This combination tablet is indicated for:

• Reducing the risk of cardiovascular death and hospitalization due to heart failure in patients with chronic heart failure (NYHA Class II–IV) and reduced ejection fraction.
• Management of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
• It is usually used along with other heart failure treatments, instead of an angiotensin-converting enzyme inhibitor (ACEi) or other ARB.

This tablet contains two active components—sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin receptor blocker). The active metabolite of sacubitril, LBQ657, inhibits the enzyme neprilysin (neutral endopeptidase; NEP), while valsartan blocks the angiotensin II type-1 (AT1) receptor. In heart failure patients, the cardiovascular and renal effects of this medicine are mainly due to increased levels of peptides such as natriuretic peptides (by inhibition of neprilysin breakdown) and simultaneous blocking of angiotensin II effects. Valsartan selectively blocks the AT1 receptor, reducing the action of angiotensin II and also decreasing aldosterone secretion.

Adult Heart Failure: The recommended starting dose is 49/51 mg orally twice daily. Double the dose after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.

Reduce the starting dose to 24/26 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.

Pediatric Heart Failure: Refer to Table 1 for the recommended dose for pediatric patients aged one year and older. Take the recommended dose orally twice daily. Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.

Recommended Dose Titration

Pediatric Patients Less than 40 kg:

• Starting: 1.6 mg/kg
• Second: 2.3 mg/kg
• Final: 3.1 mg/kg

Pediatric Patients At least 40 kg, less than 50 kg:

• Starting: 24/26 mg
• Second: 49/51 mg
• Final: 49/51 mg

Pediatric Patients At least 50 kg:

• Starting: 49/51 mg
• Second: 72/78 mg
• Final: 97/103 mg

Dual blockade of Renin-Angiotensin-Aldosterone System (RAAS): Should not be used with ACE inhibitors, aliskiren in diabetic patients, and concomitant use with ARBs 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.

This combination is contraindicated:

• In patients with known hypersensitivity to any component
• In patients with a history of angioedema related to previous ACE inhibitor or ARB therapy
• With concomitant use of ACE inhibitors (do not administer within 36 hours of switching from or to an ACE inhibitor)
• With concomitant use of aliskiren in patients with diabetes

The most common side effects include angioedema, hypotension, impaired renal function, hyperkalemia, cough, and dizziness.

Pediatric use: Safety and efficacy have not been established in children under 1 year of age.

Geriatric use: No significant pharmacokinetic differences observed in elderly (>65 years) or very elderly (>75 years) patients compared to the general population.

Hepatic impairment: No dose adjustment is required in mild hepatic impairment (Child-Pugh A). It is not recommended in severe hepatic impairment due to lack of studies.

Renal impairment: No dose adjustment is required in mild to moderate renal impairment. In severe renal impairment (eGFR <30 mL/min/1.73 m²), the recommended starting dose is 24/26 mg twice daily.

May cause angioedema; contraindicated in patients with a history of angioedema related to ACE inhibitors or ARBs and in hereditary angioedema.

May cause symptomatic hypotension due to blood pressure reduction; monitor carefully.

Monitor serum creatinine and adjust dose or interrupt treatment if clinically significant renal function decline occurs. In renal artery stenosis, renal function should be closely monitored.

Monitor serum potassium regularly, especially in patients with risk factors for hyperkalemia (e.g., severe renal impairment, diabetes, hypoaldosteronism, high potassium diet). Dose reduction or discontinuation may be required.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: No clinically relevant pharmacokinetic differences have been observed in elderly (≥65 years) or very elderly (≥75 years) patients compared to the overall population.

Renal Impairment:

• Severe: A starting dose of 24/26 mg twice daily is recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). The dose may be doubled every 2–4 weeks up to the target maintenance dose of 97/103 mg twice daily, as tolerated.
• Mild to moderate: No starting dose adjustment is required.

Hepatic Impairment:

• Moderate: A starting dose of 24/26 mg twice daily is recommended in patients with moderate hepatic impairment (Child-Pugh B). Dose may be doubled every 2–4 weeks up to the target maintenance dose of 97/103 mg twice daily, as tolerated.
• Mild: No dose adjustment is required.
• Severe: Use is not recommended in severe hepatic impairment.

Limited data are available regarding overdose in humans. In healthy volunteers, single doses up to 583 mg sacubitril/617 mg valsartan and multiple doses of 437 mg sacubitril/463 mg valsartan for 14 days were generally well tolerated. The most likely effect of overdose is hypotension due to the blood pressure–lowering action. Symptomatic treatment should be provided. Due to high protein binding, this tablet is unlikely to be removed by hemodialysis.

Store in a dry place below 30°C. Protect from moisture and keep out of the reach of children.