1. New AEDs in Pediatric Epilepsy John M. Pellock, MD Professor and Chairman Division of Child Neurology Virginia Commonwealth University Medical College of Virginia Hospitals Richmond, Virginia

2. Clinical Utility of Older and Newer AEDs: Treatment Options Pellock JM. Epilepsy in Patients with Multiple Handicaps. In: Wyllie E (ed). The Treatment of Epilepsy: Principles and Practice, 5th Edition. Baltimore:Lippincott Williams and Wilkins, 2009. VPA, LTG, TPM, ZNS, FBM, LEV, RFM

3. Anticonvulsant Drugs Marketed in the U.S. 1912Phenobarbital (Luminal ® )Winthrop 1935Mephobarbital (Mebaral ® )Winthrop 1938Phenytoin (Dilantin ® )Parke-Davis 1947Mephenytoin (Mesantoin ® )Sandoz 1954Primidone (Mysoline ® )Ayerst 1957Methsuximide (Celontin ® )Parke-Davis 1957Ethotoin (Peganone ® )Abbott 1960Ethosuximide (Zarontin ® )Parke-Davis 1968Diazepam (Valium ® )Roche 1974Carbamazepine (Tegretol ® )Ciba-Geigy 1975Clonazepam (Klonopin ® )Roche 1978Valproic acid (Depakene ® )Abbott 1981Clorazepatae (Tranxene ® )Abbott 1993Felbamate (Felbatol ® )Carter-Wallace 1993Gabapentin (Neurontin ® )Parke-Davis 1994Lamotrigine (Lamitcal ® )GlaxoSmithKline 1996Topiramate (Topamax ® )Ortho-McNeil 1997Tigabine (Gabitril ® )Abbott 2000Zonisamide (Zonegran ® )Elan Pharma 2000Levetiracetam (Keppra ® )UCB Pharma 2000Oxcarbazepine (Trileptal ® )Novartis 2000Pregabalin (Lyrica ® )Pfizer 2008Banzel (Rufinamide ® )Eisai 2009Vimpat (Lacosemide ® )UCB 2009Sabril (Vigabtrin ® )Lundbeck 2010ACTH (Acthar, IS)Questcor

4. Felbamate Efficacy  Partial, generalized, Lennox-Gastaut syndrome  Infantile spasms, myoclonic Adverse events  Neurotoxicity, GI, anorexia, weight loss, insomnia  Aplastic anemia, hepatotoxicity Advantages: children awaken, broad spectrum Disadvantages: titration, drug interactions, life-threatening adverse events

5. Felbamate Hepatotoxicity FBM 1:26,000 - 1:34,000 VPA 1:10,000 - 1:49,000 Aplastic anemia risk FBM27 - 209 :1 million General population2 - 2.5 :1 million FBM 20x CBZ

6. Felbamate: Aplastic Anemia High-Risk Profile Adult vs. children (<13 yr) Prior idiosyncratic reaction Prior cytopenia Autoimmune disease

7. Gabapentin Efficacy  Partial with / without generalization, refractory / benign  Adjunctive, monotherapy Adverse events  Neurotoxicity, hyperactivity (DD) Advantages: fast titration, well tolerated Linear pK, no interactions Disadvantages: perception JM Pellock, 2003

8. Gabapentin in Children: Dosing vs. Levels mg/kg/dayµg/mL 201-2.5 20-304.8 (0.8-7.9) 60-1008-16 Initial studies: 5 to 20-30 mg/kg/day Now: 10-20 to 60-100 mg/kg/day Increase daily or every few days

9. Significant Reduction in Seizure Frequency with Pregabalin Lyrica ® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Arroyo et al. Epilepsia 45:20-27, 2004. French et al. Neurology 60:1631-1637, 2003. Beydoun et al. Neurology 64:475-480, 2005. Median % Change from Baseline French et al. Arroyo et al.Beydoun et al. -10 0 10 20 30 40 50 60 50 TID 200 TID Pregabalin Dose (mg) 75 BID 150 BID 300 BID Pregabalin Dose (mg) * 200 TID 300 BID Pregabalin Dose (mg) * * * * * * 0 35 37 51 17 43 1 36 48 PBO *P≤0.01 vs placebo The most common adverse events occurring during all controlled clinical trials for patients taking pregabalin vs those taking a placebo were dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention).

10. Pregabalin Dosing Instructions If needed, may increase to 300 mg/day within 1 wk Some postherpetic neuralgia and partial-onset seizure patients may benefit from up to 600 mg/day based on individual response and tolerability Dosage adjustment may be necessary in patients with renal insufficiency, based on creatinine clearance Pregabalin may be taken with or without food Adverse events may increase with dose Lyrica ® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005

11. Lamotrigine Efficacy  Partial, generalized, Lennox-Gastaut syndrome Adverse events  Neurotoxicity, rash, insomnia  Severe rash 1:100 - 1: 200 Advantages: children awaken, broad spectrum Disadvantages: slow titration, dose AED dependent, life-threatening rash / hypersensitivity

12. Motte J et al. N Engl J Med 337:1807-1812, 1997 Lamotrigine for LGS: Efficacy Median change from baseline in weekly seizure counts during treatment weeks 1-16 N=78N=89N=75N=89 N=60 N=64 % Patients 36% 34% 32% -10% 9% -30 -20 -10 0 10 20 30 40 50 All Major Seizures Drop AttacksTonic-Clonic Seizures Seizure Reduction Frequency (%) LTG Placebo p=0.002 p=0.01 p=0.03

13. Lamotrigine: Adjunctive Therapy for Partial Seizures in Children Aged 2-16 Years Partial Seizure Frequency Secondary Generalized 1-18 7-18 Seizure Frequency Weeks1-187-18 Weeks % of Patients with >50% Seizure Reduction (All Partial Seizures) 33% 28% 42% 45% 1% 3% 25% 16% 0 5 10 15 20 25 30 35 40 45 50 % Patients LTG Placebo p<0.001 p=0.001 p=0.004 p=0.003

14. Lamotrigine: Typical Absence Seizures in Children Frank LM et al. Epilepsia 40:973-979, 1999 Maximum Dose mg/kg/dayNSeizure-Free 72012 (60%) 152218 (82%) All patients4230 (71%)

15. Lamotrigine Rash Potentially severe, life threatening  Adults: 1:1,000  Children: 1:100 - 1:200 Overall, rash increased by VPA; rapid escalation Differentiate benign (10%) from serious cases Recommend discontinuing LTG if rash occurs Risk of discontinuation in patients with rash Hx: Overall 2.8x AED rash 3.8x

16. AED Rash and Pharmacogenetics SJS/TEN 2 to 3 x greater prevalence in Han Chinese With CBZ 25-33% Asian vs. 5-6% Europeans HLA-B 1502 allele in 59/60 Han Chinese in Taiwan vs. 6/144 controls and 1/31 maculopapular or HSS SJS / TEN susceptibility locus maps tightly and presumptively activates CD8 T lymphocyte Questions remain: Screen all Han Chinese? LTG? Other populations with same / other alleles? Miller, Ep Curr, 2008

17. LTG Aseptic Meningitis FDA Revised label 2010 40 cases reported in 5 year period (46 million Rx) Symptoms: headache, fever, chills, nausea, vomiting, stiff neck, rash, light sensitivity, drowsiness, confusion Most resolved after discontinuation; in I5 symptoms returned when resumed LTG JAMA, 2010.

18. Topiramate Efficacy  Partial, generalized, Lennox-Gastaut syndrome, infantile spasms Adverse events  Neurotoxicity, cognitive (language)  Weight loss, insomnia, renal stones Advantages: broad spectrum Disadvantages: slow titration as add-on therapy, cognitive

19. 18% 27% 47% 46% Placebo200 mg400 mg600 mg (N=45)(N=45)(N=45)(N=46) Randomized Dose Group p=0.620* p=0.013* p=0.027* % Responder Faught E et al. Neurology 46:1684, 1996 Topiramate – Protocol YD 50% Responders: Double-Blind vs. Baseline *Comparison to placebo

20. Cognitive Outcomes: TPM vs. VPA Aldenkamp AP et al. 2000 Double-blind, randomized, parallel (17 variables) Add-on to CBZ in epilepsy patients TPMVPA Titration (mg/day/wk)25 mg150 mg Completers2429 Dropouts84 Mean dose (mg/day)2511,384 VPA >TPM on verbal memory Titration = 12 wks; maintenance = 8 wks

21. Topiramate: Dosing and Administration *Initial evaluation point Adjunctive therapy, 2-16 yrs, mg/kg/day Starting dose~1-3 nightly Increments1-3 every 1-2 wks Target dose*5-9 Monotherapy, children, 6-15 yrs Week 10.5 mg/kg nightly Week 20.5 mg/kg b.i.d. Week 31 mg/kg b.i.d. Target dose*100 mg/day If >100 mg needed, dose can be increased weekly by 50 mg/day

22. Topiramate in Infantile Spasms: Open-Label Studies *Glauser TA et al. Epilepsia 39:1324, 1998 **Spasms + ancillary seizures Study 1 (N=11): Stabilization Outcomes* >50% spasm reduction9/11 (82%) Spasm-free5/11 (45%) Dose, mean (range), mg/kg/day15 (8-24) Study 2 (N=21) >50% seizure** reduction Titration/ stabilization5/21 (24%) Entire study6/21 (29%) Spasm-free >7 days11/21 (52%) Dose, mean (range), mg/kg/day17 (4-46)

23. Topiramate vs. Valproate in JME: Open-Label Randomized Study Levisohn PM et al. Epilepsia 44(Suppl 9):267, 2003 % Patients Seizure-Free (12-wk maintenance) TPM (N=19)VPA (N=9) Myoclonic7/14 (50%)6/9 (67%) PGTCS8/12 (67%)3/4 (75%) Absence2/2 (100%)1/2 (50%) All seizures9/19 (47%)3/9 (33%) Observations Efficacy similar Adverse event profiles different  Similar neurotoxicity scale ratings  VPA: More systemic toxicity

24. Percentage Reduction in Partial Seizures During Treatment Period to 60 mg/kg/day Median % Change from Baseline Over Placebo p=0.0002 p<0.0001 % Reduction in Weekly Seizure Frequency LEV PlaceboLEV 26.8 % 16.3 % 43.3 %

25. Efficacy of Levetiracetam in Myoclonic Seizures Noachtar S. Presented at: 26th International Epilepsy Congress; August 29, 2005; Paris, France. N=121; 12-65 yrs  Refractory generalized epilepsy and myoclonic seizures  LEV 3000 mg/day or placebo added to AEDs for 12 wks Placebo LEV >50% seizure reduction23.3% 58.3% Headache23.3% 21.6% Treatment-limiting adverse events1 2

26. Adverse Events Overview Patients, % LEV (N=101) Placebo (N=97) Infection28.728.9 Somnolence22.811.3 Accidental injury16.810.3 Vomiting14.913.4 Headache13.914.4 Anorexia12.98.2 Rhinitis12.98.2 Hostility11.96.2 Cough increased10.97.2 Nervousness9.92.1 Asthenia8.93.1 Dizziness6.92.1 Agitation5.91.0 Albuminuria4.00.0 Ecchymosis4.01.0 Depression3.01.0

27. Zonisamide: Pivotal Clinical Trials % of Patients Study 2 & 3: % Responders >25%>50%>75% % Reduction in Seizures >100%

28. Zonisamide: Progressive Myoclonic Epilepsies PME of Unverricht-Lundborg type (N=2): Marked decrease in seizure frequency and significant improvement* 1 PME of Unverricht-Lundborg type (N=7) and Lafora Body (N=1): dramatic seizure frequency reduction for 2-3 years* 2 *Patients continued to receive BPS and benzodiazepine 1 Henry TR et al. Neurology 38:928-931, 1998 2 Kyllerman M et al. Epilepsy Res 29:109-114, 1998

29. Zonisamide in Juvenile Myoclonic Epilepsy Design  Retrospective; N=15 ages 11-20 yrs  ZNS 200-500 mg/day as monotherapy (N=13) or add-on therapy (N=2) Results  >50% seizure reduction in 80%  Response within 4-8 wks  Seizure-free rates:  GTC, 69%  Myoclonic, 62%  Absence, 38%  Transient adverse events during titration in 3 patients (20%): headache, weight loss, dizziness Kothare SV et al. Epileptic Disord 6:267-270, 2004

30. Zonisamide: Oligohydrosis 13 reports during 11 yrs of marketing in Japan 1,2  Age: 1.6-17 yrs  Heat stroke requiring hospitalization, N=2  All cases reported during unusually hot summers  Doses: 5-15 mg/kg/day  No reported cases of decreased sweating in US and European development program  Body temperature should be carefully monitored in pediatric patients 1 Zonegran™(zonisamide) prescribing information, Elan Pharmaceuticals. 2 Masuda Y et al. CNS Drug Reviews 4:341-360, 1998

31. Rufinamide Approved in November, 2008 as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome Approval based on single pivotal trial (orphan drug status) Triazole derivative; exact mechanism of action unknown  Thought to regulate voltage dependent sodium channels

32. Glauser T et al. Neurology 70:1950-1958, 2008 Rufinamide for Generalized Seizures Associated with Lennox-Gastaut Syndrome % Responders Rufinamide Placebo % Reduction p=0.0045 p=0.002 p=0.0015 p<0.0001

33. Glauser T et al. Neurology 70:1950-1958, 2008 *Double-blind adjunctive therapy study in LGS; includes only AEs occuring at higher incidences with Rufinamide than placebo AEs with Incidence >5% vs. Placebo in Subjects with Lennox-Gastaut Syndrome Rufinamide, %Placebo, % Total no. patients studied*N=74N=64 Somnolence24.312.5 Vomiting21.66.3 Pyrexia13.517.2 Fatigue9.57.8 Decreased appetite9.54.7 Nasopharyngitis9.53.1 Headache6.84.7 Rash6.81.6 Rhinitis5.44.7 Ataxia5.40

34. Rufinamide 34% protein bound; T max 6 hr fed, 8 hr fasted; half life 8-12 hr Hepatic metabolism to inactive metabolite Mild-moderate CYP3A4 induction, reduces oral contraceptive efficacy Few drug interactions (phenytoin and phenobarbital increase clearance by ~25%) VPA increases RFM 16-70%, concentration dependent Twice daily dosing (dose 400 to 2400 mg/day in 60 kg individual) Hakimian S, et al. Expert Opin Pharmacother. 2007 8:1931-1940

35. Lacosamide in the Treatment of Complex Partial Seizures Beydoun A et al. Expert Review 9:33-42, 2009 Percentage of patients with at least 50 or 75% reduction in seizure frequency from baseline period to maintenance period Intent to treat: SP667, SP754, SP755 *p<0.05; ** p<0.001 Responder Rates 50% Responders 75% Responders Placebo (n=359) LCM 200 mg/day (n=267) LCM 400 mg/day (n=466)

36. AEs Leading to Discontinuation (≥1% of Subjects in Lacosamide Total) during Treatment Phase (SS † ) (SP667, SP754, SP755) AE Leading to Discontinuation Placebo N=364 n (%) LCM 200mg/day N=270 n (%) LCM 400mg/day N=471 n (%) LCM 600mg/day N=203 n (%) LCM Total N=944 n (%) Any event17 (4.7)22 (8.1)81 (17.2)58 (28.6)161 (17.1) Dizziness1 (0.3)1 (0.4)20 (4.2)35 (17.2)56 (5.9) Coordination abnormal01 (0.4)6 (1.3)11 (5.4)18 (1.9) Vomiting1 (0.3)1 (0.4)11 (2.3)6 (3.0)18 (1.9) Diplopia1 (0.3)4 (1.5)10 (2.1)4 (2.0)18 (1.9) Nausea01 (0.4)8 (1.7)8 (3.9)17 (1.8) Vertigo03 (1.1)4 (0.8)5 (2.5)12 (1.3) Vision blurred01 (0.4)3 (0.6)6 (3.0)10 (1.1) Convulsion4 (1.1)2 (0.7)8 (1.7)010 (1.1) † SS – Safety Set: Subjects who received trial medication

38. Vigabatrin Approved January, 2009 for treatment of infantile spasms (orphan drug status)  Only drug approved in the US for treatment of IS Approved January, 2009 for treatment of patients with complex partial seizures who have not responded to several AEDs Previously approved years ago in other countries for partial seizures

39. Elterman RD et al. Neurology 57:1416-1421, 2001 Treatment Responders by Vigabatrin Dose and Etiology Low (75) High (67) Tuberous sclerosis (25) Dysgenetic (31) Postnatal (41) Idiopathic or cryptogenic (45) Vigabatrin doseEtiology % Responders

40. Vigabatrin and Visual Field Defects Prevalence in adults ~30-50%  May be less in infants Concentric constriction: average peripheral field 65° (normal 90°); central vision not affected Typically asymptomatic Earliest occurrence ~11 months Appears irreversible, but does not progress Appears idiosyncratic, not clearly dose related Wheless JW et al. Neurotherapeutics 4:163-172, 2007