Task Force Tackles FDA Lamotrigine Cardiac Risk Warning

Task Force Tackles FDA Lamotrigine Cardiac Risk Warning

A joint task force of the American Epilepsy Society (AES) and International League Against Epilepsy (ILAE) has issued an advisory to address concerns arising from a Food and Drug Administration (FDA) warning of cardiac risk in patients taking the antiseizure drug lamotrigine.

The task force is concerned that the FDA warning is based on data not yet widely available, and that its sweeping nature has caused alarm among patients and physicians alike.

Dr Jacqueline French

Task force co-chair Jacqueline French, MD, professor at New York University’s Comprehensive Epilepsy Center, New York City, described the wording in the FDA warning as “quite strong” and told Medscape Medical News that recommending doctors “avoid use” of lamotrigine is concerning.

Neurologists have been “happily” prescribing lamotrigine to their patients with epilepsy for 30 years, said French. Many other antiseizure drugs may affect cognition and concentration and make patients sleepy, “but lamotrigine is one of the few drugs that actually is mildly alerting,” she added.

The task force advisory addresses key issues, including which patients can safely take lamotrigine and when an ECG is warranted. Importantly, the task force advisory also notes there’s no apparent arrhythmia risk of lamotrigine therapy in patients without heart disease.

The FDA updated lamotrigine labeling last October, stating the drug may increase risk for arrhythmia in patients with heart conditions. The warning is based on unpublished in vitro data from GlaxoSmithKline, the company that produces Lamictal, the brand name version of lamotrigine.

The FDA guidance says use of lamotrigine, a sodium channel blocker, should be avoided in patients with cardiac conduction disorders including second- or third-degree heart block, ventricular arrhythmias, or myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies.

Cardiac Concerns

According to the new labeling, in vitro testing showed lamotrigine “exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations.”

In addressing this new labeling, the task force was somewhat restricted because members don’t have access to the data that the FDA warning was based on, said French. “The FDA basically told us what their conclusion was about the data, but they did not share the data.”

She added the task force was told the data “is internal to GlaxoSmithKline, who are in the process of publishing it and therefore don’t want to make it public at this time.”

While in vitro data indicate lamotrigine has Class 1B antiarrhythmic sodium channel blocking properties, research shows there’s no change in ventricular conduction (QRS duration) in healthy individuals and those with epilepsy without heart disease, said the advisory. A modest increase in the AV conduction interval (PR prolongation) may occur, especially at high doses, it noted.

The authors also said lamotrigine does not prolong repolarization (no change in QT interval) in healthy people at thorough QT testing.

“Thus, based on the absence of QRS or QT changes, and only mild PR prolongation even at high doses, there is not an apparent arrhythmia risk of lamotrigine therapy in healthy people without heart disease,” said the advisory.

Addressing whether clinicians should order an ECG in healthy patients to look for underlying cardiac disease, the advisory stressed the risk of undiagnosed asymptomatic cardiac disease under age 60 is minimal in the absence of major cardiovascular risk factors such as diabetes, hypertension, familial hypercholesterolemia, and smoking.

“Prescribe as Normal”

“So for people under 60 with no cardiac risk factors, clinicians should just prescribe as normal,” said French.

However, in those over age 60, the likelihood of undiagnosed cardiac conduction abnormalities increases, and an ECG may be considered prior to initiating lamotrigine in these patients, said the advisory. An ECG should also be considered in patients younger than 60 with known cardiac disease or significant risk factors.

As lamotrigine must be titrated slowly, and cardiac adverse events are dose-related, the initial ECG can generally be obtained while titrating — mainly when the patient is at the first dose of 25 mg/day.

If the drug is used in patients at risk, a repeat ECG should be considered at the target dose, typically “when the target dose (or the serum lamotrigine level) is near or above the upper limit of the therapeutic range, and always in the presence of concomitant use of other sodium channel blockers or substances known to impair atrioventricular and/or intra-ventricular cardiac conduction.”

The advisory authors suggest clinicians consider obtaining an ECG and/or cardiology consult in patients on lamotrigine with sudden onset syncope or pre-syncope with loss of muscular tone without a clear vasovagal or orthostatic cause.

The task force also emphasized that non-specific ECG abnormalities, including nonspecific ST-segment and T-wave abnormalities, are not concerning, and should not preclude individuals with these abnormalities from being prescribed lamotrigine.

French noted that just because this data surfaced on lamotrigine doesn’t mean cardiac complications are necessarily unique to this drug.

“It just means that someone checked it on lamotrigine; it could in fact be true of all other sodium channel blockers.”

The task force includes a cardiologist who is “probably one of world’s experts on the impact of sodium channel blockers on the heart,” said French.

She pointed out that patients with epilepsy occasionally die from sudden unexplained death from epilepsy (SUDEP). In light of the FDA warning, if such a patient was on lamotrigine, it might raise more questions about what caused the death.

To date, the European Medicines Agency (EMA) has not added any warnings to lamotrigine labeling.

“We reached out to them and they told us they are reviewing the data and will make a determination,” said French.

The task force advisory will be published in upcoming epilepsy journals and French and her colleagues are organizing a webinar to discuss it.

French receives NYU salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Adamas, Aeonian/Aeovian, Anavex, Arvelle Therapeutics Inc, Athenen Therapeutics/Carnot Pharma, Axovant, Baergic Bio, Biogen, Biomotiv/Koutif, BioXcel Therapeutics, Blackfynn, Bloom Science, Bridge Valley Ventures, Cavion, Cerebral Therapeutics, Cerevel, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epiminder, Epitel, Equilibre, Fortress Biotech, Greenwich Biosciences, GW Pharma, Idorsia, Ionis, Janssen Pharmaceutica, J&J Pharmaceuticals, Knopp Biosciences, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte Inc, Neurelis, Neurocrine, Novartis, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc, Passage Bio, Pfizer, Praxis, Redpin, Sage, Shire, SK Life Sciences, Sofinnova, Springworks, Stoke, Sunovion, Supernus, Takeda, UCB Inc, West Therapeutic Development, Xenon, Xeris, Zogenix, and Zynerba.

French reports she has also received research grants from Biogen, Cavion, Eisai, Engage, GW Pharma, Lundbeck, Neurelis, Ovid, Pfizer, SK Life Sciences, Sunovion, UCB, Xenon, and Zogenix as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is chief medical/innovation officer for the Epilepsy Foundation for which NYU receives salary support. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Adamas, Arvelle Therapeutics Inc, Axovant, Biogen, Blackfynn, Cerevel, Crossject, CuroNz, Eisai, Engage, Idorsia, Lundbeck, NeuCyte Inc, Neurelis, Novartis, Otsuka, Ovid, Pfizer, Redpin, Sage, SK Life Science, Sunovion, Takeda, UCB, Xenon, and Zogenix.

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