FDA Warning: Lamotrigine Risk with Cardiac Disorders

In 2021: Based on in-vitro studies, FDA added the following Cardiac rhythm and conduction abnormalities warning to lamotrigine package insert:

  • Lamotrigine could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias.

We have collected data from the FDA drug safety communication, lamotrigine package insert and advisory from International League Against Epilepsy (ILAE) / American Epilepsy Society (AES) Task Force on this FDA warning, and have summarized this topic in the following six sections:

  1. What is the mechanism behind this cardiac risk?

  2. Which patient population is at risk?

  3. Who needs EKG before initiating lamotrigine?

  4. Which EKG findings warrants against starting lamotrigine?

  5. When to repeat the EKG during lamotrigine treatment?

  6. How to educate your patients?

(1) What is the mechanism behind this cardiac risk?

  • Lamotrigine exhibits Class IB antiarrhythmic activity (at therapeutically relevant concentrations) –> inhibits human cardiac sodium channels (with rapid onset and offset kinetics and strong voltage dependence)

(2) Which patient population is at risk?

In Heathy individuals: lamotrigine did not slow ventricular conduction (widen QRS) at therapeutic doses.


Following patient population is at risk, where lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death:

(a) Cardiac conduction disorders:

  • second‐ or third‐degree heart block

(b) Ventricular arrhythmias

(c) Cardiac disease or anamoly:

  • Myocardial ischemia
  • Heart failure
  • Valvular heart disease
  • Congenital heart disease
  • Ventricular arrhythmias
  • Cardiac channelopathies: Brugada syndrome

(d) Drug interactions:

  • Concomitant use of other sodium channel blockers
  • Multiple risk factors for coronary artery disease (see below)


Based on studies done in dogs: Lamotrigine’s 2-N-Methyl metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block.

  • Note that similar cardiovascular effects from this metabolite are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine.

However, plasma concentrations of this metabolite could be increased in the following patient population with a reduced capacity to glucuronidate lamotrigine:

(a) Patients with liver disease

(b) Drug Interactions:

  • patients taking concomitant medications that inhibit glucuronidation.

(3) Who needs EKG before initiating lamotrigine?

(a) Age > 60 years:

  • everyone needs EKG because the likelihood of undiagnosed cardiac conduction abnormalities increases.

(b) Age < 60 years + major cardiovascular risk factors such as:

  • Diabetes
  • Hypertension
  • Familial hypercholesterolemia
  • Smoking

(c) Age < 60 years + known cardiac disease

(4) When is EKG needed for patient already on lamotrigine?

When a patient on lamotrigine is now presenting with:

  • sudden onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.

(5) Which EKG findings warrants against starting lamotrigine?

  • 2nd‐ and 3rd‐degree heart block
  • Brugada syndrome
  • Arrhythmogenic ventricular cardiomyopathy
  • Left bundle branch block (LBBB)
  • Right bundle branch block (RBBB) with left anterior or posterior fascicular block. 

Refer them to cardiology for further evaluation and clearance. 

(6) When to repeat the EKG during lamotrigine treatment?

If used in people at risk (as discussed above), a repeat EKG should be considered in following two scenerios:

(a) at the target dose:

  • mainly when the target dose (or the serum lamotrigine level) is near or above the upper limit of the therapeutic range

(b) Drug Interactions:

  • Always in the presence of concomitant use of other sodium channel blockers or substances known to impair atrioventricular and/or intraventricular cardiac conduction.

(7) How to educate your patients?

  • Lamotrigine could lead to irregular or slowed heart rhythm.
  • This risk is increased in patients with underlying cardiac disease or heart conduction problems or who are taking other medications that affect heart conduction.
  • Patients should be made aware of and report cardiac signs or symptoms to their healthcare provider right away.
  • Patients who develop syncope should lie down with raised legs and contact their healthcare provider


  • 03-31-2021 FDA Drug Safety Communication (FDA Website)
  • Lamotrigine package insert (PDF)
  • FDA safety warning on the cardiac effects of lamotrigine: An advisory from the Ad Hoc ILAE/AES Task Force. Epilepsia Open. 2021 Feb 25;6(1):45-48. (PMID: 33681647)

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