sacubitril/valsartan (Entresto)

Dosing and uses of Entresto (sacubitril/valsartan)

• Adult
• Pediatric

 

Adult dosage forms and 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

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Entresto (sacubitril/valsartan) adverse (side) 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%)

 

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

Should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of ACE inhibitor

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)

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

 

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 of Entresto (sacubitril/valsartan)

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

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