Entresto Drug Interactions: What to Avoid and What to Tell Your Doctor

Entresto (sacubitril/valsartan) is a powerful medication that affects multiple body systems — the renin-angiotensin system, kidney function, and blood pressure. Because of this, it has several important drug interactions that can be dangerous or even life-threatening. This guide covers the most critical interactions, what to watch for, and what to tell your doctor.

Tell Your Doctor About ALL Your Medications

Before starting Entresto, give your doctor and pharmacist a complete list of everything you take: prescription drugs, over-the-counter medications, vitamins, minerals, herbal products, and supplements. Even things that seem unrelated — like ibuprofen for a headache or a potassium supplement — can create meaningful interactions with sacubitril/valsartan.

CONTRAINDICATED (Never Combine)

1. ACE Inhibitors (Lisinopril, Enalapril, Ramipril, Benazepril, Captopril, etc.)

This is the most critical interaction. Combining Entresto with any ACE inhibitor dramatically increases the risk of angioedema — life-threatening swelling of the face, lips, tongue, or throat. Both drugs prevent bradykinin breakdown through different mechanisms, and together they cause bradykinin to accumulate to dangerous levels.

Rule: You must wait at least 36 hours after your last ACE inhibitor dose before taking your first Entresto dose. Similarly, wait at least 36 hours after your last Entresto dose before starting an ACE inhibitor. Never take them simultaneously under any circumstances.

2. Aliskiren (Tekturna) in Patients with Diabetes

Aliskiren is a direct renin inhibitor used for high blood pressure. Combining aliskiren with Entresto in patients with diabetes is contraindicated due to substantially increased risk of hypotension, hyperkalemia, and acute kidney injury. This combination should also be avoided in patients with impaired kidney function (eGFR < 60 mL/min/1.73m²).

3. Other ARBs (Losartan, Irbesartan, Candesartan, etc.)

Entresto already contains valsartan, which is an ARB. Adding another ARB on top creates duplicate RAAS blockade — increasing the risk of hypotension, hyperkalemia, and kidney damage. Do not take Entresto with any other ARB.

AVOID OR USE WITH CAUTION (Moderate Interactions)

4. Potassium-Sparing Diuretics (Spironolactone, Eplerenone, Triamterene, Amiloride)

Many heart failure patients take both Entresto and spironolactone (a mineralocorticoid receptor antagonist that is part of quadruple GDMT). This combination increases potassium levels. It is not contraindicated, but your doctor will monitor your potassium closely. Avoid adding extra potassium sources like supplements or salt substitutes containing potassium chloride.

5. Potassium Supplements and Salt Substitutes

Taking extra potassium while on Entresto — through supplements, high-potassium foods in excess, or potassium-containing salt substitutes — can push potassium levels into a dangerous range (hyperkalemia), which can disrupt heart rhythm. Ask your doctor or dietitian about dietary potassium guidelines while on sacubitril/valsartan.

6. NSAIDs (Ibuprofen, Naproxen, Aspirin at High Doses, COX-2 Inhibitors)

Non-steroidal anti-inflammatory drugs can reduce blood flow to the kidneys and worsen renal function, particularly in elderly patients, those taking diuretics, or those with chronic kidney disease. Combined with Entresto, the risk of acute kidney injury increases. Use the lowest effective NSAID dose for the shortest possible time, and tell your doctor if you regularly use NSAIDs for pain.

7. Lithium

Entresto (through the ARB component, valsartan) can increase serum lithium levels, raising the risk of lithium toxicity. If you take lithium for bipolar disorder or depression, your prescribers need to coordinate closely, and lithium levels should be monitored regularly.

8. Other Blood Pressure Medications and Diuretics

Adding Entresto to other blood pressure-lowering medications (beta-blockers, calcium channel blockers, loop diuretics like furosemide) increases the risk of hypotension. This is often managed by adjusting doses under physician supervision — many heart failure patients take Entresto alongside beta-blockers and loop diuretics as part of their GDMT regimen. Do not stop these medications without discussing it with your doctor.

Summary: Quick Reference Interaction Table

ACE inhibitors (lisinopril, enalapril, etc.): CONTRAINDICATED — risk of angioedema. 36-hour washout required.

Aliskiren (Tekturna) in diabetes: CONTRAINDICATED — risk of hypotension, hyperkalemia, kidney injury.

Other ARBs (losartan, etc.): AVOID — duplicate RAAS blockade.

Spironolactone / potassium-sparing diuretics: MONITOR — increased hyperkalemia risk.

NSAIDs (ibuprofen, naproxen): CAUTION — increased kidney injury risk.

Lithium: MONITOR — increased lithium toxicity risk.

Potassium supplements / salt substitutes: CAUTION — hyperkalemia risk.

Related: Entresto Side Effects

Many drug interactions with Entresto amplify its side effects. Read our guide on Entresto side effects to understand what symptoms to watch for and when to seek medical care.