Use of Newer Anti-epileptic Drugs

Major new evidence-based guidelines on epilepsy treatment from the American Academy of Neurology (AAN) encourage physicians to make far greater off-label use of 7 antiepileptic medications that have come on the market in the last 10 years.
                                       These newer medications are substantially more expensive and generally not more effective than the older drugs that most physicians still prescribe today. But the newer agents have far fewer important side effects, and on balance their use is demonstrably preferable in many common clinical situations, Dr. Jacqueline A. French said at the annual hmeeting of the AAN.
                                      The commonly used older antiepileptic drugs—phenytoin, now 50 years old, as well as carbamazepine, phenobarbital, valproic acid, and primidone, all approved prior to 1980-still have an important role. Many of the estimated 2.5 million Americans with epilepsy do fine on them. But many others do not.
                                        At state-of-the-art epilepsy centers where physicians are familiar with the newer agents, about half of patients with new-onset epilepsy start on one of the newer drugs. Most patients with refractory epilepsy receive a newer drug or a combination of newer and older agents, Dr. French said at a joint American Medical Association/AAN/American Epilepsy Society–sponsored press briefing on the new guidelines.
                                      The 23-member guidelines panel included neurologists, epilepsy specialists, pharmacists, and physicians from the National Institute of Neurological Disorders and Stroke. They evaluated 1,462 studies and other research articles on the 7 most recently approved antiepileptic drugs: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide.Dr. French and the panel cochair, Dr. Andres M. Kanner, blasted the U.S. Food and Drug Administration (FDA) for what they characterized as an overly rigid antiepileptic-drug approval process that has had a detrimental effect on patient care. All 7 of the newer antiepileptic drugs are approved as add-on therapies in patients with refractory seizures, but only one-oxcarbazepine-has received an indication as monotherapy in newly diagnosed patients. Such restricted approval has led, in the panelists’ view, to serious underutilization of the newer drugs. Based upon a thorough review of comparative and dose-controlled trials, the guidelines panel deemed 3 additional newer antiepileptic drugs to be appropriate monotherapy for partial- or mixed-seizure disorders.
In addition, the guidelines include 1 newer agent—lamotrigine—as an appropriate evidence-supported option for children with newly diagnosed absence seizures. Evidence for the efficacy of the newer antiepileptic agents in patients with other newly diagnosed, generalized epilepsy syndromes was judged unpersuasive.
                                       The problem with the FDA approval policy, Dr. French said, is that it requires placebo-controlled trials, which have been done only for oxcarbazepine among the 7 newer antiepileptic agents. It’s highly unlikely that similar trials will ever be done again, given that epilepsy is a life-threatening condition. The European drug-approval process, in which newer antiepileptic drugs are compared with older ones in order to prove efficacy, makes much more sense in this situation, she added.
                                       Dr. Kanner, an associate professor of neurological sciences at Rush Medical College in Chicago, highlighted patient populations for whom the newer medications are particularly worthy of consideration:
 Children
with epilepsy have increased rates of learning disabilities and attention-deficit disorder, and need anantiepileptic drug with the least possible impact upon cognitive function. All of the older agents have been shown to have a negative cognitive effect, in contrast to 2 newer agents—gabapentin and lamotrigine —which are free of such adverse effects.
· Women of childbearing age.
 Most of the older antiepileptic drugs can cause failure of oral contraceptives and an increased risk of unwanted pregnancy due to accelerated elimination of the estrogen component. At high doses, topiramate and oxcarbazepine can have a similar effect, but the other newer antiepileptic agents don’t have this drawback. In addition, the teratogenicity profile of the newer agents is generally more favorable, Dr. Kanner said.
                                      The AAN guidelines have been published in 2 parts. The first addresses the efficacy and tolerability of the new antiepileptic drugs for new-onset epilepsy. The second focuses on the use of these drugs in the treatment of the 30% to 40% of patients who have refractory epilepsy. The guidelines appear back to back in Neurology (62[8]:1252-60; 1261-73, 2004).

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