A new warning now sits beneath the list of life-threatening allergic reactions that can happen with lamotrigine. The anticonvulsant is suspected of causing cardiac arrhythmias in susceptible patients by slowing ventricular conduction and widening the QRS. A similar warning has long been in effect with carbamazepine, and both drugs are thought to exert this effect through sodium channel blockade. The problem is distinct from QTc prolongation, another cause of arrhythmias, which is seen with antidepressants and antipsychotics but not with lamotrigine (Rudd GD and Sake JK, Br J Clin Pharmacol 2011;71(6):963).

The American Epilepsy Society pushed back against the labeling, citing a lack of clinical support for the warning, which was based on two in-vitro studies. However, I counted six case reports of ventricular arrhythmias on lamotrigine, and the problem is well documented in lamotrigine overdose (Dream A et al, Am J Emerg Med 2018;36(7):1324.e1–1324.e2). While that suggests the risk is real, it is likely uncommon, considering lamotrigine has been in widespread use since 1994.

The original warning from October 2020 advised clinicians to “avoid” lamotrigine in at-risk patients. Last month, the FDA lightened the language to recommend weighing the risks and benefits, in line with carbamazepine’s labeling. Patients most in need of this risk-benefit consideration are those with cardiac conduction disorders (second- or third-degree heart block, bundle-branch blocks), ventricular arrhythmias, heart failure, ischemic or structural heart disease, and sodium channel disorders (eg, Brugada syndrome). Combining lamotrigine with other sodium channel blockers, such as carbamazepine, would be expected to increase risk for conduction delay.

TCPR’S TAKE: Lithium, carbamazepine, the antipsychotics, and now lamotrigine all carry warnings about cardiac arrhythmias, leaving valproate (Depakote) as the only mood stabilizer unmarked by this risk. No one is recommending routine EKGs before starting lamotrigine, but if your patient has known cardiac conduction delay or significant ischemic or structural heart disease, a friendly consultation with a cardiologist is advised.