Dosing & Uses
Dosage Forms & Strengths
sacubitril/valsartan
film-coated tablet
- 24mg/26mg
- 49mg/51mg
- 97mg/103mg
Heart Failure
Indicated to reduce risk of cardiovascular death and hospitalization in chronic heart failure (CHF) (NYHA class II-IV) and reduced ejection fraction
Recommended starting dose: 49 mg/51 mg PO BID
Target maintenance dose: After 2-4 weeks, double the dose to 97 mg/103 mg PO BID as tolerated
Dosage Modifications
Patients not taking an ACE inhibitor or other ARB, or previously taking a low dose of these agents when initiating treatment
- Reduce starting dose to 24 mg/26 mg BID
- Double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated
Renal impairment
- Mild-to-moderate (eGFR ≥30 mL/min/1.73 m²): No starting dose adjustment required
- Severe (eGFR <30 mL/min/1.73 m²): Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated
Hepatic impairment
- Mild (Child-Pugh A): No starting dose adjustment required
- Moderate (Child-Pugh B): Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated
- Severe (Child-Pugh C): Not recommended
Dosing Considerations
Contraindicated with concomitant use of an ACE inhibitor; if switching from an ACE inhibitor to sacubitril/valsartan, allow a washout period of 36 hr between administration of the 2 drugs
Usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB
sacubitril/valsartan
tablet
- 24mg/26mg
- 49mg/51mg
- 97mg/103mg
Heart Failure
Indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged ≥1 year; reduces NT-proBNP and is expected to improve cardiovascular outcomes
<1 year: Safety and efficacy not established
≥1 year
- Adjust dose q2Weeks, as tolerated
-
<40 kg
- Starting dose: 1.6 mg/kg PO BID
- Second titration: 2.3mg/kg PO BID
- Not to exceed 3.1 mg/kg PO BID
- Use oral suspension
- Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan
-
≥40 kg and <50 kg
- Starting dose: 24/26 mg PO BID
- Second titration: 49/51 mg PO BID
- Not to exceed 72/78 mg (three 24/26-mg tablets) PO BID
-
≥50 kg
- Starting dose: 49/51 mg PO BID
- Second titration: 72/78 (three 24/26-mg tablets) PO BID
- Not to exceed 97/103 PO BID
Dosage Modifications
Patients not taking an ACE inhibitor or other ARB, or previously taking a low dose of these agents when initiating treatment
- Start at half the recommended starting dose
- After initiation, increase dose as per the recommended dose escalation thereafter
- Patients weighing 40-50 kg who meet this criterion: Initiate at 0.8 mg/kg BID using oral suspension
Renal impairment
- Mild-to-moderate (eGFR ≥30 mL/min/1.73 m2): No starting dose adjustment required
-
Severe (eGFR <30 mL/min/1.73 m2)
- Start at half the recommended starting dose
- After initiation, increase dose as per the recommended dose escalation thereafter
- Patients weighing 40-50 kg who meet this criterion: Initiate at 0.8 mg/kg BID using oral suspension
Hepatic impairment
- Mild (Child-Pugh A): No starting dose adjustment required
-
Moderate (Child-Pugh B)
- Start at half the recommended starting dose
- After initiation, increase dose as per the recommended dose escalation thereafter
- Patients weighing 40-50 kg who meet this criterion: Initiate at 0.8 mg/kg BID using oral suspension
- Severe (Child-Pugh C): Not recommended
Dosing Considerations
Contraindicated with concomitant use of an ACE inhibitor; if switching from an ACE inhibitor to sacubitril/valsartan, allow a washout period of 36 hr between the administrations of the 2 drugs
Usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10%
Hypotension (18%)
Hyperkalemia (12%)
1-10%
Cough (9%)
Dizziness (6%)
Orthostasis (2.1%)
Falls (1.9%)
<1%
Angioedema, all patients (0.5%); in black patients (2.4%)
Hypersensitivity (rash, pruritus, anaphylaxis)
Warnings
Black Box Warnings
Fetal toxicity
- Discontinue as soon as possible when pregnancy is detected
- Drug affects renin-angiotensin system, causing oligohydramnios, which may result in fetal injury or death
Contraindications
Hypersensitivity to any component
History of angioedema related to previous ACE inhibitor or ARB therapy
Coadministration of neprilysin inhibitors (eg, sacubitril) with ACE inhibitors may increase angioedema risk; do not administer ACE inhibitors within 36 hr of switching to or from sacubitril/valsartan
Concomitant use with aliskiren in patients with diabetes
Cautions
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 (see Black Box Warnings)
Not for use in patients with hereditary angioedema; observe for signs and symptoms of angioedema; if angioedema occurs, discontinue drug immediately, provide appropriate therapy, and monitor for airway compromise
Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension; patients who are volume-depleted or salt-depleted, or those taking diuretics, are at greater risk
Drug interaction overview
-
Dual blockade of the renin-angiotensin-aldosterone system
- Coadministration with an ACE inhibitor is contraindicated because of the increased risk of angioedema
- Avoid use with an ARB, because drug contains the angiotensin II receptor blocker valsartan
- Concomitant use with aliskiren is contraindicated in patients with diabetes
-
Potassium-sparing diuretics
- As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium
-
Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with sacubitril/valsartan may result in worsening of renal function, including possible acute renal failure
- Effects are usually reversible; monitor renal function periodically
-
Lithium
- Increases in serum lithium concentrations and lithium toxicity have been reported during coadministration of lithium with angiotensin II receptor antagonists; monitor serum lithium levels
- Monitor renal function and potassium levels in susceptible patients (eg, diabetes, hypoaldosteronism, high-potassium diet, renal artery stenosis); dosage reduction or interruption may be required
Pregnancy
Pregnancy
Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, resulting oligohydramnios may cause fetal injury (eg, hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure) and death
Neonates with a history of in utero exposure: Direct attention toward support of blood pressure and renal perfusion; exchange transfusions or dialysis may be required
Lactation
Unknown if distributed in human breast milk; not recommended
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Combination is an angiotensin receptor-neprilysin inhibitor (ARNi)
Sacubitril: Neprilysin inhibitor; neprilysin is responsible for degradation of atrial and brain natriuretic peptide; the cardiovascular and renal effects of sacubitril’s active metabolite (LBQ657) in heart failure are attributed to the increased levels of peptides that are degraded by neprilysin (eg, natriuretic peptide); administration results in increased natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP
Valsartan: Angiotensin II receptor type I inhibitor; decreases blood pressure and blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II
Absorption
Absolute bioavailability
- Sacubitril: ≥60%
- Valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Entresto is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively
Steady-state
- Reached in 3 days
- At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold
Peak plasma concentration
- Sacubitril: 0.5 hr
- LBQ657: 2 hr
- Valsartan: 1.5 hr
Distribution
Protein bound
- Sacubitril: 94-97%
- LBQ657: 94-97%; LBQ657 crosses the blood-brain barrier to a limited extent (0.28%)
- Valsartan: 94-97%
Vd
- Sacubitril: 103 L
- Valsartan: 75 L
Metabolism
Sacubitril is a prodrug that is metabolized by esterases to the active metabolite LBQ657
LBQ657 is not further metabolized to a significant extent
Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites; a hydroxyl metabolite has been identified in plasma at low concentrations (<10%)
Elimination
Half-life
- Sacubitril: 1.4 hr
- LBQ657: 11.5 hr
- Valsartan: 9.9 hr
Excretion
- Sacubitril: 52-68% (primarily as LBQ657) in urine; 37-48% (primarily as LBQ657) in feces
- Valsartan: 13% in urine; 86% in feces
Administration
Oral Suspension Preparation
Oral suspension can be substituted in patients unable to swallow tablets
Prepare an oral suspension in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL)
Transfer eight 49/51-mg tablets into a mortar
Crush tablets into a fine powder using a pestle
Add 60 mL of Ora-Plus into mortar and triturate gently with pestle for 10 min, to form a uniform suspension
Add 140 mL of Ora-Sweet into mortar and triturate with pestle for another 10 min, to form a uniform suspension; resulting in a final concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL)
Transfer entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle
Place a press-in bottle adapter and close the bottle with a child resistant cap
Oral Administration
May take with or without food
Use oral suspension for the following
- Pediatric patients <40 kg
- Pediatric patients 40-50 kg who are not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents
- Pediatric patients 40-50 kg who are renally or hepatically impaired
Storage
Prepared oral suspension
- Store <25ºC (77ºF) for up to 15 days and do not refrigerate
- Shake before each use
Tablets
- Store at controlled room temperature (25ºC [77ºF]), with excursions between 15-30ºC (59-86ºF) permitted
- Protect from moisture
- Store in the original package
Images
Patient Handout
Formulary
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