Regulatory Affairs

ENTRESTO® (sacubitril/valsartan)

50 mg, 100 mg and 200 mg Film-coated tablets

National Succinct Statement (NSS)

Version 4.0

                                  Effective date:                                             28-Nov-2024

                                  Safety Labeling Change (SLC)

                                  Tracking number:                                        Not applicable

                              Document status:                                        Final

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without the consent of Novartis

ENTRESTO®

Important note: Before prescribing, consult full prescribing information.

Presentation: ♦ Film-coated tablets containing 50 mg, 100 mg, and 200 mg Entresto® (sacubitril/valsartan) as sodium salt complex.

Indications:

Tablets 50 mg, 100 mg, 200 mg

Heart Failure – Adult ♦Treatment of chronic heart failure to reduce the risk of cardiovascular death and heart failure hospitalization in adult patients. ♦Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. Entresto is administered, in place of an ACE inhibitor or ARB.

Heart Failure – Pediatric ♦Entresto is indicated in children and adolescents aged one year or older for treatment of chronic heart failure with left ventricular systolic dysfunction.

♦ Tablets 100 mg, 200 mg

Essential hypertension (HTN) ♦Treatment of HTN in adult patients.

Dosage and administration:

Chronic Heart Failure

The usual adult starting dose is 50 mg sacubitril valsartan per dose, taken orally twice daily. If tolerated, the dose should be increased up to 200 mg per dose sequentially by 2 to 4 weeks interval. The dose per administration is 50 mg, 100 mg, or 200 mg, taken orally twice daily in any doses. The dose should be reduced according to the tolerability.

The usual starting dose of sacubitril valsartan based on body weight for pediatric patients aged one year or older is as in the table below taken orally twice daily. If tolerated, the dose should be increased up to the target dose sequentially by 2 to 4 weeks interval. The dose should be reduced according to the tolerability.

Dosing Table for Pediatric Patients (dose per administration)

Essential Hypertension

The usual adult dose is 200 mg sacubitril valsartan per dose, taken orally once daily. The dose may be adjusted according to the patient's age and symptoms. The maximum dose is 400 mg once daily.

○: approved, ―: not approved

♦ Geriatric patients: Entresto should be carefully administered for hypertension, for example, by initiating at a lower dose. Generally, an excessive reduction in blood pressure is undesirable.

♦ Renal impairment: No dose adjustment is required in patients with mild to moderate renal impairment.

In adult and pediatric patients with heart failure and severe renal impairment, lower starting dose and caution is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

In adult patients with severe renal impairment, Careful judgment should be made as to whether Entresto is administered for hypertension. If administered, initiation at a lower dose should be considered. The blood concentration of sacubitril valsartan may increase.

♦ Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment.

In adult and pediatric patients with heart failure or hypertension and with moderate hepatic impairment, Careful judgment should be made as to whether Entresto is administered. If administered, Entresto should be administered with close monitoring of the patient’s condition. The blood concentration of sacubitril valsartan may increase. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

In patients with severe hepatic impairment use of Entresto is not recommended.

♦ Method of administration: For oral use. Film-coated tablets may be administered with or without food.

Contraindications: Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the excipients. Concomitant use with ACE inhibitors. Entresto must not be administered until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema related to previous ACE inhibitor or ARB therapy. Hereditary angioedema. Concomitant use with aliskiren in patients with Type 2 diabetes. Pregnancy.

Warnings and precautions:

♦ Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Entresto must not be administered with an ACE inhibitor due to the risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto. Entresto must not be administered with aliskiren in patients with Type 2 diabetes. Entresto should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Entresto. Concomitant use with aliskiren should be avoided in patients with renal impairment (eGFR <60 mL/min/1.73 m2).

♦ Hypotension: Blood pressure should be measured periodically, and Entresto should be administered with close monitoring of the patient’s condition especially when initiating treatment or increasing the dose. This drug should be administered with caution when co- administered with Diuretic antihypertensive medications. Rapid decrease in blood pressure accompanied by syncope and loss of consciousness may occur. Diuretic effects may be increased. In patients with hypertension, Entresto should be initiated at a lower dose, and if the dose is increased, it should be done gradually.

♦ Impaired renal function: Down titration of Entresto should be considered in patients who develop a clinically significant decrease in renal function. Caution should be exercised when administering Entresto in patients with severe renal impairment.

♦ Hyperkalemia: Medications known to raise potassium levels (e.g., potassium-sparing diuretics, potassium supplements) should be used with caution. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism or receiving a high potassium diet.

♦ Angioedema: If angioedema occurs, Entresto should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re-administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Entresto must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy, or in patients with hereditary angioedema. Black patients may have increased susceptibility to develop angioedema.

♦Patients with renal artery stenosis: Administration of Entresto should be avoided unless use is judged to be essential in the treatment. Renal function may deteriorate rapidly due to decreased renal blood flow or decreased glomerular filtration pressure.

Pregnancy, lactation, females and males of reproductive potential

Pregnancy: Entresto must not be used during pregnancy. Patients should be advised to discontinue Entresto as soon as pregnancies occur and to inform their physicians.

Lactation: Limited data show that sacubitril and sacubitrilat, a metabolite of sacubitril, are transferred into human milk. Because of the potential risk for adverse drug reactions in breastfed newborns/infants, Entresto is not recommended during breast-feeding.

Females and males of reproductive potential: Female patients of childbearing potential should be advised about the consequences of exposure to Entresto during pregnancy and to use contraception during treatment and for 1 week after their last dose of Entresto.

Adverse drug reactions:

Common (≥1 to <10%): Hyperkalemia, hypotension, renal impairment.

Uncommon (≥0.1 to <1%): Cough, dizziness, renal failure Angioedema, postural dizziness, Hypersensitivity (including rash, pruritus, and anaphylaxis), diarrhea, hypokalemia, fatigue, headache, syncope, nausea, asthenia, orthostatic hypotension, vertigo.

Unknown: Agranulocytosis, thrombocytopenia, Hypoglycemia.

Interactions:

♦ Concomitant use contraindicated: aliskiren in patients with Type 2 diabetes, Use with ACE inhibitors. Entresto must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto.

♦ Concomitant use not recommended: ARB, concomitant use of Entresto with aliskiren, should be avoided in patients with renal impairment (eGFR <60 mL/min/1.73 m2). ♦Caution when used concomitantly with statins, sildenafil, lithium, potassium-sparing diuretics including mineral corticoid antagonists (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium, non-steroidal anti-inflammatory agents (NSAIDs), inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampin, cyclosporine) or MPR2 (e.g., ritonavir).

Packs and prices: Country-specific.

Legal classification: Country-specific.

Leaflet revision date: May 2024.

NSS version number: V 4.0.

Leaflet presentation: AE Country-specific.