Regulatory Affairs

ENTRESTO® (sacubitril/valsartan)

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

National Succinct Statement (NSS)

Version 3.1

Effective date:                                13-Jul-2023

                               Safety Labeling Change (SLC)

                               Tracking number:                           Not applicable

                               Document status:                           Final

Property of Novartis Confidential

May not be used, divulged, published or otherwise disclosed

without the consent of Novartis

ENTRESTO® tablets

Important note: Before prescribing, consult full prescribing information: www.fda.gov

This link will contain the most updated product information approved by the reference country.

Presentation: Film-coated tablets containing 50 mg, 100 mg, or 200 mg Entresto® (sacubitril/valsartan).

Indications:

Adult Heart Failure

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat.

Pediatric Heart Failure

ENTRESTO is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.

Dosage and administration:

General Considerations

ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs.

Adult Heart Failure

The recommended starting dose of ENTRESTO is 100 mg orally twice-daily.

Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 200 mg twice daily, as tolerated by the patient.

Pediatric Heart Failure

For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets, or Table 2 if using the oral pellets.

Take the recommended dose orally twice daily. Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.

Table 1: Recommended Dose and Titration for Pediatric Patients Using Tablets

†Use of the oral suspension or oral pellets (see Table 2) is recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan.

‡Doses of 150 mg can be achieved using three 50 mg tablets.

Table 2: Recommended Dose and Titration for Pediatric Patients using ENTRESTO SPRINKLE†

† When using capsules, more than one capsule may be needed to achieve recommended doses. Oral pellets are contained within each capsule. Use the entire contents of the capsules to achieve the dose.

‡ Recommended mg/kg doses are of the combined amount of sacubitril and valsartan [see Dosage and administration (2.4)].

* For patients 50 kg or more, see Table 1.

Preparation of Oral Suspension Using Tablets

ENTRESTO oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets.

ENTRESTO 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL). Use ENTRESTO 100 mg tablets in the preparation of the suspension.

To make an 800 mg/200 mL (4 mg/mL) oral suspension, transfer eight tablets of ENTRESTO 100 mg film-coated tablets into a mortar. Crush the tablets into a fine powder using a pestle. Add 60 mL of Ora-Plus® into the mortar and triturate gently with pestle for 10 minutes, to form a uniform suspension. Add 140 mL of Ora-Sweet® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension. Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle. Place a press-in bottle adapter and close the bottle with a child resistant cap.

The oral suspension can be stored for up to 15 days. Do not store above 25°C (77°F) and do not refrigerate. Shake before each use.

*Ora-Sweet SF® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc. Ora-Sweet SF® and Ora-Plus® may not be registered/marketed in your country. Accordingly, use in pediatric patients is limited to patients >= 40kg

Preparation and Administration of Oral Pellets

ENTRESTO SPRINKLE are oral pellets contained within capsules. Do not swallow the capsules. Do not chew or crush the oral pellets.

ENTRESTO SPRINKLE can also be substituted in patients unable to swallow tablets. Use the entire contents of the capsules to achieve the dose.

To administer ENTRESTO oral pellets, open the capsule and sprinkle the full content onto 1 to 2 teaspoons of soft food. Consume the food containing the oral pellets immediately after adding them. Empty capsule shells must be discarded after use and not swallowed. Do not administer ENTRESTO oral pellets via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes.

Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents

In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter.

Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets.

Dose Adjustment for Severe Renal Impairment

In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m2), start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets.

No starting dose adjustment is needed for mild or moderate renal impairment.

Dose Adjustment for Hepatic Impairment

In adults and pediatric patients with moderate hepatic impairment (Child-Pugh B classification), start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets.

No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

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 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 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: If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Entresto should be reduced or the product should be temporarily discontinued. Permanent discontinuation of therapy is usually not required. Sodium and/or volume depletion should be corrected before starting treatment with Entresto.

♦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 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: Caution is required in patients with renal artery stenosis and monitoring of the renal function is recommended.

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: It is not known whether Entresto is transferred into human milk. Because of the potential risk for adverse drug reactions in breastfed newborns/infants, Entresto is not recommended during breast-feeding.

Adverse drug reactions:

• Angioedema

• Hypotension

• Impaired Renal Function

• Hyperkalemia

Interactions:

♦ Concomitant use contraindicated: aliskiren in patients with 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 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) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors).

Packs and prices: Country-specific.

Legal classification: Country-specific.

NSS Version no.: 3.1

Leaflet Revision Date: April 2024

Leaflet Presentation Type: R02