Drug Interaction Report

MONITOR: Data from a nested case-control study suggest that coadministration with levetiracetam or valproic acid may reduce the therapeutic effects of the direct-acting oral anticoagulants (DOACs) apixaban, dabigatran, and rivaroxaban. The mechanism of interaction has not been established. In humans, neither levetiracetam nor valproic acid has been reported to have significant effects on the CYP450 3A4 metabolic enzyme or P-glycoprotein (P-gp) efflux transporter, the primary pharmacokinetic pathways affecting the in vivo disposition of these DOACs. The study was conducted on a cohort of new users of DOACs from January 1, 2010 to August 24, 2020 identified in the computerized database of Clalit Health Services, which provides comprehensive health care for more than half of the Israeli population. Of 79,302 patients with a diagnosis of atrial fibrillation (AF), 48,907 (54.8%) had been dispensed apixaban; 27,914 (31.3%) rivaroxaban; and 12,463 (14.0%) dabigatran. Patients with concomitant use of levetiracetam (n=9) or valproic acid (n=15) had an increased risk of stroke or systemic embolism compared to matched controls, with an adjusted odds ratio of 2.26 and 2.38, respectively. In the 7 of 9 patients who were treated with levetiracetam and the 13 of 15 patients who were treated with valproic acid without concomitant known enzyme-inducing antiepileptics (e.g., carbamazepine, phenobarbital, phenytoin), the adjusted odds ratio for risk of stroke or systemic embolism was 2.56 and 2.55, respectively, compared to no use of these medications.

MANAGEMENT: The potential for diminished pharmacologic effects of apixaban, dabigatran, and rivaroxaban should be considered during coadministration with levetiracetam or valproic acid. Alternative treatments or dosage adjustments may be required if an interaction is suspected. Some experts recommend avoiding the concomitant use of DOACs with valproic acid.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.