Esomeprazole/Naproxen Side Effects: What to Expect and When to Call Your Doctor

Esomeprazole/naproxen (formerly Vimovo) combines two medications—an NSAID and a proton pump inhibitor—which means its side effect profile reflects both components. Most people who take it experience mild, manageable side effects. But some serious side effects require prompt medical attention. Here's what to expect and what to watch for.

Boxed Warning: Cardiovascular and GI Risks

Esomeprazole/naproxen carries the FDA's strongest safety warning—a "Boxed Warning"—for two serious risks:

• Cardiovascular thrombotic events: NSAIDs like naproxen increase the risk of serious cardiovascular events including heart attack and stroke, even in patients without known cardiovascular disease. This risk may be higher with longer duration of use.
• Gastrointestinal bleeding and ulceration: NSAIDs increase the risk of serious GI events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These can occur without warning, especially in older adults.

The esomeprazole component is intended to reduce (but not eliminate) the GI risk. This is why the combination was developed: to allow patients who need NSAID therapy for arthritis to have better stomach protection than naproxen alone provides.

Common Side Effects (Usually Manageable)

These side effects are relatively common (occurring in 1–38% of patients in clinical trials) and often improve as your body adjusts to the medication:

• Erosive gastritis (stomach inflammation) — reported in up to 38% of patients
• Dyspepsia (indigestion/heartburn) — reported in up to 27%
• Gastritis (general stomach inflammation) — up to 17%
• Diarrhea
• Nausea
• Upper abdominal pain
• Flatulence and abdominal bloating
• Constipation
• Headache

Taking this medication on an empty stomach at least 30 minutes before a meal (as directed) helps reduce many of these GI side effects. Do not crush, chew, or split the tablet.

Serious Side Effects: Call 911 or Go to the ER

Get emergency medical help immediately if you experience:

• Signs of a heart attack or stroke: Chest pain, shortness of breath, sudden weakness or numbness on one side of the face/body, sudden vision changes, slurred speech
• Signs of serious GI bleeding: Black, tarry, or bloody stools; vomiting blood or material that looks like coffee grounds; severe abdominal pain
• Severe allergic reaction (anaphylaxis): Hives, swelling of face/throat/tongue, difficulty breathing, severe rash
• Severe skin reactions: Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis (TEN), or DRESS—rash with blistering, peeling skin, fever, or swollen lymph nodes

Call Your Doctor (Not Emergency, But Soon)

Contact your healthcare provider within 1–2 days if you notice:

• Decreased urination or blood in your urine (possible kidney problem)
• Significant swelling in your ankles, feet, or legs (possible fluid retention)
• New or worsening joint pain with a skin rash on the cheeks or arms that worsens in sunlight (possible drug-induced lupus from esomeprazole)
• Persistent diarrhea (may indicate C. difficile infection, especially with antibiotic use)
• Unusual fatigue, pale skin, or shortness of breath (possible anemia)

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Long-Term Side Effects to Monitor

With longer-term use (beyond 3 months), your doctor will likely monitor for:

• Bone fractures: Long-term PPI use (>1 year) is associated with increased risk of hip, wrist, and spine fractures. Your doctor may recommend calcium and vitamin D supplementation.
• Vitamin B12 deficiency: After 3+ years of PPI therapy, reduced stomach acid can impair B12 absorption. Symptoms include fatigue, numbness/tingling, and cognitive changes.
• Hypomagnesemia: Low magnesium levels may develop with prolonged PPI use. Symptoms include muscle cramps, irregular heartbeat, and seizures in severe cases.
• Fundic gland polyps: Benign stomach growths have been reported with long-term PPI use (>1 year). Often asymptomatic but can cause GI bleeding or obstruction in rare cases.

For information on what drugs can interact with esomeprazole/naproxen, see our guide on esomeprazole/naproxen drug interactions. To learn more about what this drug treats, read what esomeprazole/naproxen is used for.