sacubitril/valsartan (Rx)

Brand and Other Names:Entresto
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

sacubitril/valsartan

film-coated tablet

  • 24mg/26mg
  • 49mg/51mg
  • 97mg/103mg

Heart Failure

Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with 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 the target maintenance dose of 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

Safety and efficacy not established

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Interactions

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            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)

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            Warnings

            Black Box Warnings

            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

            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

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            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.

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            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
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            Administration

            Instructions

            May take with or without food

            Storage

            Store at controlled room temperature (25°C [77°F]), with excursions between 15-30°C (59-86°F) permitted

            Protect from moisture

            Store in the original package

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.