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New Epilepsy Drugs, More Solutions

Schuster, Larry

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Atrial attorney, married with two children in college, has epilepsy for a decade, the result of a benign brain tumor. He was on a combination of two older drugs. But with the drugs, he needed 12 hours of sleep daily; he used to need only eight hours a day. He switched to a new anti-epileptic drug which helped him to resume his regular schedule.

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A 35-year-old mother of three young school-age children is vacationing in Florida with her family. One morning, she begins having convulsions. She is rushed back home, but the doctors can't find out what triggered her epilepsy. Even with a combination of medications—first an older one, then a newer one added—her seizures continue. She is unable to drive and, at times during a seizure, she falls and hits her head hard, leading to talk she may have to wear a helmet to protect herself. The solution? Taking her off both medications and putting her on yet another new one.

A third-grade teacher develops epilepsy after a bout with encephalitis. She is treated with what is now described as an older class of drugs, considered the therapies of choice more than a decade ago. Finally, her doctor switched her to a new group of drugs, and she's been seizure-free for three years.

All of these patients who asked to be anonymous to protect their privacy had epilepsy from different causes. But they all found relief from side effects or from persistent seizures in trying a different drug: in these cases, by using newer drugs, some of which were used in a different way than the Food and Drug Administration (FDA) approved.

“The take-home message is you have to keep finding different drugs until you find the one that works for you,” says their neurologist, Jacqueline A. French, M.D., a professor of neurology at the University of Pennsylvania School of Medicine in Philadelphia. “I see many people who are on the older drugs and are doing well; but they're not for everyone.”

At the same time, such success stories don't mean new drugs have a greater chance of stopping seizures in a particular patient compared to any other drug, and, in fact, there's no evidence that they do, says Andres M. Kanner, M.D., a professor of neurological sciences at Rush Medical College in Chicago, Ill. If the older one fully prevents all seizures and is working without side effects, leave well enough alone, he cautions.

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Newer Drugs, More Options

What this means, though, is that patients and their doctors have additional options. But these new choices also can present challenges. Since 1990, the FDA has approved seven new drugs for epilepsy, but only one— oxcarbazepine (Trileptal)—is approved for use as the first drug that can be tried. All the others were approved for use only in combination with other drugs, the exception being lamotrigine (Lamictal), which can be phased in with increasing doses, while the previous drug is phased out completely.

Doctors have found that many of these drugs are also effective for use as a single epilepsy drug, used right from the start. Yet many general neurologists and other physicians who treat epilepsy patients in private, non-academic practices hesitate to use these drugs in any way other than recommended by the FDA, even when studies support these additional applications. Physicians at epilepsy centers at major universities are more likely to base their decisions on scientific studies, many of which were not available to the FDA when the drugs were approved, Dr. Kanner says.

To help physicians sort through studies from the last 15 years, the American Academy of Neurology (AAN) published new guidelines in 2004 for the treatment of epilepsy featuring the seven new epilepsy medications. Dr. French and Dr. Kanner co-chaired that committee.

“We do think the drugs not approved for single therapy impact patients quite a bit,” Dr. French says. “Some insurance companies are not willing to pay for off-label use and physicians won't use them for fear of liability.” “Off-label” refers to the common practice of using drugs in ways not precisely approved by the FDA.

And that insurance issue can be significant, as the newer drugs can cost five to 10 times more than the other drugs. Drug companies have set up programs to assist patients who have financial concerns, but Dr. French says the paperwork can be a daunting disincentive for doctors to get involved with such drug issues. Patients who find their seizures are not being controlled should ask their doctors for a referral to see an epilepsy specialist.

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The New Drugs in the Guidelines

Specifically, the AAN guidelines recommend four of the new drugs for newly-onset epilepsy: oxcarbazepine, gabapentin (Neurontin), lamotrigine, and topiramate (Topamax).

The guidelines also recommended seven new drugs as additional medications for adults who have seizures that haven't responded to other medications: gabapentin, lamotrigine, topiramate, levetiracetam (Keppra), oxcarbazepine, tiagabine (Gabitril), and zonisamide (Zonegran).

In either case, the recommendations don't guarantee the new drugs will completely stop all the seizures; though, for some people, they may. As is often the case in medicine, not all people respond in the same way to each drug. But, as Dr. French and other doctors note, they do provide important new options for patients and their doctors to consider. It is hard to know which drug is better for a particular patient in a given scenario because there have been no large studies comparing one drug to another.

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Older Drugs and Unwanted Side Effects

But there are some general concepts to keep in mind, Dr. French notes. The older drugs tend to cause adverse side effects, such as sleepiness and weight gain, more often than many newer drugs. Dropout rates in trials of newly diagnosed patients were higher on the older drugs, meaning patients may be more likely to stay on the newer ones.

Also, the older drugs, such as phenytoin (Dilantin) or carbamazepine (Tegretol), can dampen the activity of other medicines, so people on chemotherapy, cholesterol-lowering therapy, or contraceptive drugs may not be getting their full benefit. This would be a valid reason for switching to a newer antiepileptic drug that does not interfere with other medications.

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Using the Guidelines

It's also important that the drugs don't cause other health problems, and at the same time solve multiple types of epilepsy if they arise. Tracy Glauser, M.D., an associate professor of pediatrics and neurology, and director of the Comprehensive Epilepsy Program at Cincinnati Children's Hospital, who also worked on the AAN guidelines, recalls treating a 10-year-old girl who had a combination of problems which the guidelines helped to remedy. His patient had childhood absence epilepsy, which is characterized by brief staring spells lasting less than 30 seconds, often hundreds of times a day. In addition, the girl also suffered an episode of convulsions, sometimes referred to as grand mal seizures.

The two drugs used for decades for this type of seizure are ethosuximide (Zarontin) and valproic acid (Depakote). The problem was that ethosuximide doesn't prevent convulsions and valproic acid causes weight gain, but the girl was already overweight.

From his work on the guidelines, Dr. Glauser says he learned that lamotrigine had been used successfully for absence epilepsy, and was also effective against convulsions; with it, however, about 10 percent of children get a rash, and perhaps one in 1,000 develops a severe rash. To minimize the possibility of rashes, Dr. Glauser started the girl on a lower dose and gradually increased it. “The child did well, and has been seizure-free for one year,” Dr. Glauser says. If she remains seizure-free for two years, he will consider stopping the medication.

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Seeking Seizure Freedom

Ultimately, says Dr. Kanner, the patient has to decide whether their treatments are getting them to what he calls “complete seizure freedom.”

“Even one seizure every six months can be quite disabling. One seizure a year is one too many. Today the goal of therapy is to eliminate all the seizures. Some patients may say, ‘I've learned to live with my seizure.’”

But that's a highly risky attitude, notes Dr. Kanner, because people with epilepsy are 25 to 40 times more likely than those in the general population to die suddenly and unexpectedly. And that risk even applies to patients who say they are not bothered by their seizures.

But in search for the better therapy, patients should not spend countless years trying every last drug, Dr. Kanner says. For patients with temporal lobe epilepsy, the most common form, the first drug has a 50-percent chance of stopping the seizures, regardless of whether it's a newer or older drug; if that doesn't work, there is a 20-percent chance a second drug will, regardless of whether it's a newer or older drug. A third drug has a less than 10-percent chance of stopping the seizures, he says. So after a second drug fails, or at most the third drug, a patient should be evaluated for surgery.

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Clinical Trial Watch

Tracy Glauser, M.D., is leading a study, sponsored by the National Institute of Neurological Disorders and Stroke, that seeks to compare lamotrigine, valproic acid, and ethosuximide, the most commonly used drugs in childhood absence epilepsy. The five-year study is enrolling more than 400 children, ages 2 to 13, at 20 centers around the country. The study is still recruiting patients. For more information, contact Jim Feuer, (513) 636-4656, jim.feuer@cchmc.org, or clinicaltrials.gov/ct/show/NCT00088452?order=1.

FOR MORE INFORMATION

See the Guidelines

More information on the American Academy of Neurology's guidelines on the newer epilepsy drugs can be obtained by calling the AAN at (800) 879-1960 or downloading the following documents:

ANN Guideline Summary for Patients and Their Families Efficacy and Tolerability of the New Antiepileptic Drugs for Treatment of New Onset Epilepsy: http://aan.com/professionals/practice/pdfs/patient_ep_onset_c.pdf

Efficacy and Tolerability of the New Antiepileptic Drugs for Treatment of Refractory Epilepsy: http://aan.com/professionals/practice/pdfs/patient_ep_refract_c.pdf

©2005 American Academy of Neurology

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