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Sacubitril and valsartan: Drug information

Sacubitril and valsartan: Drug information
(For additional information see "Sacubitril and valsartan: Patient drug information" and see "Sacubitril and valsartan: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Fetal toxicity:

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue sacubitril/valsartan as soon as possible.

Brand Names: US
  • Entresto
Brand Names: Canada
  • Entresto
Pharmacologic Category
  • Angiotensin II Receptor Blocker;
  • Neprilysin Inhibitor
Dosing: Adult

Note: Safety: Contains sacubitril (24 mg, 49 mg, or 97 mg) and valsartan (26 mg, 51 mg, or 103 mg). To reduce the risk of a prescribing error, include the dose of each component separately (eg, sacubitril 24 mg/valsartan 26 mg). Concomitant use of an angiotensin-converting enzyme (ACE) inhibitor is contraindicated; allow a 36-hour washout period when switching from an ACE inhibitor to sacubitril/valsartan. No washout period is necessary for patients previously on an angiotensin II receptor blocker (ARB) (Ref). Dosage forms: Valsartan in the combination tablet is more bioavailable than valsartan in other marketed tablet formulations; valsartan 26 mg, 51 mg, and 103 mg in the combination tablet is equivalent to valsartan 40 mg, 80 mg, and 160 mg in other marketed tablet formulations, respectively.

Heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction:

Note: Administer in place of an ACE inhibitor or ARB. Consider for use in hemodynamically stable patients with systolic BP ≥100 mm Hg, no increase in IV diuretic dose in the previous 6 hours, no use of an IV vasodilator in the previous 6 hours, no use of an IV inotrope in the previous 24 hours, and serum potassium <5 mEq/L. Monitor volume status and diuretic requirement throughout therapy; may need to reduce loop diuretic dose (Ref).

Patients previously taking a moderate to high dose of an ACE inhibitor (eg, >10 mg/day of enalapril or equivalent) or ARB (eg, >160 mg/day of valsartan or equivalent):

Oral: Initial: Sacubitril 49 mg/valsartan 51 mg twice daily. Double the dose as tolerated after ~2 to 4 weeks to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily.

Patients previously taking a low dose of an ACE inhibitor (eg, ≤10 mg/day of enalapril or equivalent) or ARB (eg, ≤160 mg/day of valsartan or equivalent):

Oral: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily. Double the dose as tolerated in ~2- to 4-week intervals to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily.

Patients not currently taking an ACE inhibitor or an ARB:

Oral: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily. Double the dose as tolerated in ~2- to 4-week intervals to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily.

Heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction:

Note: Consider for use after optimizing mineralocorticoid-receptor antagonist and sodium-glucose transport protein 2 receptor antagonist therapies, particularly in patients with ejection fraction <55%, patients who remain hypertensive, or who were recently hospitalized for heart failure (Ref).

Oral: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily or sacubitril 49 mg/valsartan 51 mg twice daily, depending on baseline BP. Double the dose as tolerated in ~2- to 4-week intervals to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function:

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary (Ref). Note: Exposure to the active metabolite, sacubitrilat, is approximately doubled in patients with eGFR 30 to 60 mL/minute/1.73 m2 (Ref); however, patients with mild to moderate kidney impairment were enrolled in clinical trials without dose adjustment (Ref).

eGFR <30 mL/minute/1.73 m2: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily. Double the dose as tolerated every 2 to 4 weeks to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily. Note: Safety and efficacy data are limited in this population, especially at eGFR <20 mL/minute/1.73 m2 (Ref).

Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed (valsartan and sacubitril are both highly protein bound) (Ref). Recommend dosing as though the patient has an eGFR <30 mL/minute/1.73 m2 (Ref). Note: Safety and efficacy data are limited in this population (Ref).

Peritoneal dialysis: Unlikely to be significantly dialyzed (valsartan and sacubitril are both highly protein bound) (Ref). Recommend dosing as though the patient has an eGFR <30 mL/minute/1.73 m2 (Ref). Note: Safety and efficacy data are limited in this population (Ref).

CRRT: Avoid use; no safety and efficacy data are available (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use; no safety and efficacy data are available (Ref).

Dosing: Hepatic Impairment: Adult

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Initial: Sacubitril 24 mg/valsartan 26 mg twice daily. Should be used with caution in patients with ascites due to cirrhosis (Ref).

Severe impairment (Child-Pugh class C): Use not recommended (has not been studied).

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Sacubitril and valsartan: Pediatric drug information")

Note: Entresto is a combination of sacubitril and valsartan. Use extra precautions when dosing. Dosing for the oral suspension is presented as the combined mg dose of sacubitril and valsartan. Dosing for the oral tablet is presented as the individual mg for each component.

An oral suspension may be extemporaneously prepared. The sacubitril:valsartan ratio varies slightly with each tablet strength; only the 49/51 mg tablets can be used to compound the oral suspension to achieve a combined sacubitril and valsartan concentration of 4 mg/mL (sacubitril 1.96 mg and valsartan 2.04 mg/mL) (see Extemporaneous Preparations). If switching between oral suspension and tablets, consider available strengths and adjust dose as needed.

The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; valsartan 26 mg, 51 mg, and 103 mg in Entresto is equivalent to valsartan 40 mg, 80 mg, and 160 mg in other marketed tablet formulations, respectively.

Heart failure, treatment

Heart failure, treatment: Note: Concomitant use of an angiotensin-converting enzyme (ACE) inhibitor is contraindicated; allow a 36-hour washout period when switching from or to an ACE inhibitor.

Patients previously taking a moderate to high dose ACE inhibitor (ie, ≥0.2 mg/kg/day or 10 mg/day of enalapril or equivalent) or angiotensin II receptor blocker (ARB):

Oral suspension (see Extemporaneous Preparations): Note: Dose presented as the combined mg dose of sacubitril and valsartan.

Children and Adolescents weighing <40 kg: Oral: Initial: 1.6 mg/kg/dose twice daily; titrate dose in 2 weeks to 2.3 mg/kg/dose twice daily, then 2 weeks later to 3.1 mg/kg/dose twice daily.

Tablets: Children and Adolescents:

40 to <50 kg: Oral: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily; titrate dose in 2 weeks to sacubitril 49 mg/valsartan 51 mg twice daily, then 2 weeks later to sacubitril 72 mg/valsartan 78 mg (three 24/26 mg tablets) twice daily.

≥50 kg: Oral: Initial: Sacubitril 49 mg/valsartan 51 mg twice daily; titrate dose in 2 weeks to sacubitril 72 mg/valsartan 78 mg (three 24/26 mg tablets) twice daily, then 2 weeks later to sacubitril 97 mg/valsartan 103 mg twice daily.

Patients not currently taking an ACE inhibitor or an ARB or previously taking low doses of an ACE inhibitor (ie, 0.1 mg/kg/day or 5 mg/day of enalapril or equivalent) or ARB:

Oral suspension (see Extemporaneous Preparations): Note: Dose presented as the combined mg dose of sacubitril and valsartan.

Children and Adolescents weighing ≤50 kg: Oral: Initial: 0.8 mg/kg/dose twice daily; titrate dose in 2 weeks to 1.6 mg/kg/dose twice daily, then 2 weeks later to 2.3 mg/kg/dose twice daily, then 2 weeks later to 3.1 mg/kg/dose twice daily.

Tablets: Children and Adolescents weighing >50 kg: Oral: Initial: Sacubitril 24 mg/valsartan 26 mg twice daily; titrate dose in 2 weeks to sacubitril 49 mg/valsartan 51 mg twice daily, then 2 weeks later to sacubitril 72 mg/valsartan 78 mg (three 24/26 mg tablets) twice daily, then 2 weeks later to sacubitril 97 mg/valsartan 103 mg twice daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children and Adolescents:

Mild to moderate impairment (eGFR ≥30 mL/minute/1.73 m2): No dosage adjustment necessary.

Severe impairment (eGFR <30 mL/minute/1.73 m2): Initial: Reduce the usual starting dose by 50%, then follow the recommended dose escalation to titrate dose.

Dosing: Hepatic Impairment: Pediatric

Children and Adolescents:

Mild impairment: No dosage adjustment necessary.

Moderate impairment: Initial: Reduce the usual starting dose by 50%, then follow the recommended dose escalation to titrate dose.

Severe impairment: Use not recommended (has not been studied).

Adverse Reactions (Significant): Considerations
Acute kidney injury

Sacubitril/valsartan may be associated with increased serum creatinine and/or acute kidney injury; increases in serum creatinine occurred less frequently than with angiotensin receptor blocker (ARB) therapy alone (Ref). Increases in serum creatinine secondary to ARBs usually stabilize within 20% to 30% from baseline and are expected; additional increases may indicate renal artery stenosis, volume depletion, or other explanations for kidney dysfunction (Ref).

Mechanism: Related to pharmacologic action; ARBs inhibit efferent renal arteriolar vasoconstriction, lowering glomerular filtration pressure which can lead to a modest reduction in glomerular filtration rate (GFR) (Ref). Neprilysin inhibition may increase renal natriuretic peptide bioavailability, leading to preserved kidney function, which could explain less frequent increases in serum creatinine with combination ARB and neprilysin inhibitor (Ref).

Onset: Expected to be similar to angiotensin-converting enzyme inhibitors: Intermediate; transient increases in serum creatinine generally occur within 2 weeks of ARB initiation and stabilize within 2 to 4 weeks (Ref).

Risk factors (ARB):

• Sodium or volume depletion (Ref)

• Heart failure (Ref)

• Concurrent diuretic or nonsteroidal anti-inflammatory drug use (Ref)

• Older patients

• Hypotension (Ref)

• Preexisting kidney impairment (Ref)

• Patients with low renal blood flow (eg, renal artery stenosis) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II (Ref)

Angioedema

Angioedema has been reported with sacubitril/valsartan (Ref). Although most reported cases are mild, some patients may require hospitalization including mechanical airway support (Ref).

Mechanism: Unknown; likely related to pharmacologic action. Inhibitors of neprilysin may increase bradykinin levels or block breakdown of A-type natriuretic peptide, and combination with valsartan may cause bradykinin overactivation (Ref).

Onset: Varied; similar to angioedema associated with angiotensin-converting enzyme inhibitors (ACEI) onset may occur at any time during treatment and may be significantly delayed. Cases have been reported during the first week of therapy but may also occur months to years after initiation (Ref).

Risk factors:

• Increased risk of angioedema with sacubitril/valsartan compared with angiotensin receptor blockers (Ref); similar risk with ACEIs (Ref)

• Black patients (similar to ACEIs) (Ref)

• Concurrent use with ACEI (contraindicated); sacubitril/valsartan should not be administered within 36 hours of switching from or to an ACEI (Ref)

• History of angioedema (contraindicated regardless of cause according to guidelines); risk is unknown, as patients with a history of angioedema were excluded from studies (Ref)

Hyperkalemia

Hyperkalemia may occur; however, studies have shown lower incidence of severe hyperkalemia than with angiotensin receptor blocker (ARB) therapy alone; neprilysin inhibition may attenuate hyperkalemia risk (Ref).

Mechanism: Related to the pharmacologic action; ARBs inhibit angiotensin II from binding to the adrenal receptor and interferes with generation of angiotensin II within the adrenal cortex, decreasing aldosterone release and impairing renal potassium excretion (Ref).

Onset: Generally occurs within 1 week of treatment initiation (Ref).

Risk factors:

• High dietary intake of potassium (Ref)

• Baseline elevated potassium (≥5 mmol/L) (Ref)

• Older patients (Ref)

• Kidney dysfunction (Ref)

• Diabetes mellitus (Ref)

• Higher NYHA heart failure class (Ref)

• Higher natriuretic peptide levels (Ref)

• Hypoaldosteronism

• Concurrent use of medications known to decrease renin and aldosterone (eg, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, cyclosporine, tacrolimus, beta-blockers, sulfamethoxazole/trimethoprim, azole antifungals) (Ref)

• Concurrent use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes (Ref)

Hypotension

Hypotension may occur during therapy initiation and occurs at a higher rate than with angiotensin receptor blocker (ARB) therapy alone. Proactive reduction in diuretic dose or initiation at a lower dose may be required; therapy discontinuation is generally not required (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Inhibition of the renin-angiotensin system and enhanced activity of natriuretic peptides leads to blood pressure lowering (Ref).

Onset: Rapid; however, delayed onset of up to 18 hours has been reported (Ref).

Risk factors:

• Higher dose (Ref)

• Rapid versus gradual titration (Ref)

• Concurrent antihypertensives

• Concurrent diuretic (or otherwise hypovolemic) (Ref)

• Lower baseline blood pressure (Ref)

• Older patients (Ref)

• ICD present (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults; adverse reactions in children and adolescents are consistent with those in adults. Also see individual agents.

>10%:

Cardiovascular: Hypotension (18%) (table 1)

Sacubitril and Valsartan: Adverse Reaction: Hypotension

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

18%

12%

Adults

4,203

4,229

Endocrine & metabolic: Hyperkalemia (12%) (table 2)

Sacubitril and Valsartan: Adverse Reaction: Hyperkalemia

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

12%

14%

Adults

4,203

4,229

Renal: Increased serum creatinine (16% to 17%) (table 3)

Sacubitril and Valsartan: Adverse Reaction: Increased Serum Creatinine

Drug (Sacubitril and Valsartan)

Comparator

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Comparator)

Comments

17%

Valsartan: 21%

Adults

2,407

2,389

Increases in serum creatinine of >50%

16%

Enalapril: 16%

Adults

4,203

4,229

Increases in serum creatinine of >50%

1% to 10%:

Cardiovascular: Orthostatic hypotension (2%) (table 4)

Sacubitril and Valsartan: Adverse Reaction: Orthostatic Hypotension

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

2%

1%

Adults

4,203

4,229

Hematologic & oncologic: Decreased hematocrit (≤7%), decreased hemoglobin (≤7%)

Hypersensitivity: Angioedema (Black patients: 2%; others: <1%) (table 5)

Sacubitril and Valsartan: Adverse Reaction: Angioedema

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

2%

0.5%

Black adult patients

N/A

N/A

0.5%

0.2%

Adult patients

4,203

4,229

Nervous system: Dizziness (6%), falling (2%)

Renal: Acute kidney injury (≤5%) (table 6), renal failure syndrome (≤5%) (table 7)

Sacubitril and Valsartan: Adverse Reaction: Acute Kidney Injury

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

Comments

≤5%

≤5%

Adults

4,203

4,229

Described as "renal failure/acute renal failure"

Sacubitril and Valsartan: Adverse Reaction: Renal Failure Syndrome

Drug (Sacubitril and Valsartan)

Comparator (Enalapril)

Population

Number of Patients (Sacubitril and Valsartan)

Number of Patients (Enalapril)

Comments

≤5%

≤5%

Adults

4,203

4,229

Described as "renal failure/acute renal failure"

Respiratory: Cough (9%)

Postmarketing:

Dermatologic: Pruritus, skin rash

Hypersensitivity: Anaphylaxis

Contraindications

Hypersensitivity to sacubitril, valsartan, or any component of the formulation; history of angioedema related to previous ACE inhibitor or ARB therapy; concomitant use or use within 36 hours of ACE inhibitors; concomitant use of aliskiren in patients with diabetes

Note: According to the ACC/AHA/HFSA guidelines, the use of sacubitril/valsartan is contraindicated in patients with a history of angioedema, regardless of cause (AHA/ACC/HFSA [Heidenreich 2022).

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Canadian labeling: Additional contraindications (not in US labeling): Recent symptomatic hypotension prior to initiation of treatment with sacubitril/valsartan; concomitant use of aliskiren in patients with moderate to severe kidney impairment (eGFR <60 mL/minute/1.73 m2); pregnancy; breastfeeding.

Warnings/Precautions

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and kidney function carefully to avoid rapid development of kidney failure (AASLD [Runyon 2013]).

• Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy, because of hypotension. Careful monitoring of BUN, serum creatinine, and potassium is necessary especially if preexisting kidney disease exists.

• Hepatic impairment: Use with caution and reduce dosage in patients with moderate hepatic impairment; use is not recommended in patients with severe hepatic impairment.

• Kidney impairment: Use with caution in preexisting kidney insufficiency; dose adjustment may be necessary.

Special populations:

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Entresto: Sacubitril 24 mg and valsartan 26 mg, Sacubitril 49 mg and valsartan 51 mg, Sacubitril 97 mg and valsartan 103 mg

Generic Equivalent Available: US

No

Pricing: US

Tablets (Entresto Oral)

24-26 mg (per each): $13.36

49-51 mg (per each): $13.36

97-103 mg (per each): $13.36

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Entresto: Sacubitril 24 mg and valsartan 26 mg, Sacubitril 49 mg and valsartan 51 mg, Sacubitril 97 mg and valsartan 103 mg

Administration: Adult

Oral: Administer with or without food.

Administration: Pediatric

Oral: Administer with or without food. If switching between oral suspension and tablets, consider available strengths and adjust dose as needed.

Use: Labeled Indications

Heart failure:

Adult: Reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with chronic HF. Benefits are most clearly evident in patients with left ventricular ejection fraction below normal.

Pediatric: Treatment of symptomatic HF with systemic left ventricular systolic dysfunction in pediatric patients ≥1 year of age.

Medication Safety Issues
High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Angiotensin II: Receptor Blockers may diminish the therapeutic effect of Angiotensin II. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Risk X: Avoid combination

Antihepaciviral Combination Products: May increase the serum concentration of Valsartan. Management: Consider decreasing the valsartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Atorvastatin: Sacubitril may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Encorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Finerenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy

Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Leflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Leniolisib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination

Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Initiate lithium at lower doses in patients receiving an angiotensin II receptor blocker (ARB). Consider lithium dose reductions in patients stable on lithium therapy who are initiating an ARB. Monitor lithium concentrations closely when combined. Risk D: Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of Angiotensin II Receptor Blockers. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Polyethylene Glycol-Electrolyte Solution: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy

Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy

Pretomanid: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Ranolazine: May enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy

Sparsentan: May enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Risk X: Avoid combination

Tacrolimus (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy

Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Trofinetide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider therapy modification

Urapidil: Antihypertensive Agents may enhance the hypotensive effect of Urapidil. Risk C: Monitor therapy

Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Pregnancy Considerations

[US Boxed Warning]: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue sacubitril/valsartan as soon as possible. Refer to the valsartan monograph for additional information.

Breastfeeding Considerations

It is not known if sacubitril or valsartan is present in breast milk. Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Monitoring Parameters

At baseline, within 1 to 2 weeks after initiation, and after dose changes, reassess BP (including postural BP changes), kidney function, and serum potassium (especially for patients taking concomitant potassium-sparing diuretics, potassium supplements, and/or potassium containing salts). Patients with systolic BP <80 mm Hg, low serum sodium, diabetes mellitus, and impaired kidney function should be closely monitored.

Mechanism of Action

Sacubitril: Prodrug that inhibits neprilysin (neutral endopeptidase) through the active metabolite LBQ657, leading to increased levels of peptides, including natriuretic peptides; induces vasodilation and natriuresis (Hubers 2016).

Valsartan: Produces direct antagonism of the angiotensin II (AT2) receptors. Displaces angiotensin II from the AT1 receptor; antagonizes AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Vd: Sacubitril: 103 L; Valsartan: 75 L

Protein binding: 94% to 97%

Metabolism:

Sacubitril: Converted to active metabolite LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent

Valsartan: Minimally metabolized (~20%; <10% as a hydroxyl metabolite)

Bioavailability: Sacubitril: ≥60%

Half-life elimination: Sacubitril: 1.4 hours; LBQ657: 11.5 hours; Valsartan: 9.9 hours

Time to peak: Sacubitril: 0.5 hours; LBQ657: 2 hours; Valsartan: 1.5 hours

Excretion:

Sacubitril: Urine (52% to 68%, primarily as LBQ657); feces (37% to 48%, primarily as LBQ657)

Valsartan: Urine (~13%, parent drug and metabolites); feces (86%, parent drug and metabolites)

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Entresto;
  • (AR) Argentina: Entresto | Hiperval plus | Neparvis;
  • (AT) Austria: Entresto | Neparvis;
  • (AU) Australia: Entresto;
  • (BD) Bangladesh: Arnigen | Sabitar;
  • (BE) Belgium: Entresto;
  • (BG) Bulgaria: Entresto;
  • (BR) Brazil: Entresto;
  • (CH) Switzerland: Entresto;
  • (CL) Chile: Entresto;
  • (CN) China: Entresto | Sacubitril valsartan sodium;
  • (CO) Colombia: Entresto;
  • (CZ) Czech Republic: Entresto;
  • (DE) Germany: Entresto;
  • (DO) Dominican Republic: Vymada;
  • (EC) Ecuador: Entresto;
  • (EE) Estonia: Entresto;
  • (EG) Egypt: Entresto;
  • (ES) Spain: Entresto | Neparvis;
  • (ET) Ethiopia: Uperio;
  • (FI) Finland: Entresto;
  • (FR) France: Entresto;
  • (GB) United Kingdom: Entresto | Neparvis;
  • (GR) Greece: Entresto | Neparvis;
  • (HK) Hong Kong: Entresto;
  • (HR) Croatia: Entresto;
  • (HU) Hungary: Entresto;
  • (ID) Indonesia: Uperio;
  • (IE) Ireland: Entresto;
  • (IN) India: Azmarda | Cidmus | Valsac | Vymada;
  • (IT) Italy: Entresto;
  • (JO) Jordan: Entresto;
  • (JP) Japan: Entresto;
  • (KR) Korea, Republic of: Entresto | Xnepri;
  • (KW) Kuwait: Entresto;
  • (LB) Lebanon: Entresto;
  • (LT) Lithuania: Entresto;
  • (LU) Luxembourg: Entresto;
  • (LV) Latvia: Entresto;
  • (MA) Morocco: Uperio;
  • (MX) Mexico: Entresto;
  • (MY) Malaysia: Entresto;
  • (NG) Nigeria: Entresto;
  • (NL) Netherlands: Entresto;
  • (NO) Norway: Entresto;
  • (NZ) New Zealand: Entresto;
  • (PE) Peru: Entresto;
  • (PH) Philippines: Entresto | Vymada;
  • (PK) Pakistan: Cubil | Sacuval | Sacuvia | Sacvin | Savesto | Uperio | Valsar s | Valsatril;
  • (PL) Poland: Entresto;
  • (PR) Puerto Rico: Entresto;
  • (PT) Portugal: Entresto | Neparvis;
  • (PY) Paraguay: Diusartan;
  • (RO) Romania: Entresto;
  • (RU) Russian Federation: Entresto | Uperio;
  • (SA) Saudi Arabia: Entresto;
  • (SE) Sweden: Entresto;
  • (SG) Singapore: Entresto;
  • (SI) Slovenia: Entresto;
  • (SK) Slovakia: Entresto;
  • (TH) Thailand: Entresto;
  • (TN) Tunisia: Entresto;
  • (TR) Turkey: Oneptus;
  • (TW) Taiwan: Entresto;
  • (UA) Ukraine: Uperio;
  • (UY) Uruguay: Entresto;
  • (ZA) South Africa: Entresto
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