1. Efficacy and Tolerability of Newer Antiepileptic drugs: Recommendations and Practice Parameters

9. Classification of evidence Definitions

16. Pharmacology

17. Mechanism of Action Deckers CLP et al. Epilepsia 2000; 41(11): 1364–1374. ++ Clobazam + + Zonisamide +++ Vigabatrin Binds to synaptic vesicle protein SV2A Levetiracetam +++ Tiagabine + + +++ Oxcarbazepine + ++ ++ Topiramate + +++ Lamotrigine + ++ + Gabapentin Antiglutamate GABA mimetic Non- T type Ca channel blockade Na channel blockade AED

18. Pharmacokinetics Panayiotopoulos CP. The Epilepsies: seizures, syndromes and management 24-60 4-7 4-9 6-8 15-23 15-30 4-6 Elimination t1/2 (hr) No No Renal 96% LEV No No Hepatic Clobazam Yes No Hepatic 40-60% Zonisamide No No Renal Vigabatrin Yes No Hepatic 40% Tiagabine Yes Ind, inh Hepatic 0% OXC Yes Ind, Inh Renal > H 9-17% Topiramate Yes Induction Hepatic 55% Lamotrigine No No Renal 0 Gabapentin Drug interactions Enzyme ind/inh Metabolism Protein binding AED

19. Practical Implications Panayiotopoulos CP. The Epilepsies: seizures, syndromes and management Not required Minimal 0-2 wks Yes Levetiracetam Not useful Minimal 4 wks No Clobazam Useful Maximal 4 wks Yes Zonisamide Not needed Maximal 4 wks No Vigabatrin Not required Minimal 4 wks No Tiagabine Not useful Maximal 4 weeks No Oxcarbazepine Useful Maximal 6 wks Yes Topiramate Very useful Maximal 8 wks Yes Lamotrigine Not required Minimal 0-2 wks No Gabapentin Drug monitoring Lab testing? Slow titration? Broad spectrum AED

20. Lamotrigine

21. New onset epilepsy Study 1: Pts aged 13-81 yrs with partial or primary generalized epilepsy Study 2: 150 elderly pts with mean age of 77 yrs 42% 18% Discontinuation No difference in the efficacy. Rash was more in the CBZ group 400-2000 mg/d 100-500 mg/d Dose Brodie MJ. Epilepsy Res 1999; 37: 81-87 Brodie MJ et al. Lancet 1995; 345: 476-9 13% 9% Rash 21% 11.5% Discontinuation 76% 78% Generalized seizures (n=122) 51% 48% Partial seizures (n=146) Seizure freedom CBZ (600 mg/d) LTG (150 mg/d) Dose

22. New onset epilepsy: Study 3 Steiner TJ et al. Epilepsia 1999; 40: 601-7 28% 7% Somnolence 29% 16% Asthenia 5% 14% Rash 11% 0 Ataxia Adverse effects 19% 15% Discontinuation 46% 45% Partial 36% 43% IGE Seizure freedom during last 24 weeks of therapy 46 pts 44 pts Partial 95 pts 86 pts IGE PHT LTG

24. Refractory partial epilepsy- adjunctive therapy Matsuo F et al. Neurology 1993; 43: 2284-91 Messenheimer J et al. Epilepsia 1994; 35: 113-21. 1% 5% 5% Discontinuation rate 0% 20% 22% 50% Responder rate Placebo 300 mg/d 400 mg/d Study 2 dose 1.4% 4.2% 14% Discontinuation rate 6% 10% 17% Rash with CBZ 8% 20% 36% Median seizure reduction 18% 20% 34% 50 % Responder rate Placebo 300 mg/d 500 mg/d Study 1 dose

25. Refractory partial epilepsy: Monotherapy Gilliam F et al. Neurology 1998; 51: 1018-25 Exit criteria: Increased duration of GTCS/ emergence of new, more severe seizure type Doubling of the highest 2 day consecutive seizure rate Doubling of baseline seizure frequency Outcome: proportion of pts meeting exit criteria during concomitant AED withdrawal or the 3 month maintenance period. 8% 11% Rash 5% 11% Discontinuation rate 57 days 168 days Median time to exit 20% 37% Completed study VPA (1000 mg/d) LTG (500 mg/d) Dose

26. Children: Refractory partial epilepsy Duchowny M et al. Neurology 1999; 53: 1724-31 LTG dose (mg/kg): 1-3 if given with VPA only, 1-5 if with VPA and enzyme inducing drugs, 5-15 if given with enzyme inducing drugs only. Asthenia Dizziness Nausea Ataxia 199 children between 2-16 yrs of age. Steven Johnson syndrome- I case Tremor Most common adverse effects 6% 5% Discontinuation rate 12.8% 44% Decrease in weekly seizure frequency 25% 45% 50% responder rate Placebo LTG

27. Lennox- Gastaut syndrome Motte J et al. N Eng J Med 1997; 337: 1807-12 Eriksson AS et al. Epilepsia 1998; 39: 495-501 Jansky J et al. Clin Neuropharmacol 2000; 23: 86-9 - 60% 50% responder rate Class II study: open label, followed by double blind phase. N=17 6% 5% Rash Dose ranged from 50-100 mg/d for pts < 25 kg on VPA to 300-400 mg/d for pts > 25 kg not on VPA. 18% 16% Discontinuation rate 16% 33% 50% responder rate for total seizures Class I study Worsening of myoclonic jerks was noted in a case report. 8% 4% Discontinuation rate Placebo LTG

28. Adverse effects Headache Somnolence Asthenia Rash Incidence of rash is more when added to CBZ containing regimens. Anorexia Incoordination Diplopia Dyspepsia Abdominal pain Vomiting Tremor Nausea Ataxia Dizziness

31. Topiramate

32. New onset epilepsy Privitera MD et al. Acta Neurol Scand 2003; 107: 165-75 No significant difference Time to first seizure 600 1250 200 100 Dose (mg/d) 613 pts with partial/primary generalized epilepsy, aged > 6 yrs 25% 23% 28% 19% Discontinuation rate No difference in efficacy between the 4 groups Proportion of seizure free pts for last 6 months of therapy: No significant difference No significant difference Time to exit CBZ VPA TPM TPM

33. Refractory partial epilepsy- adjunctive therapy Faught E et al. Neurology 1996; 46: 1684-90 Privitera M et al. Neurology 1996; 46: 1678-83 13% 47.8% 50% Responder rate No difference 50% Responder rate - 17% 10.5% 21% Discontinuation rate - 4% 9% 13% Discontinuation rate No improvement in efficacy at dose > 400 mg/d. Placebo 600 Study 3 Dose (mg/d) Placebo 1000 800 600 Study 2 Dose (mg/d) - 48% 49% 27% 50% Responder rate Placebo 200 400 600 Study 1 Dose (mg/d)

34. Refractory partial epilepsy: Monotherapy Sachdeo RC et al. Epilepsia 1997; 38: 294-300 Longer in pts on 1000 mg/d (p=0.002) Time to exit 8.3% 0 Discontinuation rate Similar but less frequent compared to add-on therapy Adverse effects 13% 0 100% seizure reduction 46% 13% 50% responder rate 62% 25% Completed study TPM (1000 mg/d) TPM (100 mg/d) N=100

35. Idiopathic refractory generalized epilepsy Biton V et al. Neurology 1999; 52: 1330-7 Age > 3 yrs with refractory GTCS, with or without other seizure types. Adverse effects were similar to other studies. 2.4% 2.6% Discontinuation rate 20% 56% 50% responder rate Placebo TPM (6 mg/kg/d) Dose One Class I study and ten Class IV studies

36. Children: Refractory partial epilepsy Elterman RD et al. Neurology 1999; 52: 1338-44 Arcas J et al. Epilepsia 2001; 42: 1363-5 Weight loss Difficulty in concentrating Memory deficits Emotional lability 86 children between 2-16 yrs of age, 16 week trial. Hypohidrosis Fatigue Most common adverse effects 2 children 0 Discontinuation rate 10.5% 33% Median reduction in seizures 20% 39% 50% responder rate Placebo TPM (125-400) Dose (mg/d)

37. Lennox- Gastaut syndrome Sachdeo RC et al. Neurology 1999; 52: 1882-7 Glauser TA et al. Epilepsia 2000; 41: S86-90 55% 50 % responder rate Above patients were followed up for 6 months Class I study 56% Median reduction in drop attacks Class IV study: open label 5.1% increase 14% decrease Drop attacks No significant difference 50% responder rate for total seizures Placebo TPM (6 mg/kg/d) Dose

38. Adverse effects Dizziness Psychomotor slowing Confusion Headache Slow titration led to less dose-related side-effects. Paresthesias Word finding difficulty Weight loss Behavioral disturbance Anorexia Anxiety Nausea Emotional lability Fatigue Renal calculi Somnolence Uncommon Common

41. Oxcarbazepine

42. New onset epilepsy Bill PA et al. Epilepsy Res 1997; 27: 195-204 53.8% 56.6% Seizure control Study 1: Partial epilepsy= 184 pts, Primary GTCS= 104 pts Outcome measured: Seizure control during a 48 wk maintenance period. Similar in both groups Discontinuation rate VPA (600-2700) OXC (600-2400) Dose (mg/dl) Christe W et al. Epilepsy Res 1997; 26: 451-60 Study 2: Partial epilepsy= 154 pts, Primary GTCS= 95 pts Higher in PHT group Discontinuation rate 58% 59.3% Seizure control 144 143 No of patients PHT (100-560) OXC (600-2100) Dose (mg/dl)

43. New onset epilepsy 60% 61% Seizure control 26% 14% Discontinuation rate Dam M et al. Epilepsy Res 1989; 3: 70-76. 14.5% 2% Discontinuation rate Study 3: 190 patients with GTCS (primary or secondary) Outcome measured: Seizure control during a 48 wk maintenance period. PHT (100-400) OXC (100-1350) Dose (mg/dl) Guerreiro MM et al. Epilepsy Res; 1997; 27: 205-13 Children aged 5-18 yr with partial epilepsy= 151 pts, primary GTCS= 31 pts Study 4 60% 52% Seizure control CBZ (300-1400) OXC (300-1800) Dose (mg/dl)

44. Refractory partial epilepsy- adjunctive therapy 694 pts aged 15-65 yrs. Barcs G et al. Epilepsia 2000; 41: 1597-1607 67% 50% 50% 2400 3% 36% 12% Discontinuation rate 6.8% 40% 22% Median seizure reduction 12.7% 41.2% 26.8% 50% Responder rate Placebo 1200 600 Dose (mg/d)

45. Refractory partial epilepsy: Monotherapy Beydoun A et al. Neurology 2000; 54: 2245-51 Schachter SC et al. Neurology 1999; 52: 732-7 2% 21.6% Hyponatremia Sachdeo R et al. Neurology 2001; 57: 864-71 68 days 28 days Median time to exit OXC (2400 mg/d) OXC (300 mg/d) Study 3 12% 0 100% seizure free 41.2% 93.3% % exiting study OXC (2400 mg/d) OXC (300 mg/d) Study 2 84% 47% % exiting study Placebo OXC Study 1: 10 d trial

46. Children: Refractory partial epilepsy Elterman RD et al. Neurology 1999; 52: 1338-44 Arcas J et al. Epilepsia 2001; 42: 1363-5 3% 10 Discontinuation rate Nausea Headache Vomiting Somnolence 267 children between 3-17 yrs of age. Dizziness Most common adverse effects 5% 4 Rash 8.9% 35% Median reduction in seizures 22% 41% 50% responder rate Placebo OXC (30-46) Dose (mg/kg/d)

48. Adverse effects Vomiting Enzyme induction Nausea Hyponatremia Dizziness Hypersensitivity reaction Headache Rash Somnolence Uncommon Common

49. Gabapentin All studies are Class I evidence unless specified otherwise.

52. Children: Refractory partial epilepsy Appleton R et al. Epilepsia 1999; 40: 1147-54 Weight gain Fever Fatigue Viral infection 247 children between 3-12 yrs of age, 12 week trial. Hostility Most common adverse effects 2% 5% Discontinuation rate 13% 28% 2. Secondary GTCS 12% 35% 1. CPS Median reduction in seizures Placebo GBP (23-35 mg/kg/d)

54. Adverse effects No significant drug interactions. Less adverse effects with slow titration of dose. Weight gain Choreoathetosis Fatigue Myoclonus Dizziness Sphincter incontinence Somnolence

55. Tiagabine Currently not available in India

57. Adverse effects Richens A et al. Epilepsy Res 1995; 21: 37-42 Psychosis Headache Abdominal pain Tiredness Nervousness Vomiting Abnormal thinking Emotional lability Tremor Nonconvulsive Status epilepticus Dizziness Uncommon Common

59. Zonisamide

60. Refractory partial epilepsy- adjunctive therapy Schmidt D et al. Epilepsy Res 1993; 15: 67-73 Faught E et al. Neurology 2001; 57: 1774-9 Serum ZNS levels did not differ between responders and non-responders. 10% 10% 10% 10% Discontinuation rate 9% 43% 25% 25% 50% responder rate Placebo 400 200 100 Dose (mg/d) Study 2 9.4% 30% 50% responder rate Placebo 20 mg/kg Dose Study 1

61. Schmidt D et al. Epilepsy Res 1993; 15: 67-73 Faught E et al. Neurology 2001; 57: 1774-9 Summary: Effective as add-on therapy in refractory partial epilepsy AAN and AES practice parameters 2004. Adverse effects Depression Abnormal thinking Paranoia Anorexia Rash Somnolence Rhinitis Dizziness Renal calculi Fatigue Uncommon Common

62. Levetiracetam

64. Adverse effects Ben-Menachem E et al. Epilepsia 2000; 41: 1276-83 Cramer JA et al. Epilepsia 2000; 868-74 Betts T et al. Seizure 2000; 9: 80-87 Infection Headache Psychosis Asthenia Depression Somnolence Behavioural problems Dizziness Uncommon Common

68. LTG, ZNS, OXC, TGB CBZ,PHT, VPA Metabolism affected by hepatic disease GBP, LEV, TPM PB Metabolism affected by renal disease - PHT Hypoalbuminemia with increased free fraction OXC CBZ Hyponatremia risk - VPA Metabolic disorder may increase risk of hepatotoxicity Newer AEDs Older AEDs Comorbid conditions and adverse effects of AEDs

69. Recommendations

70. AAN and AES practice parameters 2004. No No Zonisamide # Not FDA approved for this indication No No Levetiracetam No Yes (A) Oxcarbazepine No No Tiagabine No Yes # (A) Topiramate Yes # (B) Yes # (A) Lamotrigine No Yes # (A) Gabapentin Absence seizures Partial/mixed seizures Drug AAN Guidelines: Level A or B recommendation for new onset epilepsy (adults and children)

71. ILAE Guidelines 2006 A: Gabapentin (GBP), Lamotrigine (LTG) C: CBZ 2 1 1 Elderly A: Oxcarbazepine (OXC) C: CBZ, PB, PHT, TPM, VPA 17 0 1 Children A: Carbamazepine (CBZ), Phenytoin (PHT) B: Valproic acid (VPA) C: GBP, LTG, OXC, PB, TPM, VGB 30 1 2 Adult AED III II I Initial monotherapy for partial seizures

72. ILAE Guidelines 2006 Initial monotherapy for GTCS C: Ethosuximide, LTG, VPA 6 Absence seizure AED III C: CBZ, VPA 2 BECTS C: CBZ, PB, PHT, TPM, VPA 14 Children C: CBZ, LTG, OXC, PB, PHT, TPM, VPA 23 Adult

73. AAN level A or B recommendations for refractory primary generalized epilepsy AAN and AES practice parameters 2004. No (U) Zonisamide No (U) Levetiracetam No (U) Oxcarbazepine No (U) Tiagabine Yes (A) Topiramate (only GTCS) No (U) Lamotrigine No (U) Gabapentin Adults and children

74. AAN level A or B recommendations for refractory partial epilepsy: Adults AAN and AES practice parameters 2004. # Not FDA approved for this indication No (U) Yes (A) Zonisamide No (U) Yes (A) Levetiracetam Yes (A) Yes (A) Oxcarbazepine No (U) Yes (A) Tiagabine Yes# (A) Yes (A) Topiramate Yes (B) Yes (A) Lamotrigine No (U) Yes (A) Gabapentin Monotherapy Adjunctive

75. AAN level A or B recommendations for adjunctive therapy in refractory epilepsy: Children AAN and AES practice parameters 2004. Symtomatic epilepsy group largely comprises of LGS pts No (U) No (U) Zonisamide No (U) No (U) Levetiracetam No (U) Yes (A) Oxcarbazepine No (U) No (U) Tiagabine Yes (A) Yes (A) Topiramate Yes (A) Yes (A) Lamotrigine No (U) Yes (A) Gabapentin Symptomatic generalized Partial

83. Busy days ahead: More AEDs Bialer M et al. Epilepsy Res 2009; 83: 1-43 8. Lacosamide 15. Propylisopropyl acetamide 7. JZP-4 14. YKP 3089 6. Huperzine A 13. Valrocemide 5. Ganaxolone 12. Tonabersat 4. Eslicarbazepine acetate 11. T2000 3. 2-Deoxy-2 glucose 10. Retigabine 2. Carisbamate 9. NAX-5055 1. Brivaracetam

84. Thank you