Sacubitril, a neprilysin inhibitor, inhibits neprilysin (a natural endopeptidase; NEP) via the active metabolite of the prodrug Sacubitril. Valsartan, an angiotensin receptor blocker, blocks the angiotensin II type-1 (AT1) receptor. The cardiovascular and renal effects of Sacubitril/Valsartan in heart failure patients are attributed to the increased levels of peptides degraded by neprilysin, such as natriuretic peptides, through the active metabolite of Sacubitril, along with the simultaneous inhibition of the effects of angiotensin II by Valsartan. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor and also inhibits angiotensin II-dependent aldosterone release.

The Sacubitril/Valsartan combination is indicated to:

Reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
Sacubitril/Valsartan is usually administered in conjunction with other heart failure therapies, replacing an ACE inhibitor or another ARB.

The recommended starting dose of Sacubitril/Valsartan is 100 mg twice daily. Double the dose after 2 to 4 weeks to reach the target maintenance dose of 200 mg twice daily, as tolerated by the patient.

Reduce the starting dose to 50 mg twice daily for:

Patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents.
Patients with severe renal impairment.
Patients with moderate hepatic impairment.
Gradually double the dose every 2 to 4 weeks to reach the target maintenance dose of 200 mg twice daily, as tolerated by the patient.

The most common side effects include low blood pressure, high potassium levels, cough, dizziness, and kidney problems. It may cause serious side effects such as angioedema (which may lead to breathing difficulties and death) and hyperkalemia.

Sacubitril/Valsartan is contraindicated in the following cases:

Hypersensitivity to any component.
History of angioedema related to previous ACE inhibitor or ARB therapy.
Concomitant use with ACE inhibitors.

Concomitant use with aliskiren in patients with diabetes.

Monitor for signs and symptoms of angioedema and hypotension.
Renal function and potassium levels should be monitored in susceptible patients.

Pregnancy: Sacubitril/Valsartan can cause fetal harm when administered to a pregnant woman.
Lactation: The drug should be discontinued during lactation.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: No relevant pharmacokinetic differences have been observed in elderly patients (≥65 years or ≥75 years) compared to the overall population.

Hepatic Impairment: Use is not recommended.

Dual blockade of the renin-angiotensin system: Should not be used with an ACEi or aliskiren in patients with diabetes, and use with an ARB should be avoided.

Potassium-sparing diuretics: May increase serum potassium levels.
NSAIDs: May increase the risk of renal impairment.
Lithium: May increase the risk of lithium toxicity.

Limited data are available on overdose in humans. In healthy volunteers, a single dose of Sacubitril/Valsartan 1200 mg and multiple doses of Sacubitril/Valsartan 900 mg (over 14 days) have been studied and were well tolerated.

Hypotension is the most likely outcome of overdose due to the blood pressure-lowering effects of Sacubitril and Valsartan. Symptomatic treatment should be provided. Due to its high protein binding, the drug is unlikely to be removed by hemodialysis.

Store at a temperature not exceeding 30°C in a dry place. Protect from light and moisture.

Medicine: Keep out of reach of children.