Felbamate, a novel antiepileptic drug (AED), has been shown to be an effective treatment for a variety of seizure types in both adults and children. In adults, felbamate has been used for treating partial seizures with and without secondary generalization and in children it has been beneficial in treating seizures that are associated with Lennox-Gastaut syndrome. Serious and potentially life-threatening adverse effects have limited the use of felbamate. There have been 34 reported cases of aplastic anemia and 18 cases of liver failure.

John M. Pellock and colleagues reported the findings of an expert panel that evaluated data and reviewed current clinical practices with regard to felbamate (Epilepsy Research 71 (2006) 89-101). The panel determined that the effectiveness of felbamate in treating seizures that are otherwise uncontrolled by AEDs is undisputed. There are approximately 3,200 to 4,200 patients annually who are started on felbamate, and the authors note, "… during the past 10 years, it is estimated that approximately 35,000 new starts have occurred."

In pediatric patients with Lennox-Gastaut syndrome, felbamate was both effective and well tolerated. The authors noted that in a double blind controlled trial involving 73 patients, "felbamate and placebo reduced atonic seizures by 34% and 9% respectively…. Additionally felbamate resulted in a total seizure frequency decrease of 19%, compared with a 4% increase in seizure frequency among patients in the placebo group."

The panel concluded that given its risk:benefit ratio, felbamate should be considered and used with close clinical monitoring in patients with seizures that have been uncontrolled by other AEDs, following the recommendations of the American Academy of Neurology.

We asked two epilepsy experts about their use of felbamate and their reactions to the report by Pellock et al.

COMMENTS OF EPILEPSY EXPERTS

Jim Wheless
Georgia Montouris, MD
, is Co-Director of Epilepsy Services and Assistant Professor of Neurology, Boston University School of Medicine. She studied at the Universite Libre de Bruxelles, Brussels, Belgium (1975) and did her residency at Vanderbilt University School of Medicine, Nashville TN (1979). She did her post-residency at the United Cerebral Palsy Fellowship at Vanderbilt University School of Medicine, Nashville TN (1980).

Dr. Montouris's special interests are in epilepsy and seizure disorders in adults and children, pregnancy and epilepsy, and clinical trials of antiepileptic medications. Dr. Montouris is especially interested in the impact of seizure medication on pregnant women and their unborn children.

Away from Boston Medical Center, Dr. Montouris cares for her four horses and runs Epi-Camp. The camp provides recreational time for patients and families. Dr. Montouris donates availability of her horse stable in order to provide children with epilepsy and handicapped children the opportunity to ride horses safely.

Jim Wheless
Jim Wheless, MD
, is Professor and Chief of Pediatric Neurology and the Le Bonheur Chair in Pediatric Neurology at the University of Tennessee Health Science Center in Memphis. He also serves as Director of the Neuroscience Institute and the Le Bonheur Comprehensive Epilepsy Program for the Le Bonheur Children's Medical Center. He is Clinical Director and Chief of Pediatric Neurology at St. Jude Children's Research Hospital.

Dr. Wheless is a Diplomat of the American Board of Pediatrics and the American Board of Psychiatry and Neurology with special qualifications in Child Neurology and Clinical Neurophysiology. He is a fellow of the American Academy of Pediatrics.

Dr. Wheless is a member of the Editorial Board of Journal of Child Neurology, Formulary, and Epilepsy.com and serves as reviewer of a number of journals including Neurology, Epilepsia, Pediatrics, and Epilepsy & Behavior.

Dr. Wheless's primary interests include child convulsive disorders. His research is focused on pediatric anti-epileptic drug development, the ketogenic diet, epilepsy surgery, and magnetoencephalography. Dr. Wheless is the author of more than 200 chapters, articles and abstracts on these subjects. He has lectured widely on pediatric epilepsy. He received his medical degree from the University of Oklahoma and completed residency training in pediatrics at the University of Oklahoma and then pediatric neurology at Northwestern University in Chicago at Children's Memorial Hospital. His EEG/clinical epilepsy training was at the Medical College of Georgia in Augusta



When do you consider prescribing felbamate?

Georgia Montouris: In today's world it would be probably by my last line of defense to use with those in a very specialized group -- most likely for pediatric cases of refractory seizures. I say this because there are other options today. At the time I first began using felbamate this was the first new drug in 15 years. For many this was the miracle drug and still remains so. Many people swear by the drug and have remained seizure free by using it. Since then we have had many new therapies with less risk factors that would be tried well before. In certain cases, such as refractory Lennox Gastaut, or perhaps in infantile spasms, this remains a good choice when others have failed.

The only other time I might prescribe it would be for people who found that it worked for them and who took it before the scare in 1992 when cases of aplastic anemia and liver failure were reported. Today if nothing else seems to be available to help those patients with their seizures, I would consider reinitiating felbamate.

James Wheless: When prescribing felbamate, the key is the epilepsy syndrome and the seizure type(s). Before prescribing today, I might ask a subset of questions: Is the patient having drop attacks and thereby risking injury to bones, teeth, or becoming susceptible to lacerations? What prior medications has the patient used?

In terms of drop attacks -- there are some forms of intractable partial onset seizures that affect patients who are not surgical candidates. For them, felbamate might be a good choice and we might even try the drug prior to vagus nerve stimulation in some patients.

With regard to prior medicines -- I would consider reactions they might have had to other seizure medications (especially a history of drug induced rash), and any autoimmune medical illnesses (such as SLE) that would impact the decision to prescribe felbamate. If they have these risk factors (history of SLE, rash or low white blood cell count due to a seizure medication), then this would put the patient more at risk for serious side-effects from felbamate. This would affect where in the treatment hierarchy I would place the drug.

We are really individualizing the use of this drug once we go through the screening process. If it seems appropriate, because seizures are not controlled by other medications, then it would be an appropriate time to use felbamate.

With children, this tends to often put felbamate lower on the list because of the side effects. So if you think about the therapeutic sequence, felbamate is down the line.

What do you tell patients when initiating a treatment course of felbamate with respect to potential serious side effects?

Georgia Montouris: I tell them that when the drug was first introduced, I used it on over 400 patients. It was considered a miracle drug. Unfortunately after 100,000 exposures there were some serious problems -- specifically, cases of aplastic anemia and hepatic failure. Some of the hepatic failure patients did have other serious conditions such as cancer or possible organ failure from status, however, this presented as a serious adverse effect while exposed to felbamate. Nonetheless, no one under the age of 13 developed aplastic anemia. But I should also add that no one developed any problems after the first year. The serious side effects all showed within one year of exposure, noting that if one was on this drug for more than one year with no evidence of any blood or hepatic dysfunction, the risk of occurrence [of serious side effects] was not there.

James Wheless: With our patients, we have a risk-benefit discussion. When we are talking with each other I say, "I think felbamate can improve your child's seizures." However seizures for which felbamate is uniquely a benefit are not common. Usually we can tell if the drug is going to work right away. If it is going to be a home run then we know this within 4 -5 weeks. So we do regular screenings and lab monitoring to make sure it is worth it for the patient.

The flip side -- if after four or five weeks the drug is not is not helping to improve seizures, then we will get the patient right off of it. If dangerous side effects are going to occur, they will happen in the first 6 – 12 months, but not usually immediately. So we minimize the risk and give it a fair chance to see it is working for the patient. There are, of course, common nuisance side effects such as insomnia and weight loss. But we try to put the side effects in perspective.

How do you monitor patients to determine whether or not they are developing serious side effects?

Georgia Montouris: After I initiate a medication I see the patient within 4-6 weeks, with the understanding that if the patient is experiencing any side effects, they are to call me. As for blood work, I get a baseline chemistry and blood count. Then I repeat this procedure 4-6 weeks later. Typically during the first year, I have this done every 3 months. In the case of felbamate, for the first few months I might have it done more often, but the patients are not being bled every two weeks as some may suggest.

James Wheless: The most important way to monitor patients is through clear communication with families up front. We tell them what to watch for. I rely on the patient, spouse, or parent to help monitor the patient's progress and communicate with them about how to watch for signs or symptoms of toxicity. Blood work helps, but rather than blood work every four weeks, I find that open family communication is best.

How will this publication affect your decision to prescribe felbamate?

Georgia Montouris: It will not affect my decision. I have a comfort level with felbamate, but given the other choices we have today, I would reserve it for special cases and not use it as a routine 2nd or 3rd line of therapy.

I had treated over 400 patients with felbamate. The vast majority of my patients who came off the drug did so either because of side effects as insomnia or headaches or they lost too much weight. It had nothing to do with liver function problems or aplastic anemia, nor did I have any cases of these conditions. The other drugs just did not work. So the vast majority who stayed on felbamate were people who responded to it. Felbamate was a difficult drug to work with in that it has many drug –drug interactions and as such many adjustments needed to be made. Often making the adjustments enabled us to simplify the medication regimen in those patients on polypharmacy, and still achieve seizure freedom.

James Wheless: In my case it won't change what I do because I continue to start patients on felbamate. It is very effective – it is one of the more effective drugs that we have had in the past 16 years. I prescribe it and continue to have conversations with families about what they should watch for. However, if it is not a home run for the patient, we do not continue it. The study has allowed us to make better risk: benefit decisions with families.

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