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Approval of (Lamictal™) lamotrigine by the FDA as adjunctive treatment for primary generalized tonic-clonic seizures in children and adults. How does it impact care?
On September 25, 2006, the FDA approved the adjunctive use of Lamictal™ (lamotrigine) for treatment of primary generalized tonic-clonic (PGTC) seizures in children and adults, aged 2 years and over. Lamotrigine had been previously approved for adjunctive use of partial epilepsy in that same age range. What impact does this new FDA indication have for the treatment of PGTC seizures?
PGTC seizures and their treatment
Primary generalized tonic-clonic seizures, formerly known as “grand mal” seizures, are somewhat more common in children, similar to other generalized seizure types and syndromes. It is important to differentiate these generalized seizures from a complex partial seizure with secondary generalization, as the treatment can be very different. These seizures are often seen in older children and adults, and in many cases are parts of either generalized epilepsy syndromes or idiopathic generalized epilepsy. Some examples include juvenile myoclonic epilepsy, juvenile absence epilepsy, generalized tonic-clonic seizures upon awakening, and several others. In these syndromes, PGTC seizures may be infrequent when compared to absence or myoclonic seizures. However, PGTC seizures can be very dramatic and are more likely to be associated with injury and even mortality.
Fortunately, PGTC seizures are often very treatable with commonly used anticonvulsant medications. The vast majority of patients will be controlled with medications. Prior to this study, only topiramate had FDA approval for the adjunctive treatment of PGTC seizures. Valproate had been used for decades for PGTC, however, and is effective in nearly 80% of adults, but had not undergone the FDA scrutiny to receive actual approval.
Lamotrigine study for PGTC seizures
The information leading to the recent FDA approval for lamotrigine for PGTC seizures came from two published studies. The adult study of 117 adults, aged 2-55 years, was published in Neurology in 2005. A smaller subset analysis of the larger study was more recently published in the July 2006 issue of Pediatrics by Dr. Edwin Trevathan from Washington University in St. Louis and colleagues, evaluating 45 children with PGTC only (partial epilepsy patients excluded). All patients had previously tried at least 1-2 other anticonvulsants, typically valproate. They were randomized to either placebo or increasing doses of lamotrigine over 12 weeks, followed by a 12-week maintenance phase. The target doses of lamotrigine for children under 12 were 3 mg/kg/day for those receiving valproate and 6-12 mg/kg/day for those not. In children over age 12 years, the target lamotrigine doses ranged from 200-400 mg/day.
Regardless of this limitation, the results were positive. Significantly more patients receiving lamotrigine as maintenance therapy experienced at least a 50%
reduction compared to placebo (72% versus 49%, p<0.05). In children, the median percent decrease in PGTC seizures frequency was 77% in the 21 patients receiving lamotrigine, compared to 40% of the 24 children receiving placebo, p=0.04. There was a nonsignificant trend towards a higher likelihood of seizure freedom for children as well, 48% with lamotrigine compared to 17% of placebo. Side effects were low in both groups, with only one non serious rash reported (in an adult).
Parameters and guideline information for PGTC seizures
How does this information compare with published treatment guidelines by the major neurology and epilepsy societies? In 2004, an American Academy of Neurology practice guideline on epilepsy was published in Neurology. This guideline evaluated all the current literature on epilepsy treatments, and for PGTC, stated that only topiramate had either Level A or B evidence for its use. Lamotrigine, at that time, had insufficient evidence (“Level U”) for its use. Just recently, in July of 2006, the International League against Epilepsy sponsored their own practice parameter, which was published in Epilepsia. They determined that no medications met their Class A or B criteria for the treatment of PGTC seizures in either adults or children, although valproate was the most commonly studied. They believed for most anticonvulsants, PGTC or otherwise, there existed a “marked deficiency” in evidence.
What do the experts say?
What impact do these parameters have on the practicing neurologist? Certainly, no physician would quote the AAN and ILAE parameters to a patient or parent and subsequently not prescribe any anticonvulsant. Most neurologists and epileptologists treat based on a combination of smaller, retrospective studies in existence, posters and presentations at conferences and presentations, and their own anecdotal experience with the newer anticonvulsants. One additional resource has been the recent emergence of “expert consensus guidelines” that have been published in Epilepsy and Behavior for adults in 2001 and 2006 and Journal of Child Neurology in 2005. These surveys of identified adult and pediatric epileptologists provide an instant consultation of sorts, with the experts given at the time clinical scenarios and then asked for their opinion of reasonable anticonvulsant choices. These surveys reflect the “real world” decision-making we make as neurologists, and FDA approval has no bearing on these choices. For the initial treatment of PGTC in adults, valproate was the highest ranked anticonvulsant, followed closely by lamotrigine and topiramate. Levetiracetam and zonisamide were also judged as “usually appropriate” as first-line therapy. For the pediatrics expert opinion survey, valproate was also the top choice for most scenarios of GTCs, followed by topiramate and zonisamide. In children with symptomatic GTC seizures, lamotrigine was a second choice. In both surveys, phenytoin, carbamazepine, and oxcarbazepine, were determined to be “equivocal” therapies.
What impact and influence does this study have?
This study of lamotrigine is the latest in a recent flurry of scientific studies of new anticonvulsants for generalized epilepsies. Although unlikely to significantly change the current practice patterns of most epileptologists who are already clearly using lamotrigine for PGTC, the increase in scientific investigation of the generalized epilepsies as demonstrated by this study is good news for those of us treating children. Other studies have led to the FDA approval of levetiracetam for the myoclonic seizures associated with juvenile myoclonic epilepsy, lamotrigine for absence seizures, and years ago felbamate for Lennox-Gastaut syndrome. Hopefully this trend will continue, however, this author hopes specifically for the more refractory idiopathic and symptomatic generalized epilepsies, as opposed to relatively easy-to-control seizures such as PGTC. There is a clear need for further randomized, controlled studies of both newer anticonvulsant drugs as well as nonpharmacologic therapies (ketogenic diet and vagus nerve stimulation) for conditions such as Lennox-Gastaut syndrome, infantile spasms, myoclonic-astatic epilepsy, and the progressive myoclonic epilepsies. Should the pharmaceutical companies find efficacy for these difficult-to-control conditions, there would truly be a significant positive impact on the epilepsy community.
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