Starting Lamotrigine: Who Needs an EKG?

Andrew N. Wilner, MD; Jacqueline A. French, MD


November 22, 2022

This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I'm your host, Dr Andrew Wilner. Today I have the pleasure of speaking with a fellow epileptologist, Dr Jacqueline French, professor in the Department of Neurology at New York University Grossman School of Medicine and clinician at the New York University Comprehensive Epilepsy Center in New York City. Dr French, welcome to Medscape.

Jacqueline A. French, MD: Thank you so much for having me. It's really a pleasure.

Wilner: I heard you on another podcast talking about this topic. You were lead author of a short and concise but very important paper about the FDA's new warning on lamotrigine. Could you tell us about that?

French: We first got news that the FDA was concerned around the end of 2020 or early 2021. We woke up to a warning that the FDA had put out saying that physicians should avoid the use of lamotrigine in any patient who had a history of cardiac disease. As epileptologists, we actually think that lamotrigine — among the many drugs that are available for treatment of epilepsy — is an excellent choice, particularly among elderly people, because it doesn't cause sleepiness, memory problems, or confusion. It's pretty well tolerated overall. There are issues, because it has to be started slowly and can cause a rash. But nonetheless, epileptologists are quite enthusiastic about using lamotrigine.

Many of our patients have some sort of cardiac history. The original warning on lamotrigine said to avoid its use, and that is a strong warning that usually requires quite a bit of background indicating that harm has occurred before such a warning would be issued. But in fact, this one was based, as we found out, not on human data about people who were harmed by this drug, but on in vitro data suggesting that there was the possibility of harm.

In addition, we first spoke to our cardiology colleagues who believe very strongly that this would be a class effect. It would not be exclusive to lamotrigine, but this finding would likely be true for all of the sodium channel blockers. There are quite a few in the field, including phenytoin, carbamazepine, and other commonly used drugs. So there was a lot to take in at first when we talked to our cardiology colleagues.

They believed we should be cautious about the use of lamotrigine. It doesn't mean that there isn't an effect. It means that we should think about the effect. We should be cautious. There are patients in whom an EKG probably is warranted. But that is probably true for all of the sodium channel blockers and not just lamotrigine, and even in those patients, the drug can be safely used. Certainly nobody should consider taking their patients who are doing well on it off of lamotrigine.

We discussed these matters with the FDA. And fortunately, after several months, they made a change in the wording to the label of lamotrigine. Now it says (appropriately) that when you use this drug in certain populations, you should weigh the risks and the benefits, and that fits much better with the way we feel about it.

Wilner: This topic caught my attention because lamotrigine is widely used. It's a great drug in the epilepsy patient population. It's also approved for bipolar disorder, and it's widely used by psychiatrists even for broad mood disorder. Depakote (divalproex sodium) used to be a very popular drug for young adults, but because of the teratogenicity data, lamotrigine tends to be the go-to drug instead of Depakote. When I looked this up, it said that lamotrigine was FDA-approved in 1994 — a long time ago. Although we remember that time (we were working as epileptologists), it seems like a long time ago. Why is this information suddenly coming to light now?

French: It basically related to a an in vitro test that was done by GlaxoSmithKline, if you remember who they were. They are the manufacturers of branded lamotrigine. They had this in vitro study, and they felt obliged to report the results to the FDA. And the FDA then required them to do additional testing. And because this was proprietary data between the FDA and GlaxoSmithKline, it wasn't in the public domain at that time, so we did not have the ability to go and look at the data. We just knew that there were in vitro data supporting this.

We do believe that in people who have heart block, bundle-branch block, and other cardiac issues, there is a reason for clinicians to use lamotrigine with caution in certain populations — women of childbearing age, for example. In people under the age of 60, you probably don't need to do an EKG. But in a patient in whom you don't have an EKG and you are thinking about starting lamotrigine, it's probably a good idea just to get an EKG in patients with a history of any cardiac issues, to make sure that there's no bundle-branch block, Brugada syndrome, or something else that would make you concerned.

The good news is that we used to think that having to titrate lamotrigine was a bad thing. But in this case, it's a good thing because at the low doses that you start with, there really is very little concern for harm. You have a little time to get that EKG in case there isn't one on the patient's chart, and you have time to act on the EKG and refer the patient to a cardiologist if you find something unexpected. It doesn't interfere with starting the drug when you want to start it.

Wilner: So, from a practical point of view, if it's a young, healthy patient under age 60, you don't have to do anything different?

French: Unless they have a cardiac history, and then you want to look at them.

Wilner: If they have a cardiac history or they are older than 60, you should get an EKG. You can get the EKG the same day that you write the prescription. Is that right?

French: As a neurology community, I've heard a lot of people significantly push back on this because we're not accustomed to getting EKGs first. My husband, who is an infectious disease specialist, said it happens quite often that they have to get an EKG before starting different medications. To him, it seemed like a nothingburger, as they say. But to a neurologist who's not accustomed to it, it sounds like an enormous burden. But I just want to reassure everybody that it really isn't. In this day and age, quite frankly, 95% of our patients have an EKG on their chart from some visit or other at the time we're seeing them. And if they don't, it's not a bad idea for us to get an EKG because there is an interaction between the brain and the heart.

Wilner: Back to our experience with lamotrigine. We've been using it for 10 years, right? A decade. How is it that if this risk for arrhythmia and death is real, nobody noticed?

French: This is very interesting. There are a lot of data to support that there is no risk. Since this warning came out, meta-analyses have been published suggesting that there really isn't a smoking gun, and that the sodium channel blockers as a group pose a higher risk for cardiac death than other drugs that you might expect.

Unfortunately, in the epilepsy world, sudden death is not uncommon. Sudden unexplained death in epilepsy (SUDEP) occurs in 1 out of 1000 people with epilepsy, and the risk is higher in certain groups. If the incidence were much lower than that it would get lost, because we would presume that any sudden death was a SUDEP. So, it's a little difficult for us to get a signal. That's why people have looked again to see whether SUDEP deaths or overall deaths are higher than expected in this group. So far, it's been relatively reassuring.

In addition, studies have been done of lamotrigine vs other drugs in elderly people. If this is occurring (which again, I don't think that there is a very high risk), it must be an extremely low risk because when you do studies of several hundred people, you don't see it even if you start with an elderly population. Any risk that might be present is hidden within the larger group of people who have other reasons for SUDEP.

Wilner: Now, in terms of the cardiac workup, you mentioned the EKG. Is there any reason to get a cardiology consult or an echo, or is a normal EKG good enough?

French: If the EKG is normal, you don't have to worry. I'm happy to say that an article was written by the International League Against Epilepsy, a collaboration of neurologists and cardiologists. We knew that the community would need operational instructions on what to do, and that is exactly what is in that article. It's very clearly written: who needs an EKG, who doesn't need an EKG. If the EKG is abnormal, these are the kind of abnormalities that would not bother you, and these are the kinds of abnormalities that require a cardiology consult.

Wilner: One last question: Does the FDA work in total isolation? It would seem to me that if you're going to come out with a warning about an epilepsy drug, you would talk to the epilepsy people first. Does that happen? It didn't look like it happened. How does this work?

French: They actually don't, because they are concerned that we might be biased in favor of our drugs, which, of course, we probably are. However, I run something through the Epilepsy Foundation (where I'm chief medical innovation officer) called the Research Roundtable for Epilepsy. This occurs once a year. We actually sit down with the members of the FDA who are involved in approving epilepsy drugs. So, we can increase the lines of communication. It's been working extremely well. There may be differences of opinion, and we sit down at the table and discuss them. It has led to real improvement in the communication. Our colleagues at the FDA are doing their best and they're really smart people. It's a question of getting that information across in both directions.

Wilner: Terrific. Well, Dr French, is there anything you'd like to add before we close?

French: I will just add what I said when I gave a talk on this at the American Epilepsy Society meeting, which is don't panic. Continue to use lamotrigine because it's an excellent drug.

Wilner: Yes. I'll feel reassured when I'm writing that script and explaining to the patient; I'll keep that "over 60, under 60, no heart disease" in mind. It's been a great discussion. Thank you for sharing your insights on this important topic with Medscape.

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