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GUIDELINES
CLARIFY ROLE OF NEW ANTIEPILEPTIC DRUGS
SAN FRANCISCO—In response to the FDA approval of eight new antiepileptic drugs (see Table 1) in the last decade, the American Academy of Neurology, the American Epilepsy Society, and the American Medical Association partnered to develop clinical guidelines for the pharmacologic treatment of new-onset epilepsy and refractory epilepsy. According to Sandra Olsen, MD, “these clinical guidelines are meant to enhance, rather than supplant physician judgment.” Dr. Olsen, President of the American Academy of Neurology and Professor of Clinical Neurology at the Feinberg School of Medicine, Northwestern University, Chicago, was among several speakers on a panel announcing the new guidelines at the 56th Annual Meeting of the American Academy of Neurology.
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TABLE 1
THE NEW ANTIEPILEPTIC DRUGS
Generic Name
Felbamate*
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Zonisamide
*Felbamate was addressed in a practice advisory (Neurology. 1999;52:1540-1545), and is not included in these guidelines.
Source: Adapted from Neurology. 2004;62:1252-1260.
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EVIDENCE–BASED RECOMMENDATIONS
Jacqueline French, MD, lead author of both guidelines, explained the procedure of developing the recommendations. “Our task was to take the literature and pull out what is unbiased and determine what is clearly true. We screened 1,462 articles, identified the relevant studies, and graded them. The experts on the panel were not allowed to go beyond the evidence in forming their conclusions,” Dr. French noted. She is Professor of Neurology at the University of Pennsylvania School of Medicine in Philadelphia.
Despite the vast number of articles, the panel determined that very few contained sufficient high quality evidence to merit rating as Class I trials, Dr. French said. Class I articles must be based on prospective, randomized, controlled clinical trials with blinded outcomes, in a representative population, she explained (see Table 2). Other criteria for the selection of articles included relevancy to efficacy, safety, tolerability, or mode of use; case series, observational, case control, cohort, or randomized controlled trials of human subjects; and publication in English—though randomized controlled trials could be published in any language.
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TABLE 2
ARTICLE RATING SCALE
Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a respective population. The following are required:
- primary outcome(s) is/are clearly defined
- exclusion/inclusion criteria are clearly defined
- adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a randomized clinical trial in a representative population that lacks one criterion a-d.
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment.
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.
Source: Adapted from Neurology. 2004;62:1252-1260.
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NEW–ONSET GUIDELINES
For new onset epilepsy, gabapentin had only one Class I trial, lamotrigine had three Class I or Class II trials, topiramate had two Class I trials, and oxcarbazepine had three Class I and one Class II trials, Dr. French said.
She emphasized that although new onset epilepsy is easily treated—60% of patients will be controlled with either new or old antiepileptic drugs—“the choice of the initial drug is extremely important. It can have a profound effect on that individual for years and years. The newer antiepileptic drugs could potentially offer some advantages for patients with newly diagnosed epilepsy, such as better tolerability, less effect on the body’s homeostasis, particularly liver function, and a lower FDA rating for birth defects. Although only oxcarbazepine is FDA approved for newly diagnosed partial or mixed epilepsy, we have added gabapentin, lamotrigine, and topiramate as well, even though they are not FDA approved as such.” In addition, the panel recommended lamotrigine as appropriate for newly diagnosed absence seizures (see Table 3).
Dr. French explained that FDA recommendations are based on the results of clinical trials, which are often expensive, difficult to complete, and may have difficult standards for approval. In the case of newly diagnosed epilepsy, the FDA requires demonstration of superiority over a comparator, which is difficult to do in this patient population without using placebo. “The only such trial that was completed was the oxcarbazepine trial. If the FDA standard is the only standard that is maintained, we won’t have any choices for the newly diagnosed patient.”
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TABLE 3
SUMMARY OF EVIDENCE-BASED
RECOMMENDATIONS FOR NEW-ONSET EPILEPSY
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Antiepileptic
Drug |
Newly Diagnosed
Monotherapy
Partial/Mixed |
Newly Diagnosed
Absence |
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Zonisamide |
Yes*
Yes*
No
Yes
No
Yes*
No |
No
Yes*
No
No
No
No
No |
*Not FDA approved for this indication.
Source: Adapted from Neurology. 2004;62:1252-1260. |
REFRACTORY GUIDELINES
For refractory epilepsy, the expert panel agreed with the FDA recommendations that all of the new antiepileptic drugs are appropriate for add-on therapy. There were seven Class I studies for monotherapy, four Class I studies for generalized epilepsy, four Class I studies for refractory epilepsy in children, and two Class I studies for efficacy in Lennox-Gastaut syndrome.
Additional panel recommendations for the treatment of refractory epilepsy included:
- Topiramate for withdrawal to monotherapy for partial seizures, (in addition to lamotrigine and oxcarbazepine, which are FDA approved for this indication).
- For refractory primary generalized epilepsy, only topiramate was recommended, and there was sufficient evidence to determine that gabapentin was not effective for this seizure type.
- Gabapentin, lamotrigine, oxcarbazepine, and topiramate are appropriate for children with refractory partial seizures.
- Topiramate and lamotrigine appear to be effective in Lennox-Gastaut syndrome.
OUT WITH THE OLD?
With respect to choosing between the new or old antiepileptic drugs for refractory epilepsy, the panel determined that there was no Class I evidence, leaving antiepileptic drug selection to clinical determinants such as pharmacology, side-effect profile, and risk of toxicity. While FDA rating categories for pregnancy for the new drugs are all category C (teratogenicity in animals, but human risk unknown), older antiepileptic drugs such as carbamazepine, phenytoin, and valproic acid are category D (teratogenicity in animals and humans). However, the clinical experience for new antiepileptic drugs is far more limited than for the old antiepileptic drugs, the investigators noted, and evidence for teratogenicity as well as the incidence of idiosyncratic reactions and other adverse effects may reflect this shorter duration of clinical observation.
Andres Kanner, MD, Professor of Neurology, Rush University Medical Center, Chicago, observed, “Old antiepileptic drugs can yield complete seizure control with no adverse events in a large number of patients,” but certain clinical situations require consideration of the new antiepileptic drugs. These included:
- Patients with uncontrolled seizures on old antiepileptic drugs.
- Patient with adverse events on old antiepileptic drugs.
- Patients in whom old antiepileptic drugs are interfering or may interfere with the efficacy or safety of concomitant medications.
Dr. Kanner recommended that physicians factor any past or present comorbid condition that may be affected by, or interfere with, the intended treatment of the seizure disorder. “If you are treating a chronic comorbid condition, such as hypertension, diabetes, or depression, and you are taking an antiepileptic drug that accelerates the elimination of the other drugs, you may be limiting the other drugs’ efficacy by accelerating their elimination. With respect to metabolic interactions of the new antiepileptic drugs with the birth control pill, only topiramate and oxcarbazepine in high doses affect the birth control pill,” he added.
INTERACTIONS AND ADVERSE EFFECTS
Drug interactions are a particularly important issue for the elderly, Dr. Kanner observed. “Elderly patients with epilepsy living in a nursing home take an average of four medications in addition to their antiepileptic drugs,” he said. Consequently, antiepileptic drugs that do not cause drug interactions manifest a potential advantage in this patient population.
Adverse events are another important consideration, explained Dr. Kanner, “All of the older antiepileptic drugs have been shown to impact negatively on a variety of neuropsychological measures. Two of the new antiepileptic drugs (gabapentin and lamotrigine) have been shown to have a lesser impact on neuropsychological measures than older antiepileptic drugs.”
Dr. Kanner added that although the newer antiepileptic drugs have a greater purchase price than the older antiepileptic drugs, “The higher cost of the newer antiepileptic drugs may actually be neutralized by the expenses that we have to go through in measuring blood levels (of old antiepileptic drugs) or giving additional medication.”
A VOICE FOR PATIENTS
Eric Hargis, President and Chief Executive Officer of the Epilepsy Foundation, Landover, Maryland, offered his view. “Today there is a significant gap between what can be done for patients with epilepsy and what is done. Prescribing patterns of general neurologists have not changed in the last 10 years despite the new antiepileptic drugs, so these guidelines will help. Patients and physicians need to have access to all drug options,” he said. “These new guidelines are a powerful weapon to fight restrictive formularies. These restrictions are a disaster, because one size does not fit all when it comes to epilepsy drugs. In an attempt to contain costs, Medicare, Medicaid, and insurance companies are also using formularies—supposedly based on safety, efficacy, and cost—but unfortunately this system does not guarantee that the patient is getting the best treatment,” Mr. Hargis observed.
“If patients have a seizure because they are on the wrong medication, it can cost thousands [of dollars], and patients can be forced out of work or out of school. The cost savings obtained by restricting drug access are often illusory when it comes to treating epilepsy,” he added. “We believe these guidelines will boost both the art and the science of the treatment of epilepsy. Treatment decisions need to be made by informed physicians and their patients, not by Congress, HMOs, or insurance companies.”
FARTHER STILL TO GO
Dr. French concluded that more research needs to be done, particularly head-to-head trials in newly diagnosed and refractory patients, more studies in children, more randomized clinical trials for syndromes other than partial epilepsy, and better designed trials for monotherapy. Additional clinical guidelines are in preparation by the International League Against Epilepsy, which will be published in Neurology and Epilepsia, she said.
NR
—Andrew S. Wilner, MD
Suggested Reading
French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.
French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy. Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1261-1273.
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