ENTRESTO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ENTRESTO (ENTRESTO).

How it works

Entresto is a combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker). Sacubitril inhibits neprilysin, increasing levels of natriuretic peptides and bradykinin, leading to vasodilation, natriuresis, and reduced sympathetic tone. Valsartan blocks AT1 receptors, reducing vasoconstriction, aldosterone release, and cardiac remodeling.

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to sacubitrilat (active moiety). Valsartan is metabolized minimally via CYP2C9 (less than 20%), with the remainder excreted unchanged. Both agents are substrates of OATP1B1/1B3 transporters.
Excretion	Approximately 51-68% of sacubitril and 37-48% of valsartan are excreted in urine; the remainder is eliminated in feces via biliary excretion.
Half-life	Sacubitril: 1.4 hours; Sacubitrilat (active metabolite): 11.5 hours; Valsartan: 6.1 hours. The effective half-life for the ARNI effect is driven by sacubitrilat, allowing twice-daily dosing.
Protein binding	Sacubitril: 94-97%; Sacubitrilat: 94-97%; Valsartan: 95%, primarily to albumin.
Volume of Distribution	Sacubitril: 103 L; Valsartan: 75 L (approximately 1.17 L/kg for sacubitril and 0.85 L/kg for valsartan based on 70 kg), indicating extensive extravascular distribution.
Bioavailability	Oral bioavailability of sacubitril/valsartan is >60% based on urinary recovery; food has no significant effect.
Onset of Action	Hemodynamic effects (reduction in blood pressure) observed within 1-2 hours after oral administration.
Duration of Action	Clinical effects (e.g., blood pressure reduction) persist for approximately 24 hours with twice-daily dosing. Steady state is reached within 3-5 days.

Classification & Brands

Dosing & administration

Initial: 24 mg sacubitril/26 mg valsartan orally twice daily; double dose every 2-4 weeks to target maintenance of 97 mg sacubitril/103 mg valsartan twice daily.

Dosage form	TABLET
Renal impairment	eGFR ≥30 mL/min/1.73 m2: no adjustment; eGFR <30 mL/min/1.73 m2: not recommended; avoid if eGFR <15 mL/min/1.73 m2.
Liver impairment	Child-Pugh Class A: no adjustment; Child-Pugh Class B: initial 24 mg/26 mg twice daily; Child-Pugh Class C: not recommended.
Pediatric use	Age ≥1 year: start at 0.8 mg/kg sacubitril/0.8 mg/kg valsartan (as sacubitril/valsartan) twice daily; titrate to target of 3.1 mg/kg/3.1 mg/kg twice daily based on tolerability. Maximum single dose 3.1 mg/kg/3.1 mg/kg.
Geriatric use	No specific dose adjustment; start at low end of dosing range (24 mg/26 mg twice daily) due to potential for renal impairment and hypotension; monitor closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ENTRESTO (ENTRESTO).

Breastfeeding	No human data; present in rat milk. M/P ratio unknown. Avoid breastfeeding due to potential adverse effects in infant.
Teratogenic Risk	Category D in second and third trimesters due to oligohydramnios, fetal renal dysfunction, skull ossification defects, and neonatal morbidity/mortality. Avoid in first trimester unless no alternative.
Fetal Monitoring	Monitor fetal renal function via ultrasound; assess amniotic fluid volume; perform serial fetal growth scans. Monitor maternal blood pressure and renal function.

Warnings & precautions

■ FDA Black Box Warning

WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Entresto as soon as possible. Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Concomitant use with ACE inhibitors (do not start within 36 hours of ACE inhibitor discontinuation)","History of angioedema related to previous ACE inhibitor or ARB therapy","Bilateral renal artery stenosis","Pregnancy","Severe hepatic impairment (Child-Pugh C)","Hypersensitivity to any component"]

Clinical Precautions

Precautions

["Angioedema (risk increased with prior ACE inhibitor use)","Hypotension (symptomatic, especially in volume-depleted patients)","Renal impairment (monitor serum creatinine and eGFR)","Hyperkalemia (monitor potassium levels, avoid with K+ supplements)","Hepatic impairment (avoid in severe hepatic impairment)"]

Clinical Tips & Counseling

Drug interactions

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ENTRESTO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ENTRESTO (ENTRESTO).

How it works

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to sacubitrilat (active moiety). Valsartan is metabolized minimally via CYP2C9 (less than 20%), with the remainder excreted unchanged. Both agents are substrates of OATP1B1/1B3 transporters.
Excretion	Approximately 51-68% of sacubitril and 37-48% of valsartan are excreted in urine; the remainder is eliminated in feces via biliary excretion.
Half-life	Sacubitril: 1.4 hours; Sacubitrilat (active metabolite): 11.5 hours; Valsartan: 6.1 hours. The effective half-life for the ARNI effect is driven by sacubitrilat, allowing twice-daily dosing.
Protein binding	Sacubitril: 94-97%; Sacubitrilat: 94-97%; Valsartan: 95%, primarily to albumin.
Volume of Distribution	Sacubitril: 103 L; Valsartan: 75 L (approximately 1.17 L/kg for sacubitril and 0.85 L/kg for valsartan based on 70 kg), indicating extensive extravascular distribution.
Bioavailability	Oral bioavailability of sacubitril/valsartan is >60% based on urinary recovery; food has no significant effect.
Onset of Action	Hemodynamic effects (reduction in blood pressure) observed within 1-2 hours after oral administration.
Duration of Action	Clinical effects (e.g., blood pressure reduction) persist for approximately 24 hours with twice-daily dosing. Steady state is reached within 3-5 days.

Classification & Brands

Dosing & administration

Initial: 24 mg sacubitril/26 mg valsartan orally twice daily; double dose every 2-4 weeks to target maintenance of 97 mg sacubitril/103 mg valsartan twice daily.

Dosage form	TABLET
Renal impairment	eGFR ≥30 mL/min/1.73 m2: no adjustment; eGFR <30 mL/min/1.73 m2: not recommended; avoid if eGFR <15 mL/min/1.73 m2.
Liver impairment	Child-Pugh Class A: no adjustment; Child-Pugh Class B: initial 24 mg/26 mg twice daily; Child-Pugh Class C: not recommended.
Pediatric use	Age ≥1 year: start at 0.8 mg/kg sacubitril/0.8 mg/kg valsartan (as sacubitril/valsartan) twice daily; titrate to target of 3.1 mg/kg/3.1 mg/kg twice daily based on tolerability. Maximum single dose 3.1 mg/kg/3.1 mg/kg.
Geriatric use	No specific dose adjustment; start at low end of dosing range (24 mg/26 mg twice daily) due to potential for renal impairment and hypotension; monitor closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ENTRESTO (ENTRESTO).

Breastfeeding	No human data; present in rat milk. M/P ratio unknown. Avoid breastfeeding due to potential adverse effects in infant.
Teratogenic Risk	Category D in second and third trimesters due to oligohydramnios, fetal renal dysfunction, skull ossification defects, and neonatal morbidity/mortality. Avoid in first trimester unless no alternative.
Fetal Monitoring	Monitor fetal renal function via ultrasound; assess amniotic fluid volume; perform serial fetal growth scans. Monitor maternal blood pressure and renal function.