Skip to Content

Entresto

Generic Name: Sacubitril and Valsartan
Class: Renin-Angiotensin-Aldosterone System Inhibitors, Miscellaneous
Chemical Name: 4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid
Molecular Formula: C24H29NO5C24H29N5O3
CAS Number: 149709-62-6

Warning(s)

WARNING: FETAL TOXICITY 1

See full prescribing information for complete boxed warning. 1

  • When pregnancy is detected, discontinue sacubitril and valsartan as soon as possible.1

  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.1

Introduction

The fixed combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB), is a renin-angiotensin-aldosterone system inhibitor.1

Uses for Entresto

Sacubitril and valsartan has the following uses:

Sacubitril and valsartan is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB), indicated 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.1

Sacubitril and valsartan is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.1

Entresto Dosage and Administration

General

The fixed combination of sacubitril and valsartan is available in the following dosage form(s) and strength(s):

  • Film-coated tablets (sacubitril/valsartan): 24/26 mg; 49/51 mg; 97/103 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • The recommended starting dose of sacubitril and valsartan is 49/51 mg (sacubitril/valsartan) twice-daily. Double the dose of sacubitril and valsartan after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.1

  • Reduce the starting dose to 24/26 mg (sacubitril/valsartan) twice-daily for: patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents, patients with severe renal impairment, and patients with moderate hepatic impairment. Double the dose of sacubitril and valsartan every 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.1

Cautions for Entresto

Contraindications

  • Hypersensitivity to any component.1

  • History of angioedema related to previous ACE inhibitor or ARB therapy.1

  • Concomitant use with ACE inhibitors.1

  • Concomitant use with aliskiren in patients with diabetes.1

Warnings/Precautions

Fetal Toxicity

Sacubitril and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue sacubitril and valsartan. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.1

Angioedema

Sacubitril and valsartan may cause angioedema. In the double-blind period of PARADIGM-HF, 0.5% of patients treated with sacubitril and valsartan and 0.2% of patients treated with enalapril had angioedema. If angioedema occurs, discontinue sacubitril and valsartan immediately, provide appropriate therapy, and monitor for airway compromise. Sacubitril and valsartan must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.1

Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway.1

Sacubitril and valsartan has been associated with a higher rate of angioedema in Black than in non-Black patients. 1

Patients with a prior history of angioedema may be at increased risk of angioedema with sacubitril and valsartan. Sacubitril and valsartan should not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.1

Hypotension

Sacubitril and valsartan lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. In the double-blind period of PARADIGM-HF, 18% of patients treated with sacubitril and valsartan and 12% of patients treated with enalapril reported hypotension as an adverse event, with hypotension reported as a serious adverse event in approximately 1.5% of patients in both treatment arms. Correct volume or salt depletion prior to administration of sacubitril and valsartan or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue sacubitril and valsartan. Permanent discontinuation of therapy is usually not required.1

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with sacubitril and valsartan. In the double-blind period of PARADIGM-HF, 5% of patients in both the sacubitril and valsartan and enalapril groups reported renal failure as an adverse event. In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt sacubitril and valsartan in patients who develop a clinically significant decrease in renal function. 1

As with all drugs that affect the RAAS, sacubitril and valsartan may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function.1

Hyperkalemia

Through its actions on the RAAS, hyperkalemia may occur with sacubitril and valsartan. In the double-blind period of PARADIGM-HF, 12% of patients treated with sacubitril and valsartan and 14% of patients treated with enalapril reported hyperkalemia as an adverse event. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of sacubitril and valsartan may be required. 1

Specific Populations

Pregnancy

Risk Summary: Sacubitril and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction studies, sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits. When pregnancy is detected, consider alternative drug treatment and discontinue sacubitril and valsartan. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Fetal/Neonatal Adverse Reactions: Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. 1

Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to sacubitril and valsartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to sacubitril and valsartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.1

Animal Data: Sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥ 49 mg sacubitril/51 mg valsartan/kg/day (≤ 0.14 [LBQ657, the active metabolite]- and 1.5 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses ≥ 5 mg sacubitril/5 mg valsartan/kg/day (4-fold and 0.06-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively). Sacubitril and valsartan is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a sacubitril and valsartan dose of ≥ 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of sacubitril and valsartan are attributed to the angiotensin receptor antagonist activity.1

Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (4.5-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with sacubitril and valsartan during organogenesis, gestation, and lactation may affect pup development and survival.1

Lactation

There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with sacubitril and valsartan. 1

Following an oral dose (15 mg sacubitril/15 mg valsartan/kg) of [14C] sacubitril and valsartan to lactating rats, transfer of LBQ657 into milk was observed. After a single oral administration of 3 mg/kg [14C] valsartan to lactating rats, transfer of valsartan into milk was observed. 1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. 1

Geriatric Use

No relevant pharmacokinetic differences have been observed in elderly (≥65 years) or very elderly (≥75 years) patients compared to the overall population. 1

Hepatic Impairment

No dose adjustment is required when administering sacubitril and valsartan to patients with mild hepatic impairment (Child-Pugh A classification). The recommended starting dose in patients with moderate hepatic impairment (Child-Pugh B classification) is 24/26 mg twice daily. The use of sacubitril and valsartan in patients with severe hepatic impairment (Child-Pugh C classification) is not recommended, as no studies have been conducted in these patients. 1

Renal Impairment

No dose adjustment is required in patients with mild (eGFR 60 to 90 mL/min/1.73 m2) to moderate (eGFR 30 to 60 mL/min/1.73 m2) renal impairment. The recommended starting dose in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) is 24/26 mg twice daily.1

Common Adverse Effects

Adverse reactions occurring ≥5% are hypotension, hyperkalemia, cough, dizziness, and renal failure.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Dual blockade of the renin-angiotensin system: Do not use with an ACEi, do not use with aliskiren in patients with diabetes, and avoid use with an ARB.1

  • Potassium-sparing diuretics: May lead to increased serum potassium.1

  • NSAIDs: May lead to increased risk of renal impairment.1

  • Lithium: Increased risk of lithium toxicity.1

Actions

Mechanism of Action

Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.1

Advice to Patients

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Patient Information).1

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to sacubitril and valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible.1

Angioedema: Advise patients to discontinue use of their previous ACE inhibitor or ARB. Advise patients to allow a 36 hour wash-out period if switching from or to an ACE inhibitor.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Tablet, Film Coated

24 mg sacubitril, 26 mg valsartan

Entresto

Novartis Pharmaceuticals Corporation

49 mg sacubitril, 51 mg valsartan

Entresto

Novartis Pharmaceuticals Corporation

97 mg sacubitril, 103 mg valsartan

Entresto

Novartis Pharmaceuticals Corporation

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 12, 2016
Last reviewed: September 12, 2016
Date modified: October 12, 2016

References

1. Novartis Pharmaceuticals Corporation. ENTRESTO (Sacubitril and Valsartan) ORAL prescribing information. 2015 Aug.

Hide