SACUBITRIL AND VALSARTAN

Clinical safety rating: avoid

NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.

How it works

Sacubitril inhibits neprilysin, increasing natriuretic peptides; Valsartan blocks angiotensin II type 1 receptor, reducing vasoconstriction and aldosterone release. Combined, they enhance vasodilation, decrease sympathetic activity, and reduce cardiac remodeling.

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to active metabolite sacubitrilat; Valsartan is primarily metabolized by CYP2C9.
Excretion	Sacubitril is converted to sacubitrilat, which is primarily eliminated renally (52–68% as sacubitrilat) and via biliary/fecal routes (37–48% as metabolites). Valsartan is predominantly eliminated via biliary/fecal route (83%) with renal elimination accounting for 13%.
Half-life	Sacubitrilat terminal half-life is approximately 11.5 hours; valsartan terminal half-life is approximately 9.9 hours. Twice-daily dosing maintains therapeutic concentrations.
Protein binding	Sacubitrilat: 94–97% bound to plasma proteins; valsartan: 94–97% bound primarily to albumin.
Volume of Distribution	Sacubitrilat: Vd approximately 7–10 L (0.1 L/kg assuming 70 kg); valsartan: Vd approximately 17 L (0.24 L/kg). Vd does not suggest extensive tissue distribution.
Bioavailability	Oral bioavailability of sacubitril is ≥60%; valsartan bioavailability is ~23% (range 10–35%). Food reduces all exposure but not clinically relevant.
Onset of Action	Oral: Reduction in NT-proBNP observed within 2–4 hours; hemodynamic effects (e.g., reduction in systolic blood pressure) within 2 weeks of initiation.
Duration of Action	Duration of hemodynamic effect (e.g., blood pressure reduction) persists over the 12-hour dosing interval. Clinical benefit in heart failure is sustained with chronic therapy.

Classification & Brands

Dosing & administration

Initial dose: 24 mg/26 mg (sacubitril 24 mg/valsartan 26 mg) orally twice daily, then double at 2- to 4-week intervals to target maintenance dose of 97 mg/103 mg twice daily.

Dosage form	TABLET
Renal impairment	eGFR >=30 mL/min/1.73m2: No adjustment. eGFR 15-29 mL/min/1.73m2: Starting dose 24/26 mg twice daily; target dose 97/103 mg twice daily if tolerated. eGFR <15 mL/min/1.73m2: Not recommended.
Liver impairment	Child-Pugh A (mild): No adjustment. Child-Pugh B (moderate): Starting dose 24/26 mg twice daily. Child-Pugh C (severe): Not recommended.
Pediatric use	Weight ≥40 kg: 24/26 mg twice daily initially, titrate to 49/51 mg twice daily after 2-4 weeks, then to 97/103 mg twice daily as tolerated. Weight <40 kg: Not established.
Geriatric use	No specific dose adjustment based on age alone. Use caution due to higher risk of hypotension, renal impairment, and hyperkalemia; initiate at 24/26 mg twice daily and titrate slowly.

Use during pregnancy

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

Clinical note

NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.

FDA category	Contraindicated
Breastfeeding	No data on excretion in human milk. M/P ratio unknown. Consider risk of infant hypotension and renal impairment; use with caution only if benefit outweighs risk.
Teratogenic Risk	First trimester: Possible risk. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification delay, and neonatal toxicity due to renin-angiotensin system blockade. Contraindicated in second and third trimesters.

Warnings & precautions

■ FDA Black Box Warning

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

Side Effect Profile

Common Effects	heart failure
Serious Effects

Absolute Contraindications

["History of angioedema with ACE inhibitors or ARBs","Concomitant use with ACE inhibitors (within 36 hours of switching)","Hereditary or idiopathic angioedema","Pregnancy (second and third trimesters)"]

Clinical Precautions

Precautions

["Angioedema (especially if prior ACE inhibitor-associated)","Hypotension","Renal impairment","Hyperkalemia","Do not coadminister with ACE inhibitors (risk of angioedema)","Monitor serum potassium and renal function"]

Clinical Tips & Counseling

Drug interactions

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SACUBITRIL AND VALSARTAN

Clinical safety rating: avoid

NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.

How it works

What the body does with it

Metabolism	Sacubitril is metabolized by esterases to active metabolite sacubitrilat; Valsartan is primarily metabolized by CYP2C9.
Excretion	Sacubitril is converted to sacubitrilat, which is primarily eliminated renally (52–68% as sacubitrilat) and via biliary/fecal routes (37–48% as metabolites). Valsartan is predominantly eliminated via biliary/fecal route (83%) with renal elimination accounting for 13%.
Half-life	Sacubitrilat terminal half-life is approximately 11.5 hours; valsartan terminal half-life is approximately 9.9 hours. Twice-daily dosing maintains therapeutic concentrations.
Protein binding	Sacubitrilat: 94–97% bound to plasma proteins; valsartan: 94–97% bound primarily to albumin.
Volume of Distribution	Sacubitrilat: Vd approximately 7–10 L (0.1 L/kg assuming 70 kg); valsartan: Vd approximately 17 L (0.24 L/kg). Vd does not suggest extensive tissue distribution.
Bioavailability	Oral bioavailability of sacubitril is ≥60%; valsartan bioavailability is ~23% (range 10–35%). Food reduces all exposure but not clinically relevant.
Onset of Action	Oral: Reduction in NT-proBNP observed within 2–4 hours; hemodynamic effects (e.g., reduction in systolic blood pressure) within 2 weeks of initiation.
Duration of Action	Duration of hemodynamic effect (e.g., blood pressure reduction) persists over the 12-hour dosing interval. Clinical benefit in heart failure is sustained with chronic therapy.

Classification & Brands

Dosing & administration

Initial dose: 24 mg/26 mg (sacubitril 24 mg/valsartan 26 mg) orally twice daily, then double at 2- to 4-week intervals to target maintenance dose of 97 mg/103 mg twice daily.

Dosage form	TABLET
Renal impairment	eGFR >=30 mL/min/1.73m2: No adjustment. eGFR 15-29 mL/min/1.73m2: Starting dose 24/26 mg twice daily; target dose 97/103 mg twice daily if tolerated. eGFR <15 mL/min/1.73m2: Not recommended.
Liver impairment	Child-Pugh A (mild): No adjustment. Child-Pugh B (moderate): Starting dose 24/26 mg twice daily. Child-Pugh C (severe): Not recommended.
Pediatric use	Weight ≥40 kg: 24/26 mg twice daily initially, titrate to 49/51 mg twice daily after 2-4 weeks, then to 97/103 mg twice daily as tolerated. Weight <40 kg: Not established.
Geriatric use	No specific dose adjustment based on age alone. Use caution due to higher risk of hypotension, renal impairment, and hyperkalemia; initiate at 24/26 mg twice daily and titrate slowly.

Use during pregnancy

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

Clinical note

NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.

FDA category	Contraindicated
Breastfeeding	No data on excretion in human milk. M/P ratio unknown. Consider risk of infant hypotension and renal impairment; use with caution only if benefit outweighs risk.
Teratogenic Risk	First trimester: Possible risk. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification delay, and neonatal toxicity due to renin-angiotensin system blockade. Contraindicated in second and third trimesters.

Warnings & precautions

■ FDA Black Box Warning

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

Side Effect Profile

Common Effects	heart failure
Serious Effects