Apixaban × Naproxen

This pair has two mechanisms. The first is additive bleeding risk. Naproxen inhibits platelet aggregation, prolongs bleeding time and can cause ulcers and bleeding in the stomach and gut (naproxen SmPC), while apixaban blocks clotting factor Xa. Together they raise the bleeding risk (apixaban SmPC of the European Medicines Agency, EMA). The second is pharmacokinetic: naproxen inhibits the P-glycoprotein transporter that clears apixaban. A single 500 mg dose of naproxen raised the apixaban area under the curve (AUC) 1.5-fold and peak concentration 1.6-fold. Bleeding time did not change in a clinically relevant way in that study, and this kinetic effect needs no apixaban dose change (apixaban SmPC, EMA).

Black, tarry stools (melena), vomiting blood or coffee-ground material, upper abdominal pain. Other bleeding can occur: bruising without trauma, nosebleeds, blood in the urine. Risk is higher in older patients, after a previous ulcer and at higher naproxen doses (naproxen SmPC).

Avoid non-steroidal anti-inflammatory drugs (NSAIDs) in a patient on an anticoagulant when they are not needed: the European Society of Cardiology (ESC) advises offering other pain relief or disease-modifying treatment (ESC 2024). If naproxen is still needed, use the lowest effective dose for the shortest time (naproxen SmPC) and give apixaban with caution during that period (apixaban SmPC of the European Medicines Agency, EMA). For older patients and those with a previous ulcer, the naproxen SmPC recommends gastroprotection with misoprostol or a proton pump inhibitor, and suggests considering it when other drugs raise the risk of gastrointestinal bleeding (naproxen SmPC). The ESC advises a proton pump inhibitor when gastrointestinal bleeding risk is high (ESC 2024). Apixaban is contraindicated with an active or recent gastrointestinal ulcer (apixaban SmPC, EMA). Naproxen is contraindicated with active or recurrent peptic ulcer or bleeding and after previous NSAID-related bleeding, and is not recommended with creatinine clearance below 30 mL/min (naproxen SmPC). During NSAID use, the European Heart Rhythm Association (EHRA) suggests an extra blood test: haemoglobin, kidney and liver function (EHRA 2021). Stop naproxen at once if gastrointestinal bleeding or an ulcer occurs (naproxen SmPC), and also stop apixaban in severe bleeding (apixaban SmPC, EMA).