Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- combination therapy of gemfibrozil with dasabuvir
- …gemfibrozil is a CYP2C8 inhibitor, which may increase exposure of CYP2C8 substrates when administered concomitantly… gemfibrozil inhibits OATP1B1 and may increase exposure of drugs that are substrates of OATP1B1…
- a precautionary statement for dose reduction of drugs that are mainly metabolized by the CYP2C8 enzyme when gemfibrozil is used concomitantly;
- a subsection to detail the impact of gemfibrozil on dasabavir’s AUC and Cmax in support of the contraindication for concomitant use of gemfibrozil with dasabuvir;
- information from in vitro studies showing the effect of gemfibrozil on CYP enzymes, UGTA enzymes and OATP1B1 transporter.
WARNINGS and PRECAUTIONS
- Concomitant Anticoagulants – Caution should be exercised when warfarin is given in conjunction with LOPID. The dosage of warfarin should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been definitely determined that the prothrombin level has stabilized.
- Combination therapy of gemfibrozil with simvastatin
- The concomitant administration of gemfibrozil with simvastatin is contraindicated. Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly...
- HMG-CoA Reductase Inhibitors: The concomitant administration of Lopid with simvastatin is contraindicated
- Colchicine: Myopathy, including rhabdomyolysis, has been reported with chronic administration of colchicine at therapeutic doses. Concomitant use of Lopid may potentiate the development of myopathy. Patients with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when prescribing Lopid with colchicine, especially in elderly patients or patients with renal dysfunction.
Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration 7 hours after thedose. In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinide increases the risk of severe hypoglycemia and is contraindicated
- Bile Acid-Binding Resins: Gemfibrozil AUC was reduced by 30% when gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as colestipol (5 g). Administration of the drugs two hours or more apart is recommended because gemfibrozil exposure was not significantly affected when it was administered two hours apart from colestipol
- Combination therapy of gemfibrozil with repaglinide (due to the risk for severe hypoglycemia)
- Repaglinide: In healthy volunteers, co-administration with gemfibrozil increased the plasma concentration of repaglinide and prolonged its hypoglycemic effects. Coadministration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia and is contraindicated.