Methotrexate × Naproxen

Naproxen, like other prostaglandin synthesis inhibitors, reduces methotrexate clearance and may increase its toxicity (naproxen SmPC). With high-dose methotrexate, NSAID co-administration produced high and prolonged methotrexate levels, up to fatal haematological and gastrointestinal toxicity (AEMPS and FDA methotrexate labels). Naproxen has a half-life of 12–17 hours (FDA label), so its effect lasts longer than that of short half-life NSAIDs.

Mucositis, leukopenia, thrombocytopenia, rising creatinine within 1–2 weeks.

With high-dose methotrexate (oncology regimens, e.g. osteosarcoma), do not give naproxen before or during administration; the AEMPS and FDA methotrexate labels state this directly and give no washout interval. With low-dose methotrexate (rheumatology, psoriasis), the combination may be used with caution: monitor full blood count and renal function, especially if the two are taken less than 24 hours apart. With impaired renal function, including mild impairment, the combination is not recommended (methotrexate SmPCs, including EMA).