Sacubitril

ENTRESTO is a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and 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. ( 1.1 ) 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. …

• The recommended starting dosage for adults is 49 mg/51 mg orally twice daily
• The target maintenance dose is 97 mg/103mg orally twice daily
• Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient
• For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions
• Reduce starting dose to half the usually recommended starting dosage for: patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. patients with severe renal impairment. patients with moderate hepatic impairment
• 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 [see Contraindications and Drug Interactions ]
• Adult Heart Failure The recommended starting dose of ENTRESTO is 49/51 mg orally twice-daily
• Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 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. …

ENTRESTO film-coated tablets are supplied as unscored, ovaloid tablets in the following strengths: ENTRESTO 24/26 mg, (sacubitril 24 mg and valsartan 26 mg) are violet white and debossed with “NVR” on one side and “LZ” on the other side. ENTRESTO 49/51 mg, (sacubitril 49 mg and valsartan 51 mg) are pale yellow and debossed with “NVR” on one side and “L1” on the other side. …

• The safety and effectiveness of ENTRESTO have been established
• For the treatment of heart failure
• In pediatric patients 1 year to less than 18 years
• Use of ENTRESTO was evaluated in a multinational, randomized, double-blind trial comparing ENTRESTO and enalapril in 375 patients aged 1 month to less than 18 years (ENTRESTO n = 187; Enalapril n = 188) (PANORAMA-HF) [see Clinical Studies ]
• The safety profile
• In pediatric patients (1 year to less than 18 years) receiving ENTRESTO was similar to that seen in adult patients. …

There were 4,143 and 3,971 heart failure patients 65 years of age and older in PARADIGM-HF and PARAGON-HF, respectively [see Clinical Studies (14)] . Of the total number of ENTRESTO-treated patients, 2,087 (49.6%) and 1,995 (82.9%) were 65 years of age and older, while 786 (18.7%) and 1,100 (45.7%) were 75 years of age and older in PARADIGM-HF and PARAGON-HF, respectively. …

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use)
• Pregnancy: Advise female patients of childbearing age about the consequences of exposure to ENTRESTO during pregnancy
• Discuss treatment options with women planning to become pregnant
• Ask patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions and Use in Specific Populations ]
• Lactation: Advise patients that breastfeeding is not recommended during treatment with ENTRESTO [see Use in Specific Populations ]
• Angioedema: Advise patients to discontinue use of their previous ACE inhibitor or ARB. …

• ENTRESTO is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warnings and Precautions ] with concomitant use of ACE inhibitors
• Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions ] with concomitant use of aliskiren in patients with diabetes [see Drug Interactions ] Hypersensitivity to any component. …

Avoid concomitant use with aliskiren in patients with estimated glomerular filtration rate (eGFR) less than 60. ( 7.1 ) Potassium-sparing diuretics: May lead to increased serum potassium. ( 7.2 ) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): May lead to increased risk of renal impairment. ( 7.3 ) Lithium: Increased risk of lithium toxicity. ( 7.4 ) 7.1 Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of ENTRESTO with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see Contraindications (4)] . Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan. …

Observe for signs and symptoms of angioedema and hypotension. ( 5.2 , 5.3 ) Monitor renal function and potassium in susceptible patients. ( 5.4 , 5.5 ) 5.1 Fetal Toxicity ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. …

Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema [see Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Impaired Renal Function [see Warnings and Precautions (5.4)] Hyperkalemia [see Warnings and Precautions (5.5)] Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . …

8.1 Pregnancy Risk Summary ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). …

Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO. Symptomatic treatment should be provided. ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

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