Entresto

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• Combining Entresto with ACE inhibitors increases the risk of angioedema and other side effects. Combining aliskiren (Tekturna) with Entresto increases the risk of kidney failure, high blood potassium, and low blood pressure. Aliskiren should not be combined with Entresto.
• Combining Entresto with potassium-sparing diuretics (for example, spironolactone [Aldactone], triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
• Increases in blood lithium (Eskalith, Lithobid) levels and lithium toxicity have occurred when lithium and ARBs were combined. Blood lithium levels should be monitored if lithium is combined with Entresto.
• Combining Entresto with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure.

Serious side effects have been reported with Entresto.

Common side effects of Entresto include:

• low blood pressure
• high blood potassium levels
• poor function of the kidneys.

This is not a complete list of Entresto side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Do not use if you are pregnant. Stop using and tell your doctor right away if you become pregnant. Sacubitril and valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

If you have diabetes, do not use sacubitril and valsartan together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not use potassium supplements or salt substitutes while you are taking sacubitril and valsartan, unless your doctor has told you to.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of sacubitril and valsartan.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. You may be more likely to have an allergic reaction if you are African-American.

Also call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• extreme tiredness;

• high potassium--slow heart rate, weak pulse, muscle weakness, tingly feeling; or

• kidney problems--little or no urinating, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath.

Common side effects may include:

• dizziness; or

• cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Sacubitril and valsartan combination is used together with other medicines to treat chronic heart failure in adults and cut down on the number of hospital visits for heart problems.

This medicine is available only with your doctor's prescription.

• If you have an allergy to this medicine or any part of Entresto.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have liver disease.
• If you have ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
• If you are taking of these drugs: Azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, or telmisartan.
• If you are taking or have recently taken any of these drugs: Benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.
• If you are taking a drug that has aliskiren in it and you also have high blood sugar (diabetes) or kidney problems. Check with your doctor or pharmacist if you are not sure if a drug you take has aliskiren in it.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Entresto with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

     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 [see Use in Specific Populations (8.1)].

     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 [see Adverse Reactions (6.1)]. 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 [see Adverse Reactions (6.1)]. Entresto should not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy [see Contraindications (4)].

     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 [see Adverse Reactions (6.1)], 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 [see Adverse Reactions (6.1)]. 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 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.1)].

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.

Entresto contains a combination of sacubitril and valsartan. Sacubitril is a blood pressure medicine. It works by increasing the levels of certain proteins in the body that can dilate (widen) blood vessels. This helps lower blood pressure by reducing sodium levels.

Valsartan is an angiotensin II receptor blocker (sometimes called an ARB). Valsartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Entresto is used in certain people with chronic heart failure. This medicine helps lower the risk of needing to be hospitalized when symptoms get worse, and helps lower the risk of death from heart failure.

Entresto is usually given together with other blood pressure medications.

Do not use Entresto if you are pregnant. Stop using and tell your doctor right away if you become pregnant. Entresto can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

If you have diabetes, do not use Entresto together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

Get emergency medical help if you have signs of an allergic reaction to Entresto: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. You may be more likely to have an allergic reaction if you are African-American.

Also call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• extreme tiredness;

• high potassium - slow heart rate, weak pulse, muscle weakness, tingly feeling; or

• kidney problems - little or no urinating, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath.

Common Entresto side effects may include:

• dizziness; or

• cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Animal studies have revealed evidence of embryofetal lethality. In humans, use of drugs that act on the renin angiotensin system (RAS) during the second and third trimesters increases fetal and neonatal morbidity and death. There are no controlled data in human pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

This drug should not be used during pregnancy unless there are no alternatives and the benefit outweighs the risk. US FDA pregnancy category: Not Assigned