Angiotensin receptor/neprilysin inhibitors: Uses, common brands, and safety info

An angiotensin receptor/neprilysin inhibitor (ARNI) is a type of medication used to treat heart failure. As of 2024, the only available ARNI is the brand-name prescription drug Entresto. Entresto contains two ingredients: the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan. Continue reading to learn more about the uses, side effects, and other important information of Entresto.

What are angiotensin receptor/neprilysin inhibitors?

Entresto is the only angiotensin receptor neprilysin inhibitor (ARNI) currently available in U.S. pharmacies. Entresto contains two medications:

• Valsartan, an ARB

• Sacubitril, a neprilysin inhibitor

Entresto is generally used in combination with other medicines to lower the risk of hospitalization and death in adults with certain types of heart failure. It can also be used to treat certain types of heart failure in children one year and older. 

How do angiotensin receptor/neprilysin inhibitors work?

The ARNI Entresto contains two ingredients that work together:

• Valsartan, an ARB, works by improving blood flow and helping the heart pump more efficiently

• Sacubitril, a neprilysin inhibitor, works by helping control blood volume

What are angiotensin receptor/neprilysin inhibitors used for?

Entresto is approved by the U.S. Food & Drug Administration (FDA) for the following uses:

• Heart failure in adults: Entresto lowers the risk of hospitalization and cardiovascular death in adult chronic heart failure patients. It is most effective in people with reduced left ventricular ejection fraction (LVEF).

• Heart failure in pediatric patients: Entresto is used to treat symptomatic heart failure with systemic left ventricular systolic dysfunction and improve outcomes in children one year and older.

What are the formulations and dosages of Entresto?

Entresto is available as:

• An oral tablet in the following dosages (sacubitril/valsartan): 24/26 mg, 49/51 mg, 97/103 mg

• A sprinkle capsule in the following dosages (sacubitril/valsartan): 6/6 mg, 15/16 mg

In adults, the starting dose is 49/51 mg by mouth twice daily. The healthcare provider may increase the dose after several weeks to the target dose of 97/103 mg twice daily, if the medicine is well-tolerated.

The dosage for children depends on weight. The medication is taken twice daily, and the healthcare provider may adjust the dose if needed.

Who can take an angiotensin receptor/neprilysin inhibitor (ARNI)?

Men

Men can take an ARNI, as long as they do not fall into any of the restricted categories below.

Women

Women can take an ARNI, as long as they do not fall into any of the restricted categories below.

Pregnant or breastfeeding individuals

Individuals who are pregnant should never take an ARNI, because it could cause harm or cause death to the unborn baby. ARNIs also should not be taken while breastfeeding. Consult your healthcare provider for medical advice.

Children 

Children one year and older can take Entresto if they fit the criteria for use and if they do not fall into any of the restricted categories below.

Older adults

Older adults can take an ARNI, as long as they do not fall into any of the restricted categories below.

Are angiotensin receptor/neprilysin inhibitors safe?

Recalls

There have been no recalls on Entresto.

Restrictions

You should not take ARNI if:

• You are allergic to sacubitril, valsartan, or any ingredient in the medication

• You have a history of angioedema (swelling) associated with taking an angiotensin-converting enzyme (ACE) inhibitor or ARB medication

• You also take an ACE inhibitor such as enalapril or lisinopril (you should not take an ARNI within 36 hours of an ACE inhibitor)

• You also take aliskiren, and you have diabetes

• You are pregnant 

• You are breastfeeding

Does Entresto interact with other medicines?

Before you take Entresto, be sure to tell your healthcare provider about all your medications, including prescription and OTC drugs, vitamins, and supplements. 

Possible drug interactions include:

• ACE inhibitors or other ARBs should not be used with Entresto.

• People with diabetes or kidney problems should not take Entresto with aliskiren.

• Potassium-sparing diuretics (such as spironolactone), potassium supplements, or salt substitutes that contain potassium can cause an increase in potassium levels.

• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, combined with Entresto, can worsen kidney function and possibly cause kidney failure.

• Combining lithium with Entresto could result in increased levels of lithium in the body, as well as lithium toxicity. 

This is not a full list of drug interactions, and others may occur. Consult your healthcare provider for more information about drug interactions and how they may affect you. 

Are ARNIs controlled substances?

No, Entresto is not a controlled substance and does not cause abuse or dependence.

Common angiotensin receptor/neprilysin inhibitor side effects

Common side effects of Entresto include:

• Hypotension, or low blood pressure (experienced by 18% of people in clinical studies). The risk of low blood pressure is higher if you take diuretics (water pills).

• Hyperkalemia, or high potassium levels (12%)

• Cough (9%)

• Dizziness (6%)

• Kidney (renal) problems, including kidney failure (5%)

This is not a full list of adverse effects, and others can occur. Consult your healthcare provider, such as your primary care provider or cardiologist (doctor of cardiology), for more information about side effects.

How much do angiotensin receptor/neprilysin inhibitors cost?

Without insurance, Entresto costs about $924 for a one-month supply. 

For those with commercial insurance, Novartis offers a copay program. Contact the manufacturer for more information and eligibility requirements. This offer does not apply to individuals with Medicare, Medicaid, or any other federal or state insurance.

People who need financial assistance and have limited or no prescription insurance coverage may be eligible for the Novartis Patient Assistance Foundation. Eligible patients can get their medicine for free. Contact Novartis for more information and financial eligibility requirements.

Individuals with Medicare can visit the Novartis website and access a 30-day free trial of Entresto. (This free trial is available to all patients.) After the first free month, most people with Medicare prescription coverage will pay the lowest copay for brand-name drugs. You can contact your specific plan to ask about your out-of-pocket costs.

You can always visit the SingleCare website to access savings on Entresto and other prescriptions. The coupons can be used on any medication and can be reused every month. Although the price without insurance is $924 for one month, you can use a free SingleCare card or coupon to pay as low as $667 per month, a savings of $257 per month, or $3,084 per year.