Rufinamide, the generic name for a medication used to control both convulsive and non-convulsive seizures, is not yet approved for use in the United States. In European countries, rufinamide is marketed under the brand name Inovelon® for adjunctive therapy in Lennox-Gastaut Syndrome, a severe form of epilepsy that develops in early childhood.
Eisai Medical Research, Inc. acquired exclusive North American and European manufacturing and marketing rights to rufinamide from Novartis Pharma, AG, in 2004.
Currently the US Food and Drug Administration (FDA) is seeking to determine whether to approve rufinamide as an add-on therapy for two uses: partial seizures with or without secondary generalization in adults and adolescents 12 years of age and older, and Lennox-Gastaut syndrome in children ages 4 and over.
We asked two experts for their opinions regarding rufinamide: John Pellock, MD, Professor and Chairman, Division of Child Neurology at Virginia Commonwealth University and Rajesh Sachdeo, MD, Department of Neurology at Robert Wood Johnson University Hospital.
COMMENTS OF EXPERTS
John M. (Jack) Pellock, MD is Chairman of the Division of Child Neurology, Vice Chairman of the Department of Neurology and Professor of Neurology, Pediatrics, Pharmacy and Pharmaceutics at the Medical College of Virginia, Virginia Commonwealth University Health System, in Richmond, Virginia.
Dr. Pellock is a diplomate of the American Board of Pediatrics and of the American Board of Psychiatry and Neurology with Special Qualification in Child Neurology. He is a fellow of the American Academy of Neurology and the American Academy of Pediatrics and is a member of several professional organizations including the American Neurological Association, The Child Neurology Society, and the American Epilepsy Society where he is Treasurer. He has been included in Best Doctors in America and Who’s Who in America and Internationally.
Dr. Pellock has been Principal Investigator for over 80 trials evaluating epilepsy treatments in children and adults, and a co-investigator for many others. He is funded by the NIH for various studies in pediatric and adult epilepsy. Dr. Pellock has been involved in antiepileptic drug development and studying epilepsy in children for over thirty years. Dr. Pellock is a member of the editorial board of the Journal of Child Neurology, Pediatric Neurology, Epileptic Disorders, Journal of Pediatric Pharmacology and Therapeutics and serves as reviewer of a number of journals including the New England Journal of Medicine, Neurology, Epilepsia, and Pediatrics. He has published extensively and lectured widely on pediatric epilepsy He received the 2004 J. Kiffin Penry Award for Excellence in Neurology from the American Epilepsy Society.
Rajesh C. Sachdeo, MD, is Clinical Professor of Neurology, where he has served since 1996 at the University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School. Dr. Sachdeo did his fellowship in Neurophysiology and Epilepsy at Rush-Presbyterian St. Luke’s Medical Center in Chicago.
Dr. Sachdeo is a Fellow of the American Academy of Neurology, Fellow of the American EEG Society, Fellow of the American Epilepsy Society, a member of the American Association of Electromyography and Electrodiagnosis and American Academy of Clinical Neurophysiology, Fellow of the Academy of Medicine and Honorary Member of the New Jersey Academy of Developmental Medicine. He is also recipient of the Humanitarian Award from the New Jersey Epilepsy Foundation. Dr. Sachdeo has extensive experience in conducting clinical trials. He has been a Principal Investigator for over 100 clinical trials. Dr. Sachdeo has written and co-authored numerous articles on epilepsy.
What are the current challenges in treating patients with Lennox-Gastaut syndrome?
John Pellock: Unfortunately we are unable to help most of these persons become seizure-free. Although we have used valproate and there have been some advances in the past 20 years with other medications, the results are not as beneficial as we would like to see. For example we have had trials with felbamate, lamotrigine, and topiramate. While these show some benefits with some individuals, the results have been disappointing either because of lack of ability to control side effects or lack of efficacy.
Rajesh Sachdeo: This is one of the worst of all epilepsy syndromes. There are several seizure types that occur and seizures are difficult to control. Prognosis is not good. I use two drugs, lamotrigine and topiramate, but each has its own side effects. Lamotrigine creates bad dreams and nightmares, and there is a risk of serious drug rash. Children are tired and eventually become angry or stubborn. Topiramate can cause cognitive and behavior problems in and of itself. So these children have a very difficult time. It is a real burden on the family. Many of these children end up in group homes.
To compensate for side effects, I give lamotrigine in the morning and topiramate at night. In this way, the children can sleep well. I use both together very often since it is, in my opinion, one of the best combinations for Lennox-Gastaut.
What is your impression of the clinical trials data for rufinamide?
John Pellock: The clinical trials using rufinamide for Lennox-Gastaut are impressive. The results of the trials place it with the best treatments we have available today, if not superior to those that we now have. The size and scope of the study suggests that this agent will certainly be clinically useful.
Rajesh Sachdeo: For Lennox-Gastaut there is no question in my mind that rufinamide reduced the frequency and types of seizures. The patients seemed to tolerate the drug very well. It is not clear whether this will ultimately change prognosis. I am looking forward to rufinamide being available for my patients.
How do you think the results of the clinical trials will translate to clinical practice?
John Pellock: I believe that once available, rufinamide will be used by most clinicians who are treating persons with Lennox-Gastaut. The first uptake will probably be used by clinicians who are familiar with the medication because they participated in clinical trials. Others, when presented with the data, will slowly add it for use with patients who have refractory Lennox-Gastaut syndrome. As more experience is reported, wider use will occur, if the drug remains as promising as the studies suggest.
Rajesh Sachdeo: My feeling is when you look at the efficacy for Lennox-Gastaut patients with seizures, I think we will see success since the drug was well tolerated in the trials. But I don’t want to be boldly optimistic. Having seen what happens when drugs are manufactured for widespread use and there are many people using them, I need to be cautious. Felbamate is an example. We thought it was a very good drug. Then patients began having serious side effects. My mentor, Frank Morrell used to say: “New drugs have papers written showing efficacy. Old drugs have papers written showing side effects. With new drugs, we are hopeful and we have a tendency to look at the efficacy. Nonetheless side effects take time and numbers.”
However, I will be using rufinamide for patients with whom we have not seen success with other drugs.
What are your concerns with regard to using a new drug to treat children?
John Pellock: My concerns -- again, we want to look at side effects. I think that wider experience will carefully define side effect profiles. I have not seen anything that is overwhelmingly dangerous right now, but we need to follow its course as it is given to many more patients. Also, we will learn how to best use this drug in certain combinations and we need to check the titration schedule. I think the information about the trials is very encouraging.
Rajesh Sachdeo: With Lennox-Gastaut the seizures are so bad, and the problems so severe that I have a different threshold for using it because choices are very limited. For other types of seizures we have lots of choices. But with Lennox-Gastaut many medications make the seizures worse.
What are your concerns with regard to using a new drug to treat partial seizures in adults and adolescents 12 years of age and older?
John Pellock: First of all I think for people with refractory epilepsy we should give them the opportunity to use all drugs. But what do I feel about the data regarding partial seizures? It is not as robust shall I say as it is for those with Lennox-Gastaut. But certainly it is “acceptable.” However, experience will dictate acceptable titration schedules. During early trials very strict titration schedules must be followed. But in clinical use faster or more delayed titration -- when beginning a new drug -- are developed depending on patient tolerability. I believe the initial recommended dosing and titration will be done as in the studies reported. The information is encouraging and will probably be the basis of the initial package insert.
Rajesh Sachdeo: For partial seizures, I did not find rufinamide to be useful, and for this form of epilepsy there are other anti-epileptics (e.g. Trileptal) which are available with a proven track record. I was not impressed with clinical results regarding partial seizures at all. I am not sure if I would use it. Time will tell us.
Given that other drugs effective for Lennox-Gastaut syndrome are effective in other epilepsy syndromes, do you anticipate that rufinamide may be effective for other epilepsy syndromes? If so, which ones?
John Pellock: I think that for those persons with multiple seizure types we will have to acquire more trials and investigation and experience to determine how good rufinamide will be with myoclonic seizures and other seizure types. We need more numbers and more information to determine if it will be as effective for persons with less refractory seizures – or much less encephalopathy. However, I would hope that additional experience and trials will demonstrate what we need.
Rajesh Sachdeo: Having seen the efficacy in Lennox-Gastaut, it is possible that rufinamide may work for myoclonic seizures and perhaps absence seizures, but we do not have enough data. However, we don’t have too many good choices for myoclonic and absence seizures. We use Depakote often. So I do think people will be using it, off-label.