The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1474 Volume 56 August 3, 2015 IN THIS ISSUE Sacubitril/Valsartan (Entresto) for Heart Failure p Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea p Polidocanol (Varithena) for Varicose Veins p In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease p 107 109 111 112 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 1474 Volume 56 ▶ August 3, 2015 Take CME Exams ALSO IN THIS ISSUE Rifaximin (Xifaxan) for Irritable Bowel Syndrome with Diarrhea p 109 Polidocanol (Varithena) for Varicose Veins p 111 In Brief: Duopa – A Carbidopa/Levodopa Enteral Suspension for Parkinson’s Disease p 112 Sacubitril/Valsartan (Entresto) for Heart Failure The FDA has approved Entresto (Novartis), an oral fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan, to reduce the risk of cardiovascular death and heart failure hospitalization in patients with heart failure with reduced ejection fraction Sacubitril is the first neprilysin inhibitor to become available in the US Pronunciation Key Sacubitril: sak ue’ bi tril Entresto: en tress’ toh Valsartan: val sar’ tan Neprilysin: nep" ri lye' sin STANDARD TREATMENT — Patients with symptomatic heart failure with reduced ejection fraction generally take an angiotensin-converting enzyme (ACE) inhibitor, a beta blocker, and an aldosterone antagonist If volume overloaded, they may take a diuretic as well An ARB is recommended for patients who cannot tolerate an ACE inhibitor.1 MECHANISM OF ACTION — Neprilysin is a neutral endopeptidase that degrades some vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin Inhibition of neprilysin by LBQ657, the active metabolite of sacubitril, increases the levels of these peptides, decreasing vasoconstriction, sodium retention, and maladaptive remodeling Valsartan blocks the angiotensin II type-1 (AT1) receptor, inhibiting angiotensin II and the release of aldosterone.2 CLINICAL STUDIES — Approval of Entresto was based on a double-blind trial (PARADIGM-HF) in 8442 patients with class II-IV heart failure and a reduced ejection fraction who were randomized to Entresto 200 mg (sacubitril 97 mg/valsartan 103 mg) twice daily or the ACE inhibitor enalapril Table Pharmacology Class Formulation Route Tmax Elimination Half-life Angiotensin-receptor neprilysin inhibitor Sacubitril/valsartan - 24/26 mg, 49/51 mg, 97/103 mg tablets Oral 0.5 hrs (sacubitril); hrs (LBQ657)1; 1.5 hrs (valsartan) Sacubitril (52-68% urine; 37-48% feces); Valsartan (~13% urine; 86% feces) 1.4 hrs (sacubitril); 11.5 hrs (LBQ657)1; 9.9 hrs (valsartan) Active metabolite of sacubitril (Vasotec, and generics) 10 mg twice daily, both in addition to other drugs The study was stopped early because a prespecified interim analysis showed lower cardiovascular mortality in patients randomized to Entresto After a median follow-up of 27 months, the primary endpoint, a composite of first hospitalization for worsening heart failure or cardiovascular death, occurred in significantly fewer patients taking the combination compared to those taking enalapril (21.8% vs 26.5%) The combination significantly reduced the risk of first hospitalization for worsening heart failure (12.8% vs 15.6%), death from cardiovascular causes (13.3% vs 16.5%), and all-cause mortality (17.0% vs 19.8%).3 It also slowed the progression of heart failure.4 ADVERSE EFFECTS — Hypotension and hyperkalemia were the most common adverse effects in the clinical trial; symptomatic hypotension occurred in 14% of patients taking Entresto, even though the study excluded those with baseline hypotension Cough (11.3%) and elevated serum creatinine (3.3%) occurred in patients treated with the combination, but less frequently than with enalapril Neprilysin inhibition can cause angioedema, which occurred in 0.5% of patients treated with the combination compared to 0.2% of those treated with enalapril 107 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® August 3, 2015 Vol 57 (1474) Table Some Drugs for Heart Failure with Reduced Ejection Fraction Drug Some Oral Formulations Angiotensin-Converting Enzyme (ACE) Inhibitors Captopril – generic 12.5, 25, 50, 100 mg tabs3 Enalapril – generic 2.5, 5, 10, 20 mg tabs Vasotec (Valeant) Fosinopril – generic 10, 20, 40 mg tabs3 Lisinopril – generic 2.5, 5, 10, 20, 40 mg tabs Prinivil (Merck) 5, 10, 20 mg tabs Zestril (Almatica) 2.5, 5, 10, 20, 30, 40 mg tabs Perindopril erbumine4 – generic 2, 4, mg tabs Aceon (Symplmed) Quinapril – generic 5, 10, 20, 40 mg tabs Accupril (Pfizer) Ramipril – generic 1.25, 2.5, 5, 10 mg caps Altace (Merck) Trandolapril – generic 1, 2, mg tabs Mavik (Abbvie) Angiotensin Receptor Blockers (ARBs) Azilsartan medoxomil4 – Edarbi (Arbor) 40, 80 mg tabs Candesartan cilexetil – generic 4, 8, 16, 32 mg tabs Atacand (AstraZeneca) Losartan4 – generic 25, 50, 100 mg tabs Cozaar (Merck) Valsartan – generic 40, 80, 160, 320 mg tabs3 Diovan (Novartis) Beta-Adrenergic Blockers Bisoprolol4 – generic 5, 10 mg tabs3 Zebeta (Duramed/Barr) Carvedilol – generic 3.125, 6.25, 12.5, 25 mg tabs Coreg (GSK) extended-release – Coreg CR 10, 20, 40, 80 mg ER caps Metoprolol succinate ER – generic 25, 50, 100, 200 mg ER tabs3 Toprol-XL (AstraZeneca) Aldosterone Antagonists Eplerenone – generic 25, 50 mg tabs Inspra (Pfizer) Spironolactone – generic 25, 50, 100 mg tabs3 Aldactone (Pfizer) Vasodilators Isosorbide dinitrate/hydralazine6 – BiDil (Arbor)7 20/37.5 mg tabs Loop Diuretics Bumetanide – generic 0.5, 1, mg tabs Furosemide – generic Lasix (Sanofi) Torsemide – generic Demadex (Meda) Digitalis Glycoside Digoxin – generic Lanoxin (Covis) 20, 40, 80 mg tabs 5, 10, 20, 100 mg tabs Usual Initial Adult Dosage1 Usual Maximum Adult Dosage1 6.25 mg tid 2.5 mg bid 50 mg tid 20 mg bid 5-10 mg once/d 2.5-5 mg once/d 40 mg once/d 40 mg once/d mg once/d 16 mg once/d mg bid 20 mg bid 1.25-2.5 mg once/d 10 mg once/d mg once/d mg once/d 40-80 mg once/d 4-8 mg once/d 80 mg once/d 32 mg once/d 25-50 mg once/d 150 mg once/d 20-40 mg bid 160 mg bid 1.25 mg once/d 10 mg once/d 3.125 mg bid 10 mg once/d 12.5-25 mg once/d Cost2 $151.50 39.90 1311.60 10.40 2.70 94.10 48.00 37.30 196.20 23.60 185.10 15.80 139.90 16.20 59.10 24.60 149.70 25 mg bid 14.70 (50 mg bid for pts >85kg) 218.70 80 mg once/d 219.60 200 mg once/d 45.00 85.50 25 mg once/d5 50 mg once/d5 12.5-25 mg once/d5 25 mg once/d or bid5 20 mg/37.5 mg tid 40 mg/75 mg tid 0.5-1 mg once/d or bid 10 mg once/d or in divided doses 20-40 mg once/d or bid 600 mg once/d or in divided doses 10-20 mg once/d 200 mg once/d or in divided doses 0.125, 0.25 mg tabs 0.125 mg once/d 0.0625, 0.125, 0.1875, 0.25 mg tabs 162.60 103.30 131.10 16.20 297.40 52.40 319.20 0.125-0.25 mg once/d or once every other day 104.10 217.80 6.30 48.30 528.70 166.10 31.10 274.50 54.20 585.00 16.70 34.80 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker Ivabradine – Corlanor (Amgen) 5, 7.5 mg tabs Angiotensin-Receptor Neprilysin Inhibitor Sacubitril/valsartan – Entresto (Novartis) 24/26, 49/51, 97/103 mg tabs 2.5-5 mg bid 7.5 mg bid 375.00 49/51 mg bid8 97/103 mg bid 375.009 ER = extended-release Dosage adjustment may be needed for hepatic or renal impairment Approximate WAC for 30 days’ treatment at the lowest usual maximum 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 July 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Available as scored tablets Not approved by the FDA for treatment of heart failure For patients with an eGFR ≥50 mL/min/1.73 m2 For patients with an eGFR 30-49 mL/min/1.73 m2, the initial dose is 25 mg every other day for eplerenone and 12.5 mg once daily or every other day for spironolactone and the maintenance dose is 25 mg once daily for eplerenone and 12.5-25 mg once daily for spironolactone Both of these drugs are available generically as single agents Isosorbide dinitrate is available in 5, 10, 20, and 30-mg tablets and hydralazine in 10, 25, 50, and 100-mg tablets FDA-approved as adjunctive therapy for treatment of heart failure in black patients For patients with an eGFR