Drug Safety-related Labeling Changes (SrLC)

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ENTRESTO (NDA-207620)

(SACUBITRIL; VALSARTAN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/02/2019 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Pediatric Heart Failure

The adverse reactions observed in pediatric patients 1 to <18 years old who received treatment with ENTRESTO were consistent with those observed in adult patients.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of ENTRESTO in pediatric heart failure patients 1 to <18 years old are supported by the reduction from baseline to 12 weeks in NT-proBNP in a randomized, double-blind clinical study. The analysis of NT-proBNP included 90 patients age 6 to 18 years and 20 patients age 1 to 6 years.

Safety and effectiveness have not been established in pediatric patients less than 1 year of age.

Animal Data

Sacubitril given orally to juvenile rats from postnatal day (PND) 7 to PND 35 or PND 70 (an age approximately equivalent to neonatal through pre-pubertal development or adulthood in humans) at doses ?400 mg/kg/day (approximately 2-fold the AUC exposure to the active metabolite of sacubitril, LBQ657, at an ENTRESTO pediatric clinical dose of 3.1 mg/kg twice daily) resulted in decreases in body weight, bone length and bone mass. The decrease in body weight was transient from PND 10 to PND 20 and the effects for most bone parameters were reversible after treatment stopped. Exposure at the No-Observed-Adverse-Effect-Level (NOAEL) of 100 mg/kg/day was approximately 0.5-fold the AUC exposure to LBQ657 at the 3.1 mg/kg twice daily dose of ENTRESTO. The mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown.

Valsartan given orally to juvenile rats from PND 7 to PND 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels. Exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at 3.1 mg/kg twice daily dose of ENTRESTO based on AUC. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.

11/22/2017 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Angioedema

(Additions and/or revisions are underlined)

Patients with a prior history of angioedema may be at increased risk of angioedema with ENTRESTO. ENTRESTO must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy. ENTRESTO should not be used in patients with hereditary angioedema.

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added subsection)

The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity including rash, pruritus, and anaphylactic reaction

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information ENTRESTO (en-TRESS-toh) (sacubitril/valsartan) tablets

(Additions and/or revisions are underlined)

What should I tell my doctor before taking ENTRESTO?

Before you take ENTRESTO, tell your doctor about all of your medical conditions, including if you:

 • Have a history of hereditary angioedema.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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