Warfarin and Gemfibrozil: Interaction Details

a) Coadministration of warfarin with gemfibrozil compared to warfarin with pravastatin was associated with a 79% increased risk of a composite of gastrointestinal bleeding (GIB) or intracranial hemorrhage (ICH) within the first 30 days of concomitant use (adjusted HR, 1.79; 1.36 to 2.35) in a propensity score-adjusted cohort study of users of warfarin and antihyperlipidemics (N=236,691; median age, 71 years; 63% women). The associated increased risk with gemfibrozil was most pronounced within the first 10 days of concomitant use (adjusted HR, 2.09; 1.35 to 3.24). Additionally, coadministration of warfarin with fenofibrate products was associated with an 80% increased risk of GIB/ICH during the second month of coadministration (days 30 to 59; adjusted HR, 1.8; 1.2 to 2.7); there was no significant difference in risk within the first 30 days of concomitant use. Antihyperlipidemics studied were fenofibrate (including fenofibric acid), gemfibrozil, or a statin (ie, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin). Warfarin and individual statins (including pravastatin) did not show an increased risk of GIB/ICH ².

b) Concurrent use of gemfibrozil and warfarin was associated with elevated INR values in a 46 year-old male. The patient was stable on warfarin 45 mg/week (target range, 2.0 to 3.0) for paroxysmal atrial fibrillation for the past 9 months. During routine follow-up at a anticoagulant clinic, the patient's INR value was supratherapeutic (5.8). The only change to the patient's drug regimen was the addition of gemfibrozil 600 mg twice daily 3 weeks earlier and he denied any changes in prescription, over-the-counter or herbal products as well as changes in diet. Laboratory testing revealed no other abnormalities. The patient's warfarin dose was reduced by 22% (35 to 37.5 mg/week) which maintained a therapeutic INR value. Four months later, gemfibrozil was discontinued due to myalgia, which led to subtherapeutic INRs (1.7 to 1.8). The warfarin dose was increased to 45 mg/week and the patient maintained appropriate therapeutic INR values. The Drug Interaction Probability Scale indicated a probable interaction. An empiric dosage reduction of 20% was suggested ³.

c) Gemfibrozil was reported to inhibit the metabolism of warfarin in a 38-year-old female. The patient was maintained on warfarin 5 mg for five months when gemfibrozil 1200 mg daily in divided doses was added. Two weeks after initiation of the gemfibrozil, the patient presented with prolonged menstrual bleeding with numerous blood clots. Her prothrombin time was also elevated. The warfarin dose was reduced to 2.5 mg daily. Menstrual bleeding was resolved two weeks after the dosage change. It was determined that the patient experienced severe bleeding due to the decreased metabolism of warfarin resulting from this drug interaction with gemfibrozil ⁴.

d) A 73-year-old male who had been stabilized on warfarin 5 mg alternating with 7.5 mg daily for the previous three years was admitted to the hospital after three days of fatigue, black stools, and a large bruise on his arm. Five weeks previously, he was started on gemfibrozil 1200 mg daily for hyperlipidemia. While his international normalized ratio (INR) had averaged 2.6 during his warfarin therapy, it was increased to 43 on admission, and the prothrombin time was measured at 66 seconds. Warfarin and gemfibrozil were both discontinued, and vitamin K 10 mg was administered. Three days later, warfarin therapy was again instituted without a change in dose with resulting therapeutic INRs and no evidence of bleeding ⁵.