Entresto (sacubitril and valsartan)

Entresto is a prescription medicine used to reduce the risk of death and hospitalization in people with certain types of long-lasting (chronic) heart failure.

Entresto is usually used with other heart failure therapies, in place of an ACE inhibitor or other ARB therapy.

Heart failure occurs when the heart is weak and cannot pump enough blood to your lungs and the rest of your body.

Entresto can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. If you get pregnant while taking Entresto, tell your doctor right away.

It is not known if Entresto is safe and effective in children.

Do not take Entresto if you:

• are allergic to sacubitril or valsartan or any of the ingredients in Entresto. See the end of this Patient Information leaflet for a complete list of ingredients in Entresto.
• have had an allergic reaction including swelling of your face, lips, tongue, throat or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).
• take an ACE inhibitor medicine. Do not take Entresto for at least 36 hours before or after you take an ACE inhibitor medicine. Talk with your doctor or pharmacist before taking Entresto if you are not sure if you take an ACE inhibitor medicine.
• have diabetes and take a medicine that contains aliskiren.

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

• have kidney or liver problems

WARNING

Fetal Toxicity

• 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

Entresto may cause serious side effects including:

• Serious allergic reactions causing swelling of your face, lips, tongue, and throat (angioedema) that may cause trouble breathing and death. Get emergency medical help right away if you have symptoms of angioedema or trouble breathing. Do not take Entresto again if you have had angioedema while taking Entresto.
• People who are Black and take Entresto may have a higher risk of having angioedema than people who are not Black and take Entresto.
• People who have had angioedema before taking Entresto may have a higher risk of having angioedema than people who have not had angioedema before taking Entresto. 
• Low blood pressure (hypotension). Low blood pressure may be more common if you also take water pills. Call your doctor if you become dizzy or lightheaded, or you develop extreme fatigue.
• Kidney problems. Your doctor will check your kidney function during your treatment with Entresto. If you have changes in your kidney function tests, you may need a lower dose of Entresto or may need to stop taking Entresto for a period of time.
• Increased amount of potassium in your blood. Your doctor will check your potassium blood level during your treatment with Entresto.

These are not all the possible side effects of Entresto. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• 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.
• Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.
• 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.

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.

Avoid use of Entresto with an ARB, because Entresto contains the angiotensin II receptor blocker valsartan.

The concomitant use of Entresto with aliskiren is contraindicated in patients with diabetes. Avoid use with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

Potassium-Sparing Diuretics

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with Entresto may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with Entresto.

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.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction studies, Entresto treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits.

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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with Entresto.