The FDA on Wednesday in people with cardiac disease who are taking the seizure and mental health drug lamotrigine (Lamictal) with new data.
In October 2020, the FDA added information about arrhythmia risk to lamotrigine's and medication guides based on in vitro studies. Now the agency says it wants to evaluate whether other medicines in the same drug class have similar effects and is requiring safety studies on those drugs, also.
"Other sodium channel blockers approved for epilepsy, bipolar disorder, and other indications should not be considered safer alternatives to lamotrigine in the absence of additional information," the FDA said. The agency's statement included a list of 10 such agents, including carbamazepine, phenytoin, and topiramate, for which postmarket studies must be conducted.
The addition is a very important one, said Jacqueline French, MD, of the NYU Comprehensive Epilepsy Center. "The FDA did not say this before, but now they do," she told 鶹ý.
"What they're saying now is that lamotrigine is not the only anti-seizure medicine that may have these effects," she continued. "We were worried people might see information about arrhythmia risk for lamotrigine and change to another drug, but at the end of the day they would be no better off than they were before."
The updated FDA advisory has two other important points, French noted: it recommends that patients not stop taking lamotrigine without speaking with their prescriber, and asks health care professionals to assess whether potential benefits of lamotrigine outweigh its potential risks.
One major concern about lamotrigine's possible cardiac risks remains: no one has seen the in vitro studies the FDA used as the basis for its warning, and virtually no in vivo studies have been conducted. Lamotrigine has been used widely for several decades and some neurologists have questioned why the FDA has not provided more information to support the label change.
"The FDA's warning about arrhythmias with lamotrigine treatment based on in vitro studies is irresponsible if they do not couple this with evidence of significant clinical problems in the numerous patients chronically treated with lamotrigine for epilepsy and mood disorders," Gregory Krauss, MD, of Johns Hopkins University, told 鶹ý.
In February, an International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) ad hoc task force co-chaired by French released an , saying physicians have been given little evidence about lamotrigine's potential arrhythmia risks to guide prescribing decisions, including no access to the drug's in vitro studies.
"We are aware of a by Harmer et al. that raised concerns at the FDA," the task force wrote. "While that study has limitations that bring its clinical relevance into question, it is our understanding that it led to a request by the FDA for a subsequent in vitro study from Lamictal's manufacturer, Glaxo Smith-Kline (GSK)." That work was completed in 2019 and indicated lamotrigine can weakly inhibit cardiac sodium channels, showing class IB anti-arrhythmic activity, the task force noted.
The task force requested the in vitro data from GlaxoSmithKline, but to date, it has not been provided, French said. A GSK spokesperson told 鶹ý the company is preparing the data for submission to a peer-reviewed journal. "Although we do not think that the details of the in vitro study will add information of clinical importance to the prescribing information, GSK has consistently maintained that full publication is appropriate," the company said in an emailed statement.
Risk of undiagnosed asymptomatic cardiac disease under age 60 is minimal in patients without major cardiovascular risk factors like diabetes, hypertension, familial hypercholesterolemia, or smoking, the ILAE-AES task force pointed out.
"In people over the age of 60 years, the likelihood of undiagnosed cardiac conduction abnormalities increases, and an EKG may be considered prior to initiating lamotrigine," task force members advised. "An EKG should also be considered in people younger than 60 with known cardiac disease or significant risk factors as above."