Ibuprofen × Metformin

There is no direct pharmacokinetic interaction: in the FDA label, ibuprofen 400 mg did not change the concentration of metformin 850 mg, and metformin did not change ibuprofen. The risk runs through the kidney. Ibuprofen, like other non-steroidal anti-inflammatory drugs (NSAIDs), inhibits the synthesis of prostaglandins that maintain renal blood flow. In vulnerable patients it causes fluid retention and an acute drop in kidney function. The kidney clears metformin, so when the glomerular filtration rate (GFR) falls the drug accumulates. Metformin accumulation is the main risk factor for lactic acidosis. The metformin label names NSAIDs directly among drugs that can acutely impair kidney function and raise the risk of lactic acidosis.

The first signal is worsening kidney function: rising creatinine and falling glomerular filtration rate (GFR), less urine, oedema from fluid retention. Elderly patients and those with dehydration, heart failure or diuretic treatment are most at risk. Lactic acidosis starts quietly: acidotic dyspnoea, abdominal pain, muscle cramps, weakness and hypothermia, then reduced consciousness up to coma. Laboratory findings: blood pH below 7.35, lactate above 5 mmol/L, a widened anion gap.

The combination is acceptable under kidney monitoring. Ibuprofen is started with caution in a patient on metformin (metformin label, 4.4), and kidney function is followed closely while both are used (metformin label, 4.5). Glomerular filtration rate (GFR) is measured before metformin is started and then regularly: at least once a year, and every 3–6 months in the elderly and in patients at risk of progressive kidney disease (metformin label, 4.2 and 4.4). At GFR below 30 mL/min both drugs are contraindicated (metformin and ibuprofen labels, 4.3). Ibuprofen is given at the lowest dose for the shortest time, with monitoring, especially in heart, liver or kidney disease, on diuretics and in the elderly (ibuprofen label, 4.4; FDA ibuprofen label, Renal Effects). With dehydration from diarrhoea, vomiting, fever or low fluid intake, metformin is paused (metformin label, 4.4). Ibuprofen is contraindicated in severe dehydration (ibuprofen label, 4.3). No pharmacokinetic dose change is needed: ibuprofen 400 mg does not change metformin 850 mg exposure and vice versa (FDA metformin label, 12.3). If lactic acidosis is suspected (acidotic dyspnoea, abdominal pain, muscle cramps, weakness, hypothermia), metformin is stopped and the patient needs immediate medical care (metformin label, 4.4).