Sacubitril and valsartan: Drug information

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

For abbreviations, symbols, and age group definitions 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

Dosage guidance:

Safety: Entresto contains sacubitril and valsartan. To reduce the risk of a prescribing error, include the dose of each component separately (eg, sacubitril 24 mg/valsartan 26 mg).

Dosage form information: 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: Sacubitril/valsartan is a replacement for an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). 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 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 1 to 2 weeks to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily (Ref).

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 1- to 2-week intervals to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily (Ref).

Patients not currently taking an ACE inhibitor or an ARB:

Heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction:

Note: Sacubitril/valsartan is a replacement for an ACE inhibitor or ARB. 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 ARB. 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 1 to 2 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: Liver 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")

Dosage guidance:

Safety: Entresto is a combination of sacubitril and valsartan. Use extra caution when dosing.

Dosing: Dosing for the oral suspension is presented as the combined mg dose of sacubitril and valsartan. Dosing for the oral pellets (Entresto Sprinkle capsule) and oral tablets is presented as the individual mg dose for each component.

Dosage form information: 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 per mL) (see "Extemporaneous Preparations"). If switching between dosage forms (oral pellets [Entresto Sprinkle capsule], oral suspension, and tablets), consider available strengths and adjust dose as needed.

Clinical considerations: 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 pellets (Entresto Sprinkle capsule): Note: Oral pellets are contained within capsule shell; do not swallow capsules or consume capsule shell.

Children and Adolescents:

13 to <19 kg: Oral: Initial: Sacubitril 12 mg/valsartan 12 mg (two 6/6 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 18 mg/valsartan 18 mg (three 6/6 mg capsules) twice daily, then 2 weeks later to sacubitril 24 mg/valsartan 24 mg (four 6/6 mg capsules) twice daily.

19 to <26 kg: Oral: Initial: Sacubitril 18 mg/valsartan 18 mg (three 6/6 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 24 mg/valsartan 24 mg (four 6/6 mg capsules) twice daily, then 2 weeks later to sacubitril 30 mg/valsartan 32 mg (two 15/16 mg capsules) twice daily.

26 to <34 kg: Oral: Initial: Sacubitril 24 mg/valsartan 24 mg (four 6/6 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 30 mg/valsartan 32 mg (two 15/16 mg capsules) twice daily, then 2 weeks later to sacubitril 45 mg/valsartan 48 mg (three 15/16 mg capsules) twice daily.

34 to <50 kg: Oral: Initial: Sacubitril 30 mg/valsartan 32 mg (two 15/16 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 45 mg/valsartan 48 mg (three 15/16 mg capsules) twice daily, then 2 weeks later to sacubitril 60 mg/valsartan 64 mg (four 15/16 mg capsules) twice daily.

Oral suspension (extemporaneously prepared 4 mg/mL [sacubitril 1.96 mg and valsartan 2.04 mg per mL] oral suspension): 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 (one 24/26 mg tablet) twice daily; titrate dose in 2 weeks to sacubitril 49 mg/valsartan 51 mg (one 49/51 mg tablet) 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 (one 49/51 mg tablet) 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 (one 97/103 mg tablet) 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 pellets (Entresto Sprinkle capsule): Note: Oral pellets are contained within capsule shell; do not swallow capsules or consume capsule shell.

Children and Adolescents:

26 to <34 kg: Oral: Initial: Sacubitril 12 mg/valsartan 12 mg (two 6/6 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 24 mg/valsartan 24 mg (four 6/6 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 30 mg/valsartan 32 mg (two 15/16 mg capsules) twice daily, then 2 weeks later to sacubitril 45 mg/valsartan 48 mg (three 15/16 mg capsules) twice daily.

34 to <50 kg: Oral: Initial: Sacubitril 15 mg/valsartan 16 mg (one 15/16 mg capsule) twice daily; titrate dose in 2 weeks to sacubitril 30 mg/valsartan 32 mg (two 15/16 mg capsules) twice daily; titrate dose in 2 weeks to sacubitril 45 mg/valsartan 48 mg (three 15/16 mg capsules) twice daily, then 2 weeks later to sacubitril 60 mg/valsartan 64 mg (four 15/16 mg capsules) twice daily.

Oral suspension (extemporaneously prepared 4 mg/mL [sacubitril 1.96 mg and valsartan 2.04 mg per mL] oral suspension): 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 (one 24/26 mg tablet) twice daily; titrate dose in 2 weeks to sacubitril 49 mg/valsartan 51 mg (one 49/51 mg tablet) 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 (one 97/103 mg tablet) 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):

Oral pellets (Entresto Sprinkle capsules): Note: Oral pellets are contained within capsule shell; do not swallow capsules or consume capsule shell.

Oral suspension (extemporaneously prepared 4 mg/mL [sacubitril 1.96 mg and valsartan 2.04 mg per mL] oral suspension): Note: Dose presented as the combined mg dose of sacubitril and valsartan.

Dosing: Liver Impairment: Pediatric

Children and Adolescents:

Mild impairment: No dosage adjustment necessary.

Moderate impairment:

Oral pellets (Entresto Sprinkle capsules): Note: Oral pellets are contained within capsule shell; do not swallow capsules or consume capsule shell.

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)Hypotension

**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)Hyperkalemia

**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)Increased Serum Creatinine

**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)Orthostatic Hypotension

**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)Angioedema

**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)Acute Kidney Injury, renal failure syndrome (≤5%) (table 7)Renal Failure Syndrome

**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.

Capsule Sprinkle, Oral:

Entresto: Sacubitril 6 mg and valsartan 6 mg, Sacubitril 15 mg and valsartan 16 mg

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

Pricing: US

Capsule, sprinkles (Entresto Oral)

6-6 mg (per each): $14.10

15-16 mg (per each): $14.10

Tablets (Entresto Oral)

24-26 mg (per each): $14.10

49-51 mg (per each): $14.10

97-103 mg (per each): $14.10

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.

Suspension (extemporaneously prepared 4 mg/mL [sacubitril 1.96 mg and valsartan 2.04 mg per mL] oral suspension): Shake well before use. Measure dose with accurate measuring device; do not use a household teaspoon (overdosage may occur).

Administration: Pediatric

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

Oral pellets (Entresto Sprinkle capsule): Open capsule and sprinkle the full contents onto 1 to 2 teaspoons of soft food. Administer food containing oral pellets immediately. Discard empty capsule shells. Do not swallow capsules/shell containing oral pellets. Do not chew or crush oral pellets. For oral administration only; do not administer via nasogastric, gastrostomy, or other enteral tubes (may cause obstruction).

Oral suspension (extemporaneously prepared 4 mg/mL [sacubitril 1.96 mg and valsartan 2.04 mg per mL] oral suspension): Shake well before use. Measure dose with accurate measuring device; do not use a household teaspoon (overdosage may occur).

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 which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Long-Term Care Settings).

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 drug interactions program by clicking on the “Launch drug interactions program” link above.

Alfuzosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Aliskiren: May increase nephrotoxic effects of Angiotensin II Receptor Blockers. Aliskiren may increase hyperkalemic effects of Angiotensin II Receptor Blockers. Aliskiren may increase hypotensive effects 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 increase hypotensive effects 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 increase hypotensive effects of Hypotension-Associated Agents. Risk C: Monitor

Amphetamines: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor

Angiotensin II: Angiotensin II Receptor Blockers may decrease therapeutic effects of Angiotensin II. Risk C: Monitor

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

Antihepaciviral Combination Products: May increase 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 increase hypotensive effects of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor

Arginine: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

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

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

Barbiturates: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Belumosudil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid coadministration of belumosudil with these substrates of OATP1B1/1B3 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the OATP1B1/1B3 substrate may be required. Risk D: Consider Therapy Modification

Benperidol: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Brigatinib: May decrease antihypertensive effects of Antihypertensive Agents. Brigatinib may increase bradycardic effects of Antihypertensive Agents. Risk C: Monitor

Brimonidine (Topical): May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Bromperidol: May decrease hypotensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase hypotensive effects of Bromperidol. Risk X: Avoid

Bulevirtide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Coadministration of bulevirtide with OATP1B1/1B3 (also known as SLCO1B1/1B3) substrates should be avoided when possible. If used together, close clinical monitoring is recommended. Risk D: Consider Therapy Modification

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

Dapoxetine: May increase orthostatic hypotensive effects of Angiotensin II Receptor Blockers. Risk C: Monitor

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

Dexmethylphenidate: May decrease therapeutic effects of Antihypertensive Agents. Risk C: Monitor

Diazoxide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Dipeptidyl Peptidase-IV Inhibitors: May increase adverse/toxic effects of Angiotensin II Receptor Blockers. Specifically, the risk for angioedema may be increased with this combination. Risk C: Monitor

Drospirenone-Containing Products: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

DULoxetine: Blood Pressure Lowering Agents may increase hypotensive effects of DULoxetine. Risk C: Monitor

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

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

Finerenone: Angiotensin II Receptor Blockers may increase hyperkalemic effects of Finerenone. Risk C: Monitor

Flunarizine: May increase therapeutic effects of Antihypertensive Agents. Risk C: Monitor

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

Heparin: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Heparins (Low Molecular Weight): May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Herbal Products with Blood Pressure Increasing Effects: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor

Herbal Products with Blood Pressure Lowering Effects: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Iloperidone: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Indoramin: May increase hypotensive effects of Antihypertensive Agents. Risk C: Monitor

Isocarboxazid: May increase antihypertensive effects of Antihypertensive Agents. Risk X: Avoid

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

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

Levodopa-Foslevodopa: Blood Pressure Lowering Agents may increase hypotensive effects of Levodopa-Foslevodopa. Risk C: Monitor

Lithium: Angiotensin II Receptor Blockers may increase 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 increase hypotensive effects of Angiotensin II Receptor Blockers. Loop Diuretics may increase nephrotoxic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Lormetazepam: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Metergoline: May decrease antihypertensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase orthostatic hypotensive effects of Metergoline. Risk C: Monitor

Methylphenidate: May decrease antihypertensive effects of Antihypertensive Agents. Risk C: Monitor

Molsidomine: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Naftopidil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Nicergoline: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Nicorandil: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Nicorandil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Nitroprusside: Blood Pressure Lowering Agents may increase hypotensive effects of Nitroprusside. Risk C: Monitor

Nonsteroidal Anti-Inflammatory Agents (Topical): May decrease therapeutic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

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

Obinutuzumab: May increase hypotensive effects 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 increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Perazine: May increase hypotensive effects of Antihypertensive Agents. Risk C: Monitor

Pholcodine: Blood Pressure Lowering Agents may increase hypotensive effects of Pholcodine. Risk C: Monitor

Phosphodiesterase 5 Inhibitors: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Polyethylene Glycol-Electrolyte Solution: Angiotensin II Receptor Blockers may increase nephrotoxic effects of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor

Potassium Salts: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Potassium-Sparing Diuretics: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Prazosin: Antihypertensive Agents may increase hypotensive effects of Prazosin. Risk C: Monitor

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

Prostacyclin Analogues: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Quinagolide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

Ranolazine: May increase adverse/toxic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Silodosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor

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

Sparsentan: May increase adverse/toxic effects of Angiotensin II Receptor Blockers. Risk X: Avoid

Tacrolimus (Systemic): Angiotensin II Receptor Blockers may increase hyperkalemic effects of Tacrolimus (Systemic). Risk C: Monitor

Terazosin: Antihypertensive Agents may increase hypotensive effects of Terazosin. Risk C: Monitor

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

Tolvaptan: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Trimethoprim: May increase hyperkalemic effects of Angiotensin II Receptor Blockers. Risk C: Monitor

Trofinetide: May increase 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 increase hypotensive effects of Urapidil. Risk C: Monitor

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

Pregnancy Considerations

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

Refer to the valsartan monograph for additional information.

Breastfeeding Considerations

Sacubitril and its active metabolite LBQ657 are present in human milk; the presence of valsartan is not known.

Data related to the presence of sacubitril in human milk are available from 5 lactating patients who were ~11 days to 23 months postpartum. All patients were taking oral sacubitril 24 mg/valsartan 26 mg twice daily at the time of the study. Breast milk was sampled over 12 hours once patients were at steady state. The highest breast milk concentrations occurred 1 hour after the maternal dose for sacubitril and 4 hours after the dose for LBQ657. Valsartan concentrations were below the limit of quantification (<0.19 ng/mL) in all samples. Using the average milk concentration for sacubitril (1.52 ng/mL), authors of the study calculated the estimated infant dose via breast milk to be 0.00049 mg/kg per 12 hours, providing a relative infant dose (RID) of 0.01% compared to the weight-adjusted maternal dose. The estimated infant dose via breast milk for LBQ657 was calculated to be 0.00071 mg/kg per 12 hours, providing a RID of 0.22% compared to the weight-adjusted maternal dose using an average breast milk concentration of 12.2 ng/mL. Two mothers breastfed their children throughout the study. Adverse events were not observed in either child, one who was full breastfed and one who was partially breastfed (Falconi 2024). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). None of the mothers in this study were taking the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily (Falconi 2024).

Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer. Refer to the Valsartan monograph for additional information.

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: V_d: 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: Dupertan | Entresto | Hiperval plus | Neparvis | Ristonel;
(AT) Austria: Entresto | Neparvis;
(AU) Australia: Entresto;
(BD) Bangladesh: Arnigen | Arnis | Arnivas | Nepitan | Sabitar | Sacutril | Savatril | Valmor | Vivanta;
(BE) Belgium: Entresto;
(BG) Bulgaria: Entresto;
(BR) Brazil: Entresto;
(CH) Switzerland: Entresto;
(CL) Chile: Entresto;
(CN) China: Entresto | Sacubitril valsartan sodium;
(CO) Colombia: Entresto | Neparvis;
(CZ) Czech Republic: Entresto;
(DE) Germany: Entresto;
(DO) Dominican Republic: Valsartec plus | 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: Alsectan | Arney | Arnicor | Arnipin | Arnisac | Arniv | Arnoza | Arnx | Azmarda | Carmada | Cedamada | Cidmus | Exduo | Hefcard | Hftril | Mymarda | Neptaz | Refsav | Remada | Sac v | Sacu v | Sacuhart | Saculysin | Sacumada | Sacurise | Sacutan | Sacuval | Sav hf | Sutval | Valentas | Valsac | Vymada | Zayo | Zuvatan;
(IQ) Iraq: Diotril;
(IT) Italy: Entresto;
(JO) Jordan: Entresto;
(JP) Japan: Entresto;
(KE) Kenya: Uperio;
(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 | Neparvis;
(MY) Malaysia: Entresto;
(NG) Nigeria: Entresto;
(NL) Netherlands: Entresto;
(NO) Norway: Entresto;
(NZ) New Zealand: Entresto;
(PE) Peru: Entresto | Terovan;
(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;
(QA) Qatar: Entresto;
(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: Neprilex | Oneptus;
(TW) Taiwan: Entresto;
(UA) Ukraine: Uperio;
(UY) Uruguay: Entresto;
(VE) Venezuela, Bolivarian Republic of: Neblum;
(ZA) South Africa: Entresto

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Topic 102505 Version 243.0

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Sacubitril and valsartan: Drug information