7/31/09. New AEDs. AEDs. Dr. Yotin Chinvarun M.D. Ph.D. Comprehensive Epilepsy and Sleep disorder Program PMK hospital. 1 st genera*on AEDs

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1 Dr. Yotin Chinvarun M.D. Ph.D. Comprehensive Epilepsy and Sleep disorder Program PMK hospital New AEDs AEDs NEW OLD Pregabalin Pregabalin 1 st genera*on AEDs Phenytoin Carbamazepine Valproate Phenobarbital Clobazam 2 nd genera*on AEDs Felbamate 1993 Lamotrigine 1994 Topiramate 1996 Tiagabine 1997 Levi*racetam 1999 Oxcarbamazepine 2000 Zonisamide 2000 Pregabalin

2 Brivaracetam Eslicarbazepine Fluorofelbamate Ganaxolone Huperzine JZP 4 Lacosamide Licarzepine Losigamone NS1209 New AEDs 3 rd genera*on AEDs Re*gabine Rufinamide RWJ (Carisbamate) Seletracetam Safinamide SPD421 S*ripentol Talampanel Valrocemide Introduced in the treatment of epilepsy in 1938 Par*al onset seizure Parenteral form and single dose daily Adverse reac*ons, dose related; ataxia, nystagmus, slurred speech, and dizziness. High dose phenytoin can cause peripheral neuropathy, cerebellar atrophy, chronic side effect cogni*ve impairment, gum hypertrophy, course faces, acnes etc Idiopathic generalized epilepsy Myoclonic epilepsy Par*al seizure Parenteral form Teratogenicity Side effect; weight gain, tremor, transient hair loss, Endocrine and metabolic dysfunc*ons s Par*al onset seizure s Common side effect; dizziness, ataxia, Severe drug erup*ons are rare Had been used since 1912 s Par*al onset seizure Effec*ve in refractory seizure Parenteral form and single dose daily s Seda*on and hypnosis Cogni*ve impairment Added on par*al seizure Rescue therapy for aura or SPS Less effec*ve Seda*ve side effect 2

3 Highly effec*ve in severe resistance epilepsy Par*al onset seizures with or without secondarily generalized seizures (adult monotherapy) Par*al and generalized seizures associated with Lennox Gastaut syndrome (children adjunc*ve therapy) Serious side effect: Aplas*c anemia, hepa*c failure Not available s s Easy to use, well tolerated, No interac*ons, no enzyme induc*on When to use it Par*al seizures Early add on Useful in the elderly Variable absorp*on Wide dosage range tds dosing, satura*on effect Moderate efficacy Unknown teratogenicity s s Broad spectrum of efficacy, favourable pharmacokine*cs, Favourable cogni*ve profile, fewer interac*ons Par*al seizure, Idiopathic generalized epilepsy alterna*ve or adjunct to valproate, Symptoma*c generalized epilepsy, Lennox Gastaut Syndrome Rash, especially with valproate (some*me severe) Slow *tra*on Interac*on with carbamazepine s s Known mode of ac*on, Favourable pharmacokine*cs, Easy to use, Few interac*ons, No enzyme induc*on Added on Par*al seizures Currently rarely used Infan*le spasms Seda*on Psychiatric effects Seizure worsening in some Irriversibel visual field constric*on Unknown teratogenicity n s Broad spectrum of efficacy, Favourable pharmacokine*cs, Few interac*ons, No enzyme induc*on Par*al seizures mono/ added on therapy Symptoma*c generalized epilepsy n s Weight loss, hypoesthesia Cogni*ve impairment Glaucoma,? cataract Very slow *tra*on, rapidly *tra*on caused language difficulty Unknown teratogenicity s Known mode of ac*on, toxicity mild, No enzyme induc*on Added on par*al onset seizure s CNS side effect, Dizziness Inducible metabolism Short half life; tds dosing Unknown teratogenicity Not available 3

4 n No drug interac*on Well tolerate and highly effec*ve Par*al seizure, alterna*ve for idiopathic generalized epilepsy Parenteral form n Side effects: somnolence, asthenia, infec*on, dizziness, headache, depression, UTI n Close structure similarly to Carbamazepine but beher tolerated, Fewer drug interac*on Par*al onset seizure n Hyponatremia in 2.5% More commonly in older pa*ents 25% cross sensi*vity with carbamazepine n FDA approved in early 2009 Good bioavailability Par*al seizure Alterna*ve valproate for myoclonic seizure, increased by approximately 30 40%, when given concomitantly with enzyme inducing AEDs Seda*on, fa*gue, dizziness, ataxia, confusion, cogni*ve impairment, including word finding difficulty, weight loss/ anorexia, Depression & psychosis has also been reported, renal stone n Add on therapy for the treatment of par*al onset seizures in adult > 17 yrs with epilepsy. Demonstrated efficacy and safety when combined with a broad range of exis*ng AEDs Oral and IV form n Mechanism; selec*vely enhances slow inac*va*on of sodium channels and interacts with the neuroplas*city relevant target collapsin response mediator protein 2 (CRMP 2) n * Dizzines * Nausea * Diplopi * Blurring Vision, * Vomi*ng, * Fa*gue, * Ataxia Novel, voltage gated sodium channel blocker Par*al onset seizures with or without secondary generaliza*on in combina*on with other an* epilep*c drugs Responder rate (> or = 50% decrease in seizure frequency) for eslicarbazepine acetate 800 mg and 1200 mg that ranged between 32 percent and 43 percent Seizure type Epilepsy syndrome Pharmacokine*c profile Interac*ons/other medical condi*ons Efficacy Expected adverse effects Cost Safety profile was favorable Incidence of CNS side effects was low. 4

5 Broad Spectrum Agents Valproate Felbamate Lamotrigine Topiramate Zonisamide Leve*racetam Rufinamide* Narrow-Spectrum Agents Partial onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide* PHT, PB CBZ, OXC GBP, VGB, PGB Absence Ethosuximide VPA, LTG, TPM, ZNS, LEV, (FBM) (Broad Spectrum AEDs) Drug Partial Secondary generalized I Tonicclonic Absenc Myoclonic e Drug Partial I GTCS Absence Myocloni c +/- *?+ + Stein and Kanner. Drugs 2009;69:

6 Monotherapy for Partial Seizures Best evidence and FDA indication: Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate Similar efficacy, likely better tolerated: Lamotrigine, Gabapentin, Levetiracetam Also shown to be effective: Valproate, Phenobarbital, Felbamate, Lacosamide Limited data but commonly used: Zonisamide, Pregabalin Landmark and Johannessen. Drugs 2008;68: Monotherapy for Generalized-Onset Tonic-Clonic Seizures Best evidence and FDA Indica*on: Valproate, Topiramate Also shown to be effec*ve: Zonisamide, Levetiracetam Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz ) Absence seizures Best evidence: Ethosuximide (limited spectrum, absence only) Valproate Also shown to be effec*ve: Lamotrigine May be considered as second line: Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies Myoclonic Seizures Best evidence: Valproate Levetiracetam (FDA indication as adjunctive tx) Clonazepam (FDA indication) Possibly effec*ve: Zonisamide, Topiramate 6

7 Lennox Gastaut Syndrome Best evidence/fda indica*on*: Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide * FDA approval is for adjunctive treatment for all except clonazepam Also effec*ve: Valproate Some evidence of efficacy: Zonisamide, Levetiracetam Simplifies treatment, reduces adverse effects Conversion to monotherapy from polytherapy Eliminate seda*ve drugs first Withdraw an*epilep*c drugs slowly over several months Simple partial carbamazepine lamotrigine oxcarbazepine levetiracetam 7