Drug Interaction Report

MONITOR: Concomitant use of lamotrigine with cenobamate may result in decreased pharmacologic effects of lamotrigine and a possible increased risk of proarrhythmias, especially in patients with structural heart disease or myocardial ischemia. According to the manufacturer, population pharmacokinetic analyses predicts that concomitant use of cenobamate (100 mg to 400 mg daily) may reduce lamotrigine plasma concentrations by 21% to 52%; however, the mechanism is unknown. In addition, in vitro studies have shown lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations. In healthy individuals, a thorough QT study did not show slowed ventricular conduction (widen QRS); however, slowed ventricular conduction and proarrhythmias may occur in patients with structural heart disease or myocardial ischemia and concomitant use of other sodium channel blockers may increase this risk.

MANAGEMENT: The potential for diminished therapeutic response to lamotrigine and potential increased risk of proarrhythmias, especially in patients with structural heart disease or myocardial ischemia should be considered during coadministration with cenobamate. Clinical and/or laboratory monitoring are advisable whenever cenobamate is added to or withdrawn from therapy, and the lamotrigine dosage adjusted as necessary. In addition, due to the potential for increased risk of proarrhythmias, the manufacturer recommends lamotrigine be avoided in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome or other sodium channelopathies). A joint task force of the International League Against Epilepsy and the American Epilepsy Society issued an advisory on Feb 25, 2021, for healthcare professionals in response to the U.S. Food and Drug Administration (FDA) safety warning on the cardiac effects of lamotrigine. For patients under 60 years with no cardiac risk factors, they advise that clinicians should prescribe lamotrigine as usual. For patients with cardiac risk (over 60 years and under 60 years with known cardiac disease or significant risk factors), they advise clinicians to consider obtaining an ECG prior to initiating lamotrigine and repeating ECG as the serum lamotrigine level approaches the upper limit of the therapeutic range and/or with concomitant use of other sodium channel blockers or substances known to impair atrioventricular and/or intra-ventricular cardiac conduction. They also advise clinicians consider obtaining an ECG and/or cardiology consult in patients with sudden onset syncope or pre-syncope with loss of muscular tone without a clear vasovagal or orthostatic cause. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate an irregular heart rhythm such as dizziness, lightheadedness, fainting, palpitation, shortness of breath, or syncope.

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.

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.