CME Efficacy and tolerability of the new antiepileptic

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Mission statement The Quality Standards and are hypermetabolized This can lead to reproductive. the Therapeutics and Technology Assessment Sub dysfunction and osteopenia 3 Enzyme inducing AEDs. committees of the American Academy of Neurology produce important interactions with many commonly. are charged with developing practice parameters for used medications such as warfarin oral contracep. neurologists for diagnostic procedures treatment tives calcium channel antagonists and chemothera. modalities and clinical disorders The selection of peutic agents to name a few 4 Valproic acid in. topics for which practice parameters are used is contrast is a potent hepatic inhibitor There is con. based on prevalence frequency of use economic im troversy about the impact of valproic acid on the. pact membership involvement controversy ur hormonal milieu 5 6 and inhibition leads to important. gency external constraints and resources required drug interactions with AED as well as other classes. This practice parameter summarizes the results of The newer agents are involved in many fewer drug. the evidence based assessment regarding the effi interactions Many of the newer agents have little if. cacy tolerability and safety of seven new antiepilep any effect on the CYP450 enzyme system and other. tic drugs in the management of new onset partial or metabolic pathways. generalized epilepsy They are gabapentin Neuron Tables 1 through 4 provide a listing of serious and. tin lamotrigine Lamictal topiramate Topamax nonserious adverse events common drug drug inter. tiagabine Gabitril oxcarbazepine Trileptal leveti actions effect of comorbid conditions and pharmaco. racetam Keppra and zonisamide Zonegran These kinetics for the drugs discussed in this parameter. antiepileptic drugs were approved by the Food and Recent studies7 8 have indicated that patients with. Drug Administration in the last 10 years We recog newly diagnosed epilepsy can be categorized into. nize that these are antiseizure and not antiepileptic those who are treatment responsive or treatment re. drugs Nevertheless we have decided to use in this sistant In fact approximately two thirds of patients. assessment the term antiepileptic drugs given its will become seizure free with the first or second drug. widespread use administered In recent studies these treatment. responsive patients responded to low doses of essen. Background and justification Almost 2 million tially all the AEDs studied both old and new. people in the United States have epilepsy A large Although this information can be interpreted as an. epidemiologic study of Rochester MN showed an indication that no new drugs are needed in this pa. age adjusted epilepsy prevalence of 6 8 1 000 popula tient group another completely different conclusion. tion and the cumulative incidence through age 74 can be arrived at Because these patients will remain. was 3 1 1 2 In the last 10 years felbamate and on the initial or second therapy for several years. seven antiepileptic drugs AEDs gabapentin lam and because they will respond to most drugs the. otrigine topiramate tiagabine oxcarbazepine leve burden is on the treating physician to select the AED. tiracetam and zonisamide were approved by the that is the most tolerable has the lowest potential. Food and Drug Administration FDA The purpose for harm and has the least likelihood of negatively. of this assessment is to provide the clinician with impacting quality of life At the same time there. evidence based data on the efficacy safety and mode must be evidence from valid well controlled trials. of use of these new AEDs which can facilitate the that the drugs are equally as effective as the older. choice of the appropriate drugs in the management medications The older AEDs have an advantage of. of children and adults with newly diagnosed partial broad familiarity lower cost known efficacy wide. seizure disorders and primary generalized epilepsy availability via coverage by third party payers and. The development of new AEDs for epilepsy over long term experience This parameter will review the. the last decade has been spurred by the fact that the available evidence on efficacy tolerability and safety. available AEDs did not provide optimal care for pa profiles of the new AEDs in newly diagnosed adults. tients with epilepsy Many patients failed all avail and children with epilepsy The AEDs are discussed. able options either because their seizures were not in the order in which they received approval by the. adequately controlled or they were experiencing side FDA Among these seven new AEDs the FDA has so. effects Prior to 1990 six major AEDs were available far approved oxcarbazepine for the treatment of new. for the treatment of all forms of epilepsy These in onset partial epilepsy. cluded carbamazepine phenobarbital phenytoin,primidone valproic acid and for absence seizures. ethosuximide The older drugs while effective in pa Description of the analytical process A litera. tients with newly diagnosed epilepsy share some ture search was performed including MEDLINE and. characteristics For example older AEDs as a class Current Contents for relevant articles published be. have complex pharmacokinetics Four of the six tween January 1987 and September 2001 A second. AEDs available prior to 1990 phenytoin carbamaz manual search was performed by panel members. epine phenobarbital and primidone are hepatic en covering September 2001 through May 2002 A man. zyme inducers Induction not only complicates ual search for class I articles was then updated to. combination AED therapy but also changes internal include articles published through March 2003 In. hormonal milieu in possibly important ways Intrin addition the Cochrane library of randomized con. sic compounds such as sex steroids and vitamin D trolled trials in epilepsy was searched in September. April 2 of 2 2004 NEUROLOGY 62 1253, Table 1 Serious and nonserious adverse events associated with the new AEDs. AED Serious adverse events Nonserious adverse events. Gabapentin None Weight gain peripheral edema,behavioral changes. Lamotrigine Rash including Stevens Johnson and toxic epidermal necrolysis increased Tics and insomnia. risk for children also more common with concomitant valproate use and. reduced with slow titration hypersensitivity reactions including risk of. hepatic and renal failure DIC and arthritis,Levetiracetam None Irritability behavior change. Oxcarbazepine Hyponatremia more common in elderly rash None. Tiagabine Stupor or spike wave stupor Weakness, Topiramate Nephrolithiasis open angle glaucoma hypohidrosis Metabolic acidosis weight loss.
language dysfunction, Zonisamide Rash renal calculi hypohidrosis Irritability photosensitivity. weight loss, This is not meant to be a comprehensive list but represents the most common adverse events based on consensus of panel Psychosis. and depression are associated with epilepsy and occur in open label studies with all new AEDs Although these side effects may appear. more commonly with some drugs than with others it is difficult to ascertain whether these relationships are causal Consequently. these side effects have been omitted from the table. Predominantly children, AED antiepileptic drug DIC disseminated intravascular coagulation. 2002 and any appropriate articles identified were patients Safety data were also derived from open. added to the review trials and case reports, Criteria for selection of articles The literature Data for each AED were reviewed by three panel. search identified all papers that included the terms members with a different group assembled for each. epilepsy and either gabapentin lamotrigine leveti drug These three panelists classified each article as. racetam oxcarbazepine tiagabine topiramate or class I through IV table 5 Disagreements on article. zonisamide and satisfied the following criteria 1 classification were resolved by discussion and. relevant to the clinical questions of efficacy safety consensus. tolerability or mode of use 2 human subjects only Panel selection The panel was comprised of a. 3 type of studies randomized controlled trials co group of general neurologists pediatric neurologists. hort case control observational or case series 4 all epileptologists and doctors in pharmacy with experi. languages for randomized controlled trials not avail ence in pharmacokinetic properties of AEDs Mem. able in English and 5 relevant to patients with bers did not review a given AED if they had served. newly diagnosed epilepsy as advisors for the pharmaceutical company that. Exclusion criteria Articles were excluded from manufactured the drug or if they had been awarded. further analysis if they were reviews or meta a research grant from that company participation in. analyses articles related to non epilepsy uses of multicenter studies was not a reason for exclusion. AEDs unless they describe relevant idiosyncratic re or if they had financial interests in that company. actions or safety concerns and articles on basic AED stock ownership or employee. mechanisms Newly diagnosed epilepsy in adults and adoles. A total of 1 462 articles were identified 240 on cents Most studies of newly diagnosed epilepsy are. gabapentin 433 on lamotrigine 244 on topiramate conducted in patients with both partial and general. 17 on levetiracetam 212 on oxcarbazepine 177 on ized seizures and therefore these will not be dis. tiagabine and 146 on zonisamide Among these data cussed separately unless there are specific data on. were extracted for classification of evidence class the individual groups The majority of these studies. from 353 articles 91 on gabapentin 63 on lam defined newly diagnosed epilepsy as two or more un. otrigine 65 on topiramate 46 on tiagabine 45 on treated seizures Many compared a new AED with. oxcarbazepine 33 on zonisamide and 11 on leveti an older AED This is the only available comparative. racetam Among these studies there was one gabap evidence of new AEDs versus old Studies of new. entin class I study three class I or II studies with AED efficacy in the newly diagnosed epilepsy popu. lamotrigine two class I studies with topiramate and lation are typically performed as active control com. three class I studies and one class II study with parison studies due to the potential risk to subjects. oxcarbazepine in patients with new onset epilepsy inherent in a placebo controlled monotherapy trial. We assessed efficacy and dose related side effects These studies differ in their methodology some. from double blind controlled studies with 20 or more study newly diagnosed patients some focus on newly. 1254 NEUROLOGY 62 April 2 of 2 2004, Table 2 Common drug drug interactions associated with the new AEDs4.
Oral Enzyme Enzyme, AED contraceptives Warfarin Other agents inducer inhibitor Clinical notes. Gabapentin Modest decrease in No known interactions with other AEDs. gabapentin bioavailability,with Maalox TC, Lamotrigine Modest induction of glucuronidation with. Decrease in slight decrease in valproic acid plasma. lamotrigine levels 25 noted interactions with,serum cytochrome p450 isozymes not seen. concentrations,contraceptives, Levetiracetam No known interactions with other AEDs. Topiramate Modest increase in Modest dose dependent induction of CYP. Dose dependent haloperidol serum 3A4 may reduce effectiveness of oral. 200 mg d concentrations modest contraceptives inhibition of CYP 2C19. decrease in decrease in lithium may result in increases in phenytoin. ethinyl serum concentrations plasma concentrations. estradiol modest decrease in,serum digoxin serum,concentrations concentrations.
Tiagabine No interaction seen with Potential for protein binding displacement. erythromycin clinical relevance unclear, Oxcarbazepine Modest decrease in Modest dose dependent induction of CYP. Decrease in felodipine serum 3A4 possible induction of. ethinyl concentration modest glucuronidation with reduced plasma. estradiol decrease in MHD concentrations of lamotrigine noted. serum concentrations following inhibition of CYP 2C19 may result in. concentrations verapamil increased phenytoin or phenobarbital. administration no plasma concentrations,interaction seen with. erythromycin,Zonisamide Clearance may be increased by enzyme. inducing AEDs, This is not meant to be a comprehensive list but represents the most common interactions based on consensus of panel There are no. data on the interactions of new AEDs with many of the non AED drugs Future research may identify pharmacokinetic or pharmacody. namic interactions between new AEDs that are metabolized and non AED drugs that could result in adverse events. AED antiepileptic drug MHD monohydroxy derivative metabolite of oxcarbazepine. treated patients and the number of seizures prior to Question 1 How does the efficacy and tolerability. entry may differ Primary outcome variables differ as of the new AEDs compare with that of older AEDs in. well and include endpoints such as time to exit time patients with newly diagnosed epilepsy. to first seizure and percentage of patients rendered Gabapentin One study with class I evidence9. seizure free All of these factors can influence re compared the safety and efficacy of three different. sponse to monotherapy and complicate comparison blinded doses of gabapentin 300 mg day 900 mg. between studies Therefore while it appears valid to day and 1 800 mg day in monotherapy to that of an. accept comparisons within a given trial it is not open label fixed dose of immediate release carbamaz. seven antiepileptic drugs AEDs gabapentin lam otrigine topiramate tiagabine oxcarbazepine leve tiracetam and zonisamide were approved by the Food and Drug Administration FDA The purpose of this assessment is to provide the clinician with evidence based data on the efficacy safety and mode of use of these new AEDs which can facilitate the choice of the appropriate drugs in the

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