Common Drug Interaction Endangers Patients on Warfarin

Administering the antiepileptic drug carbamazepine to patients on warfarin lowered the anticoagulant’s effects in a matter of weeks, according to a recent study, which suggested close monitoring of international normalized ratio (INR) is needed to prevent major bleeding and stroke associated with the common drug-drug interaction.

Warfarin’s narrow therapeutic window and sensitivity to small dosing changes make optimal therapeutic levels difficult to manage and increases the risks of thrombosis and severe bleeding. Carbamazepine adds to the difficulty by enhancing warfarin’s metabolism, therefore increasing the warfarin dose needed to maintain INR in therapeutic range.

To quantify the interaction between the drugs, Swedish researchers compared changes in baseline warfarin dosing before and after 10 to 13 weeks of co-treatment with carbamazepine in 166 elderly patients who were on a median weekly warfarin dose of 30 mg. Carbamazepine therapy increased the proportion of patients with INR below targeted 2.0 from 35% to 79%, which increased the average warfarin dose requirement by 49%.

The average INR dropped from 2.26 to 1.78 after a month of combined therapy and did not return to baseline levels until up to 20 weeks after carbamazepine therapy initiation, according to the researchers. Patients on low-dose warfarin (less than 30 mg per week) required greater dose increases when carbamazepine was added than patients on high-dose warfarin (higher than 30 mg per week), noted the study.

Carbamazepine-warfarin interaction is expected to cause an initial drop in INR before the warfarin dose is adjusted to counteract the increased elimination of the anticoagulant, reported the researchers. It’s during the time between carbamazepine initiation and INR measurement that patients are at increased risks of thrombosis and major bleeding. Notably, nearly half of the patients did not have their INR measured a week after carbamazepine initiation. Three weeks later, 11% of the patients still had not had their INR assessed.

Study author Dr. Marine Andersson, of the division of clinical pharmacology at the Karolinska University Hospital in Stockholm, Sweden, said the researchers were surprised by the amount of time that passed between initiation of carbamazepine therapy and adjustment of warfarin dosing, and that INR appeared to not be measured in most patients after carbamazepine therapy was given.

“The findings demonstrated the clinical importance of the warfarin-carbamazepine combination,” said Dr. Andersson. “Patients on the combination therapy should be closely monitored upon initiation and withdrawal of warfarin therapy, and warfarin dosing should increase as INR decreases.”

The study received no industry support. It was published online in the Journal of Thrombosis and Haemostasis.

—Dan Cook

Reference:

1. Mannheimer B, Andersson ML, Pettersson HJ, Lindh JD. The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost. 2016 Jan 21. [Epub ahead of print]