awaiting [30:<30 mL/minute per 1.73m 2 ). 1 (See Renal Impairment under Dosage and Administration.) Safety and efficacy of sacubitril/valsartan not established in dialysis patients. 31 Due to high plasma protein binding, sacubitril/valsartan not expected to be dialyzable. 1 31 Common Adverse Effects Hypotension, 1 2 cough, 1 2 dizziness, 1 renal failure or acute renal failure, 1 decreased hemoglobin and hematocrit, 1 increased S cr , 1 2 hyperkalemia. 1 2 Interactions for Sacubitril and Valsartan Drugs Affecting Hepatic Microsomal Enzymes CYP enzyme-mediated metabolism of sacubitril/valsartan is minimal; drugs that affect CYP enzymes are not expected to affect the pharmacokinetics of sacubitril/valsartan. 1 21 31 Drugs Affected by Hepatic Transport Systems Sacubitril inhibits organic anion transporter protein (OATP) 1B1 and OATP1B3. 1 30 31 Potential pharmacokinetic interactions when sacubitril/valsartan used concomitantly with drugs that are substrates for OATP1B1 and OATP1B3 (increased concentrations of the concomitant drug). 1 31 Specific Drugs Drug Interaction Comments ACE inhibitors Increased risk of angioedema 1 13 17 Concomitant use contraindicated 1 13 17 Aliskiren Increased risk of renal impairment, hyperkalemia, and hypotension 56 Concomitant use contraindicated in patients with diabetes mellitus; 1 56 avoid concomitant use in patients with GFR> <60 mL/minute per 1.73 m 2 1 56 Amlodipine No clinically relevant pharmacokinetic interaction observed 1 21 31 Atorvastatin Increased atorvastatin peak plasma concentration and AUC 1 31 No dosage adjustments proposed 31 Carvedilol No clinically relevant pharmacokinetic interaction observed 1 21 31 Digoxin No clinically relevant pharmacokinetic interaction observed 1 21 31 Diuretic, potassium-sparing (e.g., amiloride, spironolactone, triamterene) Possible additive hyperkalemic effects; 1 14 volume depletion may potentiate symptomatic hypotension 1 Monitor serum potassium concentrations 1 Furosemide No clinically relevant pharmacokinetic interaction observed; 1 31 volume depletion may potentiate symptomatic hypotension 1 Hydrochlorothiazide No clinically relevant pharmacokinetic interaction observed; 1 21 31 volume depletion may potentiate symptomatic hypotension 1 Lithium Increased serum lithium concentrations; possible toxicity 1 Monitor serum lithium concentrations 1 Metformin No clinically relevant pharmacokinetic interaction observed 1 21 31 NSAIAs, including selective COX-2 inhibitors Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients 1 Monitor renal function periodically 1 Omeprazole No clinically relevant pharmacokinetic interaction observed 1 21 31 Oral contraceptives (e.g., ethinyl estradiol and levonorgestrel) No clinically relevant pharmacokinetic interaction observed 1 21 31 Potassium supplements and potassium-containing salt substitutes Possible additive hyperkalemic effect 1 Monitor serum potassium concentrations 1 Sildenafil No clinically relevant pharmacokinetic interaction observed; 1 31 possible additive reduction in BP 1 31 Advise patients of potential adverse effects due to BP lowering with concomitant use 31 Warfarin No clinically relevant pharmacokinetic interaction observed 1 21 31 Sacubitril and Valsartan Pharmacokinetics Absorption Bioavailability Absolute bioavailability of sacubitril from sacubitril/valsartan is 60%. 1 Bioavailability of valsartan from sacubitril/valsartan is 40 60% higher than valsartan administered alone. 1 7 17 31 32 Peak plasma concentrations of sacubitril, LBQ657 (the active metabolite of sacubitril), and valsartan are reached in 0.5, 2 , and 1.5 hours, respectively. 1 Food Administration with food has no clinically relevant effect on the systemic exposures of sacubitril, LBQ657, or valsartan. 1 Special Populations Mild to moderate renal impairment: Exposure to LBQ657 increased by approximately twofold; exposure to sacubitril and valsartan not substantially altered. 31 Severe renal impairment: Exposure to LBQ657 increased by approximately 2.7-fold; exposure to sacubitril and valsartan not substantially altered. 31 Mild hepatic impairment: Exposure to sacubitril, LBQ657, and valsartan increased by 53, 48, and 19%, respectively. 31 Moderate hepatic impairment: Exposure to sacubitril, LBQ657, and valsartan increased by 245, 90, and 109%, respectively. 31 Severe hepatic impairment: Pharmacokinetics not evaluated. 31 Distribution Extent Sacubitril/valsartan is distributed into milk in rats; not known whether sacubitril/valsartan is distributed into human milk. 1 Plasma Protein Binding Sacubitril and LBQ657: Approximately 97%. 1 31 Valsartan: Approximately 94%. 1 31 Elimination Metabolism Sacubitril: Converted to the active moiety LBQ657 by ester hydrolysis; LBQ657 not further metabolized to a substantial extent. 1 31 Valsartan: Minimally metabolized; 20% of dose recovered as metabolites. 1 14 Primary metabolite of valsartan, accounting for> <10% of the dose, is a hydroxyl metabolite formed by metabolism via CYP2C9. 1 14 Elimination Route Sacubitril (mainly as LBQ657): Excreted in urine (52 68%) and feces (37 48%). 1 Valsartan and metabolites: Excreted in urine (approximately 13%) and feces (86%). 1 Half-life Average elimination half-lives of sacubitril, LBQ657, and valsartan are 1.4, 11.5, and 9.9 hours, respectively. 1 Special Populations Sacubitril/valsartan unlikely to be removed by hemodialysis. 1 Stability Storage Oral Tablets 20 25 C (may be exposed to 15 30 C). 1 Protect from moisture. 1 Actions Sacubitril/valsartan is a fixed combination of a neprilysin inhibitor and angiotensin II receptor antagonist. 1 2 4 7 8 Dual mechanism of sacubitril/valsartan suppresses harmful compensatory mechanisms of heart failure that are mediated by the RAA system, while simultaneously enhancing the beneficial adaptive mechanisms by inhibiting degradation of natriuretic peptides. 18 Sacubitril blocks neprilysin (neutral endopeptidase) via LBQ657 (the active metabolite of sacubitril), which prevents degradation of natriuretic peptides. 21 Natriuretic peptides stimulate natriuresis and diuresis, promote vasodilation, and oppose acute effects of volume overload by inhibiting RAA system and sympathetic nervous system. 3 28 Natriuretic peptides attenuate development of cardiac hypertrophy and fibrosis and enhance endothelial function. 3 28 Other substrates of neprilysin include enkephalins, oxytocin, gastrin, angiotensin I and II, endothelin-1, substance P, and bradykinin. 19 21 Inhibition of neprilysin alone results in increased natriuretic peptide concentrations at the expense of an increase in potent vasoconstrictors (angiotensin II and endothelin-1), which partly counteracts the benefits of increased natriuretic peptides. 4 21 24 25 Natriuretic peptide augmentation through neprilysin inhibition requires concomitant suppression of angiotensin II to yield a beneficial effect. 4 25 Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects. 7 14 Advice to Patients Importance of reading the manufacturer's patient information. 1 Risks of use during pregnancy. 1 45 46 (See Boxed Warning.) Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. 1 Risk of angioedema. 1 Importance of advising patients to discontinue use of any ACE inhibitor or angiotensin II receptor antagonist therapy. 1 Importance of advising patients to allow a 36-hour wash-out period if switching from or to an ACE inhibitor. 1 (See Contraindications and also see Sensitivity Reactions under Cautions.) Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium), as well as any concomitant diseases. 1 Importance of informing patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Sacubitril and Valsartan Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets, film-coated Sacubitril 24 mg and Valsartan 26 mg Entresto Novartis Sacubitril 49 mg and Valsartan 51 mg Entresto Novartis Sacubitril 97 mg and Valsartan 103 mg Entresto Novartis AHFS DI Essentials. Copyright 2017, Selected Revisions November 17, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Novartis. Entresto (sacubitril and valsartan) tablets prescribing information. East Hanover, NJ; 2015 Jul. 2. McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med . 2014; 371:993-1004. [PubMed 25176015] 3. Jessup M. Neprilysin inhibition--a novel therapy for heart failure. N Engl J Med . 2014; 371:1062-4. [PubMed 25176014] 4. Lillyblad MP. Dual Angiotensin Receptor and Neprilysin Inhibition in Chronic Systolic Heart Failure: Understanding the New PARADIGM. Ann Pharmacother . 2015; :. [PubMed 26175499] 6. Pfeffer MA, Swedberg K, Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet . 2003; 362:759-66. [PubMed 13678868] 7. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail . 2014; 2:663-70. [PubMed 25306450] 8. Ferrari L, Sada S, GrAM (Gruppo di Autoformazione Metodologica). Efficacy of angiotensin-neprilysin inhibition versus enalapril in patient with heart failure with a reduced ejection fraction. Intern Emerg Med . 2015; 10:369-71. [PubMed 25537439] 9. . Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med . 1987; 316:1429-35. [PubMed 2883575] 10. . Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med . 1991; 325:293-302. [PubMed 2057034] 11. Packer M, McMurray JJ, Desai AS et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation . 2015; 131:54-61. [PubMed 25403646] 12. McMurray JJ, Packer M, Desai AS et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail . 2014; 16:817-25. [PubMed 24828035] 13. . Sacubitril/valsartan (Entresto) for heart failure. Med Lett Drugs Ther . 2015; 57:107-9. [PubMed 26218791] 14. Novartis. Diovan (valsartan) tablets prescribing information. East Hanover, NJ; 2015 Jul. 15. Buggey J, Mentz RJ, DeVore AD et al. Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact. J Card Fail . 2015; 21:741-50. [PubMed 26209000] 16. Gan L, Langenickel T, Petruck J et al. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor. J Clin Pharmacol . 2015; :. [PubMed 26073563] 17. Andersen MB, Simonsen U, Wehland M et al. LCZ696 (Valsartan/Sacubitril) - A Possible New Treatment for Hypertension and Heart Failure. Basic Clin Pharmacol Toxicol . 2015; :. 18. Minguet J, Sutton G, Ferrero C et al. LCZ696 : a new paradigm for the treatment of heart failure?. Expert Opin Pharmacother . 2015; 16:435-46. [PubMed 25597387] 19. Singh JS, Lang CC. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond. Vasc Health Risk Manag . 2015; 11:283-95. [PubMed 26082640] 20. Gradman AH. LCZ696: the next step in improving RAS inhibition?. Curr Hypertens Rep . 2015; 17:37. [PubMed 25833460] 21. King JB, Bress AP, Reese AD et al. Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review. Pharmacotherapy . 2015; 35:823-37. [PubMed 26406774] 22. Bavishi C, Messerli FH, Kadosh B et al. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J . 2015; 36:1967-73. [PubMed 25898846] 23. von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure. Pharmacol Ther . 2014; 144:41-9. [PubMed 24836726] 24. McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail . 2015; 17:242-7. [PubMed 25756942] 25. Braunwald E. The path to an Angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol . 2015; 65:1029-41. [PubMed 25766951] 26. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med . 1998; 339:321-8. [PubMed 9682046] 27. Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev . 2006; 27:47-72. [PubMed 16291870] 28. Vardeny O, Tacheny T, Solomon SD. First-in-class angiotensin receptor neprilysin inhibitor in heart failure. Clin Pharmacol Ther . 2013; 94:445-8. [PubMed 23872864] 29. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207620Orig1s000: Summary review. From FDA website. 30. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207620Orig1s000: Pharmacology review. From FDA website. 31. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207620Orig1s000: Clinical pharmacology and biopharmaceutics review. From FDA website. 32. US Food and Drug Administration. Center for Drug Evaluation and Research. 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[PubMed 26992459] 704. Sandhu AT, Ollendorf DA, Chapman RH et al. Cost-effectiveness of sacubitril valsartan in patients with heart failure with reduced ejection fraction. Ann Intern Med . 2016. [Epub ahead of print]. doi:10.7326/M16-0057. Next Interactions Print this page Add to My Med List More about sacubitril/valsartan Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 16 Reviews Add your own review/rating Drug class: angiotensin receptor blockers and neprilysin inhibitors Consumer resources Sacubitril and valsartan Sacubitril and valsartan (Advanced Reading) Professional resources Sacubitril and Valsartan (Wolters Kluwer) Other brands: Entresto Related treatment guides Heart Failure> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Angiotensin receptor blockers and neprilysin inhibitors Related Drugs Heart Failure amlodipine , lisinopril , furosemide , carvedilol , metoprolol , diltiazem , Lasix , spironolactone , warfarin , triamcinolone , Norvasc , nitroglycerin , valsartan , benazepril , hydralazine , digoxin , Nitrostat , Coreg , enalapril , Diovan , nifedipine , ramipril , Coumadin , isosorbide mononitrate , More... 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