Sacubitril and Valsartan

Sacubitril and Valsartan
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: AKT

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Black Box Warning

FETAL TOXICITY See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue ENTRESTO as soon as possible Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

Overview

Sacubitril and Valsartan is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker that is FDA approved for the prevention of of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, increased serum potassium, hyperkalemia, and increased serum creatinine.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Dosing Information

• 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.
• The recommended starting dose of ENTRESTO is 49/51 mg 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.
• Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents
  • A starting dose of 24/26 mg twice-daily is recommended for patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents. Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.
• Dose Adjustment for Severe Renal Impairment
  • A starting dose of 24/26 mg twice-daily is recommended for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2). Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.
  • No starting dose adjustment is needed for mild or moderate renal impairment.
• Dose Adjustment for Hepatic Impairment
  • A starting dose of 24/26 mg twice-daily is recommended for patients with moderate hepatic impairment (Child-Pugh B classification). Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.
  • No starting dose adjustment is needed for mild hepatic impairment.
  • Use in patients with severe hepatic impairment is not recommended.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sacubitril and Valsartan in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacubitril and Valsartan in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Sacubitril and Valsartan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sacubitril and Valsartan in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacubitril and Valsartan in pediatric patients.

Contraindications

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.
• 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.

Warnings

FETAL TOXICITY See full prescribing information for complete Boxed Warning. When pregnancy is detected, discontinue ENTRESTO as soon as possible Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

• 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. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.
• Angioedema
  • ENTRESTO may cause angioedema. In the double-blind period of PARADIGM-HF, 0.5% of patients treated with ENTRESTO and 0.2% of patients treated with enalapril had angioedema.
  • If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
  • Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway.
  • ENTRESTO has been associated with a higher rate of angioedema in Black than in non-Black patients.
  • Patients with a prior history of angioedema may be at increased risk of angioedema with ENTRESTO. ENTRESTO should not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
• Hypotension
  • ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. In the double-blind period of PARADIGM-HF, 18% of patients treated with ENTRESTO and 12% of patients treated with enalapril reported hypotension as an adverse event, with hypotension reported as a serious adverse event in approximately 1.5% of patients in both treatment arms.
  • Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.
• Impaired Renal Function
  • As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. In the double-blind period of PARADIGM-HF, 5% of patients in both the ENTRESTO and enalapril groups reported renal failure as an adverse event.
  • In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death.
  • Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO in patients who develop a clinically significant decrease in renal function.
  • As with all drugs that affect the RAAS, ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function.
• Hyperkalemia
  • Through its actions on the RAAS, hyperkalemia may occur with ENTRESTO. In the double-blind period of PARADIGM-HF, 12% of patients treated with ENTRESTO and 14% of patients treated with enalapril reported hyperkalemia as an adverse event.
  • Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Sacubitril and Valsartan Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Sacubitril and Valsartan Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Sacubitril and Valsartan Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Sacubitril and Valsartan in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sacubitril and Valsartan in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Sacubitril and Valsartan during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Sacubitril and Valsartan in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Sacubitril and Valsartan in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Sacubitril and Valsartan in geriatric settings.

Gender

There is no FDA guidance on the use of Sacubitril and Valsartan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sacubitril and Valsartan with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Sacubitril and Valsartan in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Sacubitril and Valsartan in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Sacubitril and Valsartan in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Sacubitril and Valsartan in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Sacubitril and Valsartan Administration in the drug label.

Monitoring

There is limited information regarding Sacubitril and Valsartan Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Sacubitril and Valsartan and IV administrations.

Overdosage

There is limited information regarding Sacubitril and Valsartan overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Sacubitril and Valsartan Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Sacubitril and Valsartan Mechanism of Action in the drug label.

Structure

There is limited information regarding Sacubitril and Valsartan Structure in the drug label.

Pharmacodynamics

There is limited information regarding Sacubitril and Valsartan Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Sacubitril and Valsartan Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Sacubitril and Valsartan Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Sacubitril and Valsartan Clinical Studies in the drug label.

How Supplied

There is limited information regarding Sacubitril and Valsartan How Supplied in the drug label.

Storage

There is limited information regarding Sacubitril and Valsartan Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Sacubitril and Valsartan Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Sacubitril and Valsartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Sacubitril and Valsartan Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Sacubitril and Valsartan Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.