Interactions between repaglinide and Lopid (gemfibrozil)
gemfibrozil and repaglinide (Major Drug-Drug)
GENERALLY AVOID: Coadministration with gemfibrozil may significantly increase the plasma concentrations of repaglinide. Rare cases of severe hypoglycemia have been reported in patients taking this combination during postmarketing surveillance. The proposed mechanism is gemfibrozil inhibition of organic anion transporting polypeptide (OATP) 1B1-mediated hepatic uptake and CYP450 2C8-mediated metabolism of repaglinide. In a study of 12 healthy volunteers, gemfibrozil (600 mg orally twice a day for 3 days) increased the area under the plasma concentration-time curve (AUC) of repaglinide (0.25 mg single dose) 8.1-fold compared to placebo and prolonged its half-life from 1.3 to 3.7 hours. The magnitude of interaction is even greater with the addition of a CYP450 3A4 inhibitor. In the same study, gemfibrozil plus itraconazole (200 mg initially, then 100 mg twice a day for 3 days) increased repaglinide AUC 19.4-fold and half-life to 6.1 hours. Plasma repaglinide concentration at 7 hours was increased 28.6-fold by gemfibrozil and 70.4-fold by gemfibrozil plus itraconazole. Gemfibrozil alone and with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide as indicated by serum insulin and C-peptide concentrations measured for 3 hours postdose. In contrast, gemfibrozil and itraconazole increased the Cmax and AUC of nateglinide (30 mg single oral dose) by just 30% and 47%, respectively, and had no significant effects on the blood glucose response to nateglinide.
MANAGEMENT: Concomitant use of gemfibrozil and repaglinide should preferably be avoided whenever possible. If the patient is already taking gemfibrozil or repaglinide, then the other drug should not be started. If the patient is already taking the combination, then blood glucose concentrations should be carefully monitored and the repaglinide dosage adjusted as necessary. Patients taking repaglinide and gemfibrozil should not take itraconazole due to the synergistic metabolic inhibitory effect of gemfibrozil and itraconazole on repaglinide. Alternatives to gemfibrozil in patients taking repaglinide include bezafibrate and fenofibrate, which have been shown not to interact pharmacokinetically with repaglinide. In patients treated with gemfibrozil with or without itraconazole, nateglinide may be an appropriate substitution for repaglinide.
