Warfarin Institute of America
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GEMFIBROZIL - WARFARIN INTERACTION
Gemfibrozil is documented to be a potent inhibitor of the cytochrome P450 2C9 (CYP2C9) enzyme.1-5 There are however few case reports of a major interaction with warfarin, which is extensively metabolized by the CYP450 pathway.1,2,4,5 Inhibition of warfarin metabolism can significantly increase the risk of bleeding and can be shown by elevations in the international normalized ratio (INR).2,4,5
Our patient was on a stable regimen of warfarin at a dose of 6 mg per week for about 16 months. The patient is using warfarin for the prevention of a stroke secondary to atrial fibrillation with a target INR of 2.0-3.0. As of 8/20/06 the patient was taking the following medications: aspirin 81mg daily, digoxin 0.125mg every other day, carvedilol 12.5mg twice daily, spironolactone 12.5mg daily, KCl 10mEq daily, glipizide 5mg twice daily, isosorbide dinitrate 30mg daily, hydralazine 20mg twice daily, amiodarone 200mg twice daily, and vitamin D 50,000 international units once weekly. On 8/21/06 the patient was started on gemfibrozil 600mg twice daily for elevated triglycerides.
When the INR was measured on 8/25/06 a value of 7.7 was observed, and the patient was instructed to hold warfarin until his next visit to the anti-coagulation clinic on 8/28/06. The patient experienced a prolonged nose bleed, visited the local emergency department, and was admitted to the hospital on 8/26/07. When the patient returned to the anti-coagulation clinic on 8/31/06 he had not received any warfarin for a total of 7 days and his INR was measured at 5.4. The patient was instructed to continue holding warfarin until his next visit on 9/7/06 at which time his INR was found to be 1.6. The gemfibrozil was discontinued on 9/13/06. Warfarin was re-initiated at a dose of 1.5mg per week on 9/7/06. On 9/14/06 the INR was measured at 1.6 and the warfarin dose was increased to 2mg per week. On 10/3/06 the INR was 1.0 and the warfarin dose was again increased to 6mg per week. On 10/19/06 the INR was back in the target range at 2.0 and the patient was continued on warfarin 6mg per week.
The interaction between warfarin and gemfibrozil appears to have a delayed onset (days) and in this case resulted in hospitalization due to bleeding.1-4 The INR returned to normal (1.0) after the patient was off of warfarin for a total of 14 days. The manufacturer of gemfibrozil recommends INR monitoring until definite stability can be established when the drug is combined with warfarin.2,3 There are currently no empiric dosage reductions for warfarin when gemfibrozil is added, however, further data may suggest that this be the case in order to prevent warfarin related adverse events.2,3
References:
1. Klasco RK (Ed): DRUG-DEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://0-www.thomsonhc.com.library.uchsc.edu:80 (cited: 10/19/06).
2. Lilja JJ, Backman JT, Neuvonen PJ. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. British Journal of Clinical Pharmacology. Apr 2005;59(4):433-9.
3. Physicians' Desk Reference (electronic version), Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://0-www.thomsonhc.com.library.uchsc.edu:80 (cited: 10/19/06).
4. Rindone JP, Keng HC. Gemfibrozil-warfarin drug interaction resulting in profound hypoprothrombinemia. Chest. Aug 1998;114(2):641-2.
5. Wen X, Wang JS, Backman JT, Kivisto KT, Neuvonen PJ. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metabolism Disposition. Nov 2001;29(11):1359-61.
©2006 Michael J. Andrews Used by permission.
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Last updated October 22, 2006
