Entresto (sacubitril/valsartan) has several serious drug interactions, including one that is considered an absolute contraindication: ACE inhibitors. Taking an ACE inhibitor with Entresto, or switching between them without a proper gap, can cause life-threatening swelling of the airways. Beyond that, a number of common medications and even over-the-counter products can cause dangerous reactions when combined with Entresto.
ACE Inhibitors: The Most Dangerous Interaction
The combination of Entresto with any ACE inhibitor is strictly contraindicated. ACE inhibitors include widely prescribed drugs like lisinopril, enalapril, ramipril, and benazepril. When these two drug classes overlap in the body, the risk of angioedema rises sharply. Angioedema is severe swelling that can affect the face, tongue, throat, and airway, and it can be fatal if the airway closes.
If you’re switching from an ACE inhibitor to Entresto, you need to stop the ACE inhibitor and wait at least 36 hours before taking your first dose of Entresto. This washout period gives your body time to clear the ACE inhibitor. The same 36-hour gap applies if you’re switching in the other direction. This isn’t a soft recommendation. The FDA lists it as a formal contraindication on the drug’s label.
Other ARBs
Entresto already contains valsartan, which is an angiotensin II receptor blocker (ARB). Taking a second ARB alongside it, such as losartan, candesartan, or irbesartan, doubles up on the same type of drug. This creates excessive blockade of the system that regulates blood pressure and fluid balance, increasing the risk of dangerously low blood pressure, kidney damage, and high potassium levels. There is no reason to combine Entresto with another ARB.
Aliskiren in Diabetes or Kidney Disease
Aliskiren (brand name Tekturna) is a blood pressure medication that works on the same hormonal system as Entresto. In patients with diabetes or moderate-to-severe kidney impairment (specifically, kidney filtration rates below 60), combining aliskiren with Entresto is contraindicated. The combination amplifies the risk of kidney failure, high potassium, and severe drops in blood pressure. Even in patients without diabetes or kidney disease, the combination is generally avoided.
NSAIDs Like Ibuprofen and Naproxen
Nonsteroidal anti-inflammatory drugs are among the most commonly used over-the-counter painkillers, and they interact meaningfully with Entresto. This includes ibuprofen (Advil, Motrin), naproxen (Aleve), and prescription NSAIDs like meloxicam and diclofenac.
The problem is kidney-related. Your kidneys rely on certain chemical signals to maintain blood flow through their filtering units. NSAIDs block one set of those signals, and Entresto blocks another. When both are suppressed at the same time, the kidneys can lose the ability to maintain adequate filtration. This is especially risky if you’re older, taking a diuretic (water pill), or already have reduced kidney function. Occasional use of an NSAID may not cause immediate harm, but regular or high-dose use alongside Entresto meaningfully increases the chance of kidney deterioration.
Potassium-Raising Medications and Supplements
Entresto can raise potassium levels on its own because it blocks a hormone (aldosterone’s upstream trigger) involved in potassium excretion. Adding other potassium-raising substances to the mix can push levels into a dangerous range, a condition called hyperkalemia. At high enough levels, excess potassium disrupts the heart’s electrical signaling and can cause life-threatening irregular rhythms.
Medications that compound this risk include:
- Potassium-sparing diuretics such as triamterene and amiloride
- Mineralocorticoid antagonists such as spironolactone (Aldactone) and eplerenone (Inspra)
- Potassium supplements in pill or liquid form
- Salt substitutes that use potassium chloride in place of sodium chloride
Spironolactone deserves special mention because it’s frequently prescribed alongside Entresto for heart failure. The two can be used together, but it requires regular blood tests to monitor potassium and kidney function. The salt substitute issue catches people off guard: products like Nu-Salt or Morton Salt Substitute are marketed as heart-healthy alternatives to table salt, but they’re essentially concentrated potassium. If you’re on Entresto, using these liberally can quietly raise your potassium to problematic levels.
Lithium
Lithium, used primarily to treat bipolar disorder, has a very narrow window between an effective dose and a toxic one. Drugs in the same class as the valsartan component of Entresto are known to reduce lithium clearance through the kidneys, allowing it to build up in the blood. The combination of Entresto and lithium has not been formally studied, which is precisely why it’s flagged as not recommended. If both drugs are necessary, blood lithium levels need close and frequent monitoring. Signs of lithium toxicity include tremor, nausea, confusion, and in severe cases, seizures.
Statins
One component of Entresto (sacubitril) interferes with transport proteins in the liver that are responsible for pulling certain statin medications out of the bloodstream and into liver cells where they do their work. When these transporters are partially blocked, more of the statin stays circulating in the blood, effectively increasing exposure. Research in animal models has shown that Entresto significantly increases the bioavailability of rosuvastatin (Crestor). Atorvastatin (Lipitor) and simvastatin (Zocor) have also been evaluated for the same type of interaction. This doesn’t mean you can’t take a statin with Entresto, but your prescriber may need to adjust the statin dose or monitor you for statin-related side effects like muscle pain.
Pregnancy
While not a drug interaction, this is the one additional contraindication important enough to mention. Entresto carries an FDA boxed warning, the most serious category, for fetal toxicity. The drug can cause injury and death to a developing fetus by acting directly on the hormonal system that regulates fetal blood pressure and kidney development. If you become pregnant while taking Entresto, the drug should be stopped as soon as the pregnancy is confirmed. Anyone with a prior history of angioedema related to an ACE inhibitor or ARB should also not take Entresto, as it can trigger a recurrence.