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Sacubitril and Valsartan

Class: Renin-Angiotensin-Aldosterone System Inhibitors, Miscellaneous
Chemical Name: (αR,γS)-γ-[(3-Carboxy-1-oxopropyl)amino]-α-methyl-[1,1′-biphenyl]-4-pentanoic acid, α-ethyl ester
Molecular Formula: C24H29NO5C24H29N5O3
CAS Number: 149709-62-6
Brands: Entresto

Medically reviewed by Drugs.com on Nov 9, 2020. Written by ASHP.

Warning

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue sacubitril/valsartan as soon as possible.

Introduction

Sacubitril and valsartan (sacubitril/valsartan) is a fixed combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II type 1 [AT1] receptor antagonist [i.e., angiotensin II receptor blocker, ARB]); such combinations referred to as angiotensin receptor-neprilysin inhibitors [ARNIs]).

Uses for Sacubitril and Valsartan

Heart Failure

Fixed combination used to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II–IV) and reduced ejection fraction.

Usually administered in conjunction with other heart failure therapies (e.g., β-adrenergic blocking agent, aldosterone antagonist, diuretic), as substitute for therapy with an ACE inhibitor or other angiotensin II receptor antagonist.

Therapy with an ARNI (sacubitril/valsartan) appears to be more effective than ACE inhibitor therapy (enalapril) in improving outcomes based on reductions in cardiovascular death and heart failure-related hospitalization when given in conjunction with optimal heart failure therapy in patients with chronic heart failure and reduced ejection fraction.

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that selected patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Sacubitril and Valsartan Dosage and Administration

General

  • Available as fixed-combination tablets containing sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, or sacubitril 97 mg/valsartan 103 mg.

  • Bioavailability of valsartan in sacubitril/valsartan tablets is 40–60% higher than that of valsartan in other commercially available tablet formulations; 26, 51, or 103 mg of valsartan in sacubitril/valsartan (Entresto) is equivalent to 40, 80, or 160 mg of valsartan in other commercially available valsartan tablets, respectively.

  • When switching from an ACE inhibitor to sacubitril/valsartan, discontinue ACE inhibitor 36 hours prior to initiating sacubitril/valsartan. (See Contraindications under Cautions.) Also discontinue angiotensin II antagonist therapy.

Administration

Oral Administration

Administer sacubitril/valsartan orally twice daily without regard to meals.

Dosage

Dosage of sacubitril/valsartan in fixed combination is expressed in terms of both sacubitril and valsartan components.

Adults

Heart Failure
Oral

Patients switching from an ACE inhibitor or angiotensin II receptor antagonist: Initially, sacubitril 49 mg/valsartan 51 mg twice daily (starting after discontinuance of angiotensin II receptor antagonist or 36 hours after discontinuance of ACE inhibitor).

Patients switching from low dosages of an ACE inhibitor (e.g., ≤10 mg of enalapril daily or equivalent dosage of other ACE inhibitor) or angiotensin II receptor antagonist (e.g., ≤160 mg of valsartan daily or equivalent dosage of other angiotensin II receptor antagonist): Initially, sacubitril 24 mg/valsartan 26 mg twice daily (starting after discontinuance of angiotensin II receptor antagonist or 36 hours after discontinuance of ACE inhibitor).

Patients not currently taking an ACE inhibitor or an angiotensin II receptor antagonist: Initially, sacubitril 24 mg/valsartan 26 mg twice daily.

Maintenance dosage: Double dosage of sacubitril/valsartan every 2–4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.

Moderate hepatic impairment (Child-Pugh class B): Initial dosage of sacubitril 24 mg/valsartan 26 mg twice daily recommended. Double dosage every 2–4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Safety and efficacy not established. Use not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2): Initially, sacubitril 24 mg/valsartan 26 mg twice daily. Double dosage every 2–4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily. Safety and efficacy not established in patients undergoing dialysis. (See Renal Impairment under Cautions.)

Volume- and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of sacubitril/valsartan therapy or initiate at a lower dose.

Cautions for Sacubitril and Valsartan

Contraindications

  • Known hypersensitivity to sacubitril, valsartan, or any ingredient in the formulation.

  • History of angioedema related to prior ACE inhibitor or angiotensin II receptor antagonist treatment.

  • Concomitant use of ACE inhibitors. Do not administer sacubitril/valsartan within 36 hours of switching from or to an ACE inhibitor.

  • Concomitant use of aliskiren in patients with diabetes mellitus.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when drugs that act directly on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors) are used during the second and third trimesters of pregnancy. (See Boxed Warning.)

Discontinue sacubitril/valsartan as soon as possible when pregnancy is detected, unless continued use is considered lifesaving. If therapy is continued, advise woman of risk to the fetus. (See Advice to Patients.)

Sensitivity Reactions

Sacubitril/valsartan may cause angioedema. Do not use in patients with known history of angioedema related to previous ACE inhibitor or angiotensin II receptor antagonist therapy. (See Contraindications under Cautions.) Risk of angioedema is higher in black patients.

Other Warnings/Precautions

Precautions Related to the Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

Cardiovascular Effects

Possible symptomatic hypotension with sacubitril/valsartan, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics). (See Volume- and/or Salt-Depleted Patients under Dosage and Administration.)

If hypotension occurs, consider adjustment of dosages of diuretics and concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia).

If hypotension persists, reduce dosage of sacubitril/valsartan or temporarily discontinue. Permanent discontinuance of therapy not usually required.

Renal Effects

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe heart failure.

Increases in BUN and Scr possible in patients with unilateral or bilateral renal artery stenosis; monitor renal function.

Hyperkalemia

Hyperkalemia may occur, especially in patients with severe renal impairment, diabetes mellitus, hypoaldosteronism, or a potassium-rich diet. Monitor serum potassium periodically and treat elevated values appropriately. Dosage reduction or interruption of sacubitril/valsartan may be required.

Specific Populations

Pregnancy

Can cause fetal and neonatal morbidity and death when administered to a pregnant woman. (See Boxed Warning.)

Sacubitril/valsartan therapy during organogenesis caused embryofetal death and teratogenic effects in animal (e.g., rats, rabbits) reproduction studies.

Lactation

Sacubitril/valsartan is distributed into milk in rats; not known whether sacubitril/valsartan is distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No clinically relevant pharmacokinetic differences in patients ≥65 years of age compared with the overall population.

Hepatic Impairment

Systemic exposure may be increased (see Absorption: Special Populations, under Pharmacokinetics). Lower initial dosage recommended for patients with moderate hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Safety and efficacy of sacubitril/valsartan not established in patients with severe hepatic impairment (Child-Pugh class C); not recommended in such patients.

Renal Impairment

Systemic exposure may be increased (see Absorption: Special Populations, under Pharmacokinetics). Lower initial dosage recommended for patients with severe renal impairment (estimated GFR <30 mL/minute per 1.73m2). (See Renal Impairment under Dosage and Administration.)

Safety and efficacy of sacubitril/valsartan not established in dialysis patients. Due to high plasma protein binding, sacubitril/valsartan not expected to be dialyzable.

Common Adverse Effects

Hypotension, cough, dizziness, renal failure or acute renal failure, decreased hemoglobin and hematocrit, increased Scr, hyperkalemia.

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.

Drugs Affected by Hepatic Transport Systems

Sacubitril inhibits organic anion transporter protein (OATP) 1B1 and OATP1B3. Potential pharmacokinetic interactions when sacubitril/valsartan used concomitantly with drugs that are substrates for OATP1B1 and OATP1B3 (increased concentrations of the concomitant drug).

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Increased risk of angioedema

Concomitant use contraindicated

Aliskiren

Increased risk of renal impairment, hyperkalemia, and hypotension

Concomitant use contraindicated in patients with diabetes mellitus; avoid concomitant use in patients with GFR <60 mL/minute per 1.73 m2

Amlodipine

No clinically relevant pharmacokinetic interaction observed

Atorvastatin

Increased atorvastatin peak plasma concentration and AUC

No dosage adjustments proposed

Carvedilol

No clinically relevant pharmacokinetic interaction observed

Digoxin

No clinically relevant pharmacokinetic interaction observed

Diuretic, potassium-sparing (e.g., amiloride, spironolactone, triamterene)

Possible additive hyperkalemic effects; volume depletion may potentiate symptomatic hypotension

Monitor serum potassium concentrations

Furosemide

No clinically relevant pharmacokinetic interaction observed; volume depletion may potentiate symptomatic hypotension

Hydrochlorothiazide

No clinically relevant pharmacokinetic interaction observed; volume depletion may potentiate symptomatic hypotension

Lithium

Increased serum lithium concentrations; possible toxicity

Monitor serum lithium concentrations

Metformin

No clinically relevant pharmacokinetic interaction observed

NSAIAs, including selective COX-2 inhibitors

Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients

Monitor renal function periodically

Omeprazole

No clinically relevant pharmacokinetic interaction observed

Oral contraceptives (e.g., ethinyl estradiol and levonorgestrel)

No clinically relevant pharmacokinetic interaction observed

Potassium supplements and potassium-containing salt substitutes

Possible additive hyperkalemic effect

Monitor serum potassium concentrations

Sildenafil

No clinically relevant pharmacokinetic interaction observed; possible additive reduction in BP

Advise patients of potential adverse effects due to BP lowering with concomitant use

Warfarin

No clinically relevant pharmacokinetic interaction observed

Sacubitril and Valsartan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of sacubitril from sacubitril/valsartan is ≥60%. Bioavailability of valsartan from sacubitril/valsartan is 40–60% higher than valsartan administered alone.

Peak plasma concentrations of sacubitril, LBQ657 (the active metabolite of sacubitril), and valsartan are reached in 0.5, 2 , and 1.5 hours, respectively.

Food

Administration with food has no clinically relevant effect on the systemic exposures of sacubitril, LBQ657, or valsartan.

Special Populations

Mild to moderate renal impairment: Exposure to LBQ657 increased by approximately twofold; exposure to sacubitril and valsartan not substantially altered.

Severe renal impairment: Exposure to LBQ657 increased by approximately 2.7-fold; exposure to sacubitril and valsartan not substantially altered.

Mild hepatic impairment: Exposure to sacubitril, LBQ657, and valsartan increased by 53, 48, and 19%, respectively.

Moderate hepatic impairment: Exposure to sacubitril, LBQ657, and valsartan increased by 245, 90, and 109%, respectively.

Severe hepatic impairment: Pharmacokinetics not evaluated.

Distribution

Extent

Sacubitril/valsartan is distributed into milk in rats; not known whether sacubitril/valsartan is distributed into human milk.

Plasma Protein Binding

Sacubitril and LBQ657: Approximately 97%.

Valsartan: Approximately 94%.

Elimination

Metabolism

Sacubitril: Converted to the active moiety LBQ657 by ester hydrolysis; LBQ657 not further metabolized to a substantial extent.

Valsartan: Minimally metabolized; 20% of dose recovered as metabolites. Primary metabolite of valsartan, accounting for <10% of the dose, is a hydroxyl metabolite formed by metabolism via CYP2C9.

Elimination Route

Sacubitril (mainly as LBQ657): Excreted in urine (52–68%) and feces (37–48%).

Valsartan and metabolites: Excreted in urine (approximately 13%) and feces (86%).

Half-life

Average elimination half-lives of sacubitril, LBQ657, and valsartan are 1.4, 11.5, and 9.9 hours, respectively.

Special Populations

Sacubitril/valsartan unlikely to be removed by hemodialysis.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Protect from moisture.

Actions

  • Sacubitril/valsartan is a fixed combination of a neprilysin inhibitor and angiotensin II receptor antagonist.

  • 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.

  • Sacubitril blocks neprilysin (neutral endopeptidase) via LBQ657 (the active metabolite of sacubitril), which prevents degradation of natriuretic peptides.

  • Natriuretic peptides stimulate natriuresis and diuresis, promote vasodilation, and oppose acute effects of volume overload by inhibiting RAA system and sympathetic nervous system. Natriuretic peptides attenuate development of cardiac hypertrophy and fibrosis and enhance endothelial function.

  • Other substrates of neprilysin include enkephalins, oxytocin, gastrin, angiotensin I and II, endothelin-1, substance P, and bradykinin.

  • 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.

  • Natriuretic peptide augmentation through neprilysin inhibition requires concomitant suppression of angiotensin II to yield a beneficial effect.

  • Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.

Advice to Patients

  • Importance of reading the manufacturer's patient information.

  • Risks of use during pregnancy. (See Boxed Warning.)

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Risk of angioedema. Importance of advising patients to discontinue use of any ACE inhibitor or angiotensin II receptor antagonist therapy. Importance of advising patients to allow a 36-hour wash-out period if switching from or to an ACE inhibitor. (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.

  • Importance of informing patients of other important precautionary information. (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 2021, Selected Revisions November 17, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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