated with daclizumab compared to 1% of those treated with placebo Cutaneous adverse effects, including rashes, dermatitis, and eczema, were more common with daclizumab than with interferon beta-1a or placebo in clinical trials; patients with a history of skin conditions had the highest risk Use of daclizumab also increased the risk Vol 58 (1503) September 12, 2016 of infections and depression-related events compared to interferon beta-1a and placebo PREGNANCY AND LACTATION – There are no formal studies of daclizumab use in pregnant women Administration of daclizumab to pregnant monkeys resulted in embryofetal death and reduced fetal growth at exposures >30 times the expected exposure in humans at the recommended dose A review of data on 38 pregnancies exposed to daclizumab during clinical trials found no evidence of an increased risk for adverse fetal or maternal outcomes.8 Daclizumab has been detected in the milk of lactating monkeys DOSAGE AND ADMINISTRATION — Zinbryta is available in 150-mg single-dose prefilled syringes The recommended dosage is 150 mg injected subcutaneously once a month into the thigh, abdomen, or the back of the upper arm Patients must be trained to self-administer the drug at home Zinbryta is contraindicated in patients with pre-existing hepatic disease or impairment, or a history of autoimmune conditions involving the liver; transaminase and bilirubin levels should be monitored monthly during treatment and for up to months after the last dose of the drug CONCLUSION — Daclizumab (Zinbryta), a subcutaneously injected interleukin-2 blocking monoclonal antibody, appears to be more effective than intramuscular interferon beta-1a at reducing relapse rates in patients with relapsing-remitting multiple sclerosis (MS), but it can cause severe adverse effects including hepatotoxicity and immune-mediated disorders It has not been compared directly with any other diseasemodifying drug used to treat MS ■ New monoclonal antibodies to prevent transplant rejection Med Lett Drugs Ther 1998; 40:93 Drugs for multiple sclerosis Med Lett Drugs Ther 2016; 58:71 R Milo The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis Ther Adv Neurol Disord 2014; 7:7 R Gold et al Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial Lancet 2013; 381:2167 G Giovannoni et al Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial Lancet Neurol 2014; 13:472 R Gold et al Safety and efficacy of daclizumab in relapsingremitting multiple sclerosis: 3-year results from the SELECTED open-label extension study BMC Neurol 2016; 16:117 L Kappos et al Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis N Engl J Med 2015; 373:1418 R Gold et al Pregnancy experience: nonclinical studies and pregnancy outcomes in the daclizumab clinical study program Neurol Ther 2016 July 13 (epub) 119 The Medical Letter ® September 12, 2016 Vol 58 (1503) IN BRIEF IN BRIEF Defibrotide (Defitelio) for Hepatic Veno-Occlusive Disease Repatha Pushtronex – A New Evolocumab Injection Device The FDA has approved defibrotide sodium (Defitelio – Jazz), a mixture of mostly single-stranded polydeoxyribonucleotide sodium salts, for treatment of adults and children with hepatic veno-occlusive disease (also known as sinusoidal obstruction syndrome) and renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT) It is the first drug to be approved by the FDA for treatment of severe hepatic veno-occlusive disease Defibrotide was approved earlier by the European Medicines Agency for the same indication The PCSK9 inhibitor evolocumab (Repatha – Amgen) is now available in a single-dose, hands-free device (Repatha Pushtronex) for once-monthly subcutaneous infusion Evolocumab is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (LDL-C), and as an adjunct to diet and other LDLlowering therapies for patients with homozygous familial hypercholesterolemia (HoFH) Hepatic veno-occlusive disease is an uncommon (