Know What Interacts with Entresto Before You Start

Entresto (Sacubitril/Valsartan) is a powerful heart failure medication — but like many prescription drugs, it can interact with other medications, supplements, and even certain foods. Some of these interactions are dangerous. Others are manageable with the right monitoring.

This guide covers the most important drug interactions to be aware of, so you can have an informed conversation with your doctor and pharmacist.

How Drug Interactions Work

A drug interaction happens when one substance changes how another substance works in your body. This can mean:

• Increased effects — one drug makes another stronger, potentially causing dangerous side effects
• Decreased effects — one drug makes another weaker, reducing its benefit
• New side effects — the combination creates problems that neither drug would cause alone

Entresto affects two major body systems — the natriuretic peptide system and the renin-angiotensin-aldosterone system (RAAS). Medications that also affect these systems, or that impact blood pressure, kidney function, or potassium levels, are the ones most likely to interact.

Medications That Interact with Entresto

Major Interactions (Contraindicated or High-Risk)

These are interactions your doctor will strictly avoid or manage very carefully:

ACE Inhibitors

Examples: Lisinopril, Enalapril, Ramipril, Benazepril, Captopril

Risk: Contraindicated. Taking Entresto with an ACE inhibitor dramatically increases the risk of angioedema — a potentially life-threatening swelling of the face, lips, tongue, or throat. You must stop your ACE inhibitor and wait at least 36 hours before starting Entresto. This is one of the most critical safety rules with this medication.

Aliskiren (Tekturna)

Risk: Contraindicated in patients with diabetes. Combining Entresto with Aliskiren in diabetic patients increases the risk of kidney problems, dangerously low blood pressure, and high potassium. In non-diabetic patients, the combination should still be avoided or used with extreme caution.

Potassium-Sparing Diuretics

Examples: Spironolactone (Aldactone), Eplerenone (Inspra), Amiloride, Triamterene

Risk: Increased risk of hyperkalemia (dangerously high potassium). Many heart failure patients do take Spironolactone alongside Entresto — it's part of guideline-directed therapy — but this combination requires frequent potassium monitoring through blood tests. Your doctor will watch this closely.

Lithium

Risk: Entresto can increase lithium levels in the blood, raising the risk of lithium toxicity. Symptoms of lithium toxicity include tremor, nausea, confusion, and in severe cases, seizures. If you take Lithium for bipolar disorder or another condition, your doctor will need to monitor your lithium levels more frequently.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

Examples: Ibuprofen (Advil, Motrin), Naproxen (Aleve), Diclofenac, Celecoxib (Celebrex), Meloxicam

Risk: NSAIDs can worsen kidney function and reduce Entresto's blood-pressure-lowering effect. They can also increase the risk of kidney impairment, especially in patients who are already dehydrated or have existing kidney problems. Occasional use may be okay for some patients, but regular NSAID use should be avoided. Talk to your doctor about alternatives for pain management — Acetaminophen (Tylenol) is often a safer choice.

Moderate Interactions (Use with Caution)

These interactions don't necessarily prevent you from taking both medications, but they require monitoring:

Potassium Supplements

Risk: Since Entresto already raises potassium levels, adding potassium supplements increases the risk of hyperkalemia. Don't take potassium supplements unless your doctor specifically prescribes them and monitors your levels.

Other ARBs

Examples: Losartan (Cozaar), Candesartan (Atacand), Irbesartan (Avapro), Olmesartan (Benicar)

Risk: Entresto already contains Valsartan, an ARB. Taking another ARB on top of it creates dual RAAS blockade, which increases the risk of low blood pressure, high potassium, and kidney problems. There's no reason to take Entresto and another ARB together.

Trimethoprim

Risk: Trimethoprim (found in the antibiotic Bactrim/Septra) can increase potassium levels. Combined with Entresto, this raises the risk of hyperkalemia. If you need an antibiotic and are on Entresto, make sure your doctor knows so they can choose the safest option or monitor your potassium.

Cyclosporine

Risk: Cyclosporine may increase levels of Sacubitril in the blood, potentially increasing side effects. If you take Cyclosporine (for organ transplant, autoimmune conditions, etc.), your doctor should monitor you more closely when starting Entresto.

Supplements and Over-the-Counter Products to Watch

It's not just prescription drugs that can interact with Entresto. Pay attention to these:

• Potassium supplements — As noted above, avoid unless prescribed. This includes potassium chloride tablets and liquid potassium.
• Salt substitutes — Many "lite salt" or sodium-free salt substitutes contain potassium chloride. Using these while on Entresto can push potassium levels dangerously high.
• NSAIDs (OTC) — Ibuprofen (Advil, Motrin) and Naproxen (Aleve) are available over the counter. Just because you don't need a prescription doesn't mean they're safe to combine with Entresto. Use Acetaminophen (Tylenol) instead when possible.
• Herbal supplements affecting blood pressure — Supplements like hawthorn, garlic extract, and CoQ10 may have blood-pressure-lowering effects. While not strictly contraindicated, they could add to Entresto's blood pressure effect and increase dizziness or lightheadedness. Mention any supplements to your doctor.

Food and Drink Interactions

Entresto has no major food interactions — you can take it with or without food. However, a few dietary considerations are important:

• Potassium-rich foods: If your potassium levels are already on the high side, your doctor may recommend limiting foods like bananas, oranges, potatoes, tomatoes, and spinach. You don't need to eliminate these foods — just be mindful if your blood work shows elevated potassium.
• Alcohol: Alcohol can lower blood pressure. Since Entresto also lowers blood pressure, drinking alcohol may increase your risk of dizziness, lightheadedness, or fainting. Moderate your intake and talk to your doctor about what's safe for you.
• Grapefruit: Unlike some heart medications, Entresto does not have a known clinically significant interaction with grapefruit juice.

What to Tell Your Doctor

Before starting Entresto, make sure your doctor and pharmacist have a complete picture of everything you take. This includes:

• All prescription medications — especially ACE inhibitors, ARBs, diuretics, Lithium, and blood pressure medications
• Over-the-counter medications — particularly NSAIDs (Ibuprofen, Naproxen) and any cold/flu medications that contain them
• Supplements and vitamins — especially potassium supplements, salt substitutes, and herbal products
• Your complete medical history — kidney problems, liver disease, diabetes, and any history of angioedema are all relevant
• If you're pregnant, planning to become pregnant, or breastfeeding — Entresto is contraindicated in pregnancy due to fetal toxicity

Don't assume your doctor knows about everything you take. Many patients take OTC products or supplements without mentioning them. A complete list helps your healthcare team keep you safe.

Final Thoughts

Entresto is a highly effective heart failure medication, but understanding its interactions is essential for staying safe. The biggest rules to remember: never combine it with an ACE inhibitor (wait 36 hours), avoid NSAIDs when possible, and watch your potassium — through diet, supplements, and salt substitutes.

Keep a current list of all your medications and share it with every healthcare provider you see. And if you're ever unsure whether something is safe to take with Entresto, ask your pharmacist — they're trained in drug interactions and can give you a quick answer.

For more about Entresto, explore our guides on side effects, how it works, and how to save money on your prescription.