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

Introduction 5-10 million people with epilepsy (PWE) in India, accounting for 20% of the global burden. Monotherapy effective in 70-80%. However, 50-70% PWE either receive no treatment/ inadequate/ inappropriate treatment. Neurologist: PWE ratio is 1: 1.25 million. Multiple AEDs are now available. The health worker is unfamiliar with the use of most except few of the older ones. GEMIND. Indian Epilepsy Society. 2008.

5-10 million people with epilepsy (PWE) in India, accounting for 20% of the global burden.

Monotherapy effective in 70-80%.

However, 50-70% PWE either receive no treatment/ inadequate/ inappropriate treatment.

Neurologist: PWE ratio is 1: 1.25 million.

Multiple AEDs are now available. The health worker is unfamiliar with the use of most except few of the older ones.

The Established AEDs: Pre-1990 Phenytoin (PHT) Phenobarbitone (PB) Primidone (PRM) Carbamazepine (CBZ) Valproic acid (VPA) Ethosuximide (ESM) Lower cost Easy availability Long term experience Proven efficacy Broad familiarity Major advantages

Phenytoin (PHT)

Phenobarbitone (PB)

Primidone (PRM)

Carbamazepine (CBZ)

Valproic acid (VPA)

Ethosuximide (ESM)

The Newer AEDs: Post 1990 FDA approved: Gabapentin (GBP) Lamotrigine (LTG) Topiramate (TPM) Tiagabine (TGB) Oxcarbazepine (OXC) Levetiracetam (LEV) Zonisamide (ZNS) Fosphenytoin Clobazam Vigabatrin

FDA approved:

Gabapentin (GBP)

Lamotrigine (LTG)

Topiramate (TPM)

Tiagabine (TGB)

Oxcarbazepine (OXC)

Levetiracetam (LEV)

Zonisamide (ZNS)

New onset epilepsy n=495 Treatment responsive 80% Treatment resistant 2/3: Monotherapy 1/3: Polytherapy Older and newer AEDs are equally effective. Kwan P et al. Epilepsia 2001; 42: 1255-60

Older and newer AEDs are equally effective.

Then, why newer AEDS? Such patients are well controlled for years. Require long term AED therapy. Hence, imperative to select the right AED. Emphasis on safety and tolerability. Priority is on ‘quality of life’. However, definite evidence of superiority or atleast parity with older established AEDs is crucial.

Such patients are well controlled for years.

Require long term AED therapy.

Hence, imperative to select the right AED.

Emphasis on safety and tolerability.

Priority is on ‘quality of life’.

However, definite evidence of superiority or atleast parity with older established AEDs is crucial.

Some more reasons…. Older medications though effective, Treatment failures well known Significant adverse effects Significant drug interactions a . Hepatic enzyme inducers: DPH, PB, PRM, CBZ b . Hepatic enzyme inhibitors:VPA Newer AEDs have comparatively less interactions. Patsalos PN et al. Epilepsia 2002; 43: 365-85 Morrell MJ et al. Ann Neurol; 2002: 52: 704-11

Older medications though effective,

Treatment failures well known

Significant adverse effects

Significant drug interactions

a . Hepatic enzyme inducers: DPH, PB, PRM, CBZ

b . Hepatic enzyme inhibitors:VPA

Newer AEDs have comparatively less interactions.

Numerous studies on Newer AEDs 1462 articles, BUT, Varying study designs and methodology. Varying inclusion criteria and end points. Small sample size and short duration. Not adequately powered to show superiority of the study drug. Few studies comparing newer AEDs with each other. French JA et al. Epilepsia 2004; 45: 401-09

1462 articles, BUT,

Varying study designs and methodology.

Varying inclusion criteria and end points.

Small sample size and short duration.

Not adequately powered to show superiority of the study drug.

Few studies comparing newer AEDs with each other.

Classification of evidence Definitions

Rating of Recommendation A: Established as effective, ineffective or harmful. B: Probably effective, ineffective or harmful C: Possibly effective, ineffective or harmful U: Data inadequate or conflicting. Given current knowledge, treatment is unproven. Applies to a given condition in a specified population.

A: Established as effective, ineffective or harmful.

B: Probably effective, ineffective or harmful

C: Possibly effective, ineffective or harmful

U: Data inadequate or conflicting. Given current knowledge, treatment is unproven.

Applies to a given condition in a specified population.

Rating of Recommendations Level A: Atleast 1 convincing Class I study or atleast 2 consistent, convincing Class II studies. Level B: Atleast 1 convincing Class II study or atleast 3 consistent, convincing Class III studies. Level C: Atleast 2 convincing and consistent Class III studies. Edlund W, Gronseth G, So Y, Franklin G. American Academy of Neurology Clincal Practice Guideline Process Manual. St. Paul, Minn.: American Academy of Neurology, 2004.

Level A: Atleast 1 convincing Class I study or atleast 2 consistent, convincing Class II studies.

Level B: Atleast 1 convincing Class II study or atleast 3 consistent, convincing Class III studies.

Level C: Atleast 2 convincing and consistent Class III studies.

Definitions: Recommendation: is a statement directing decision making in specific areas of healthcare, as defined by an authoritative examination of current evidence by a suitable apex body, which may be legally binding. Guidelines: are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Practice parameters: ?? Inste of Med. Definition of key terms. National Academy Press, 1990: 33–51.

Recommendation: is a statement directing decision making in specific areas of healthcare, as defined by an authoritative examination of current evidence by a suitable apex body, which may be legally binding.

Guidelines: are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.

Practice parameters: ??

Definitions Patient: Child: less than 16 yrs of age; Adult: 16 yrs or older; Elderly: 60 yrs or older; Mixed: 2-85 yrs. Newly diagnosed epilepsy: 2 or more untreated seizures. Partial epilepsy: localization related (focal) epilepsy characterized by simple partial, complex partial or secondary GTCS. Refractory or treatment resistant epilepsy: Failure of 3 or more compatible AEDs at adequate dosages with 3 or more seizures/ month. AAN and AES practice parameters 2004. ILAE treatment guidelines 2006

Patient: Child: less than 16 yrs of age; Adult: 16 yrs or older; Elderly: 60 yrs or older; Mixed: 2-85 yrs.

Newly diagnosed epilepsy: 2 or more untreated seizures.

Partial epilepsy: localization related (focal) epilepsy characterized by simple partial, complex partial or secondary GTCS.

Refractory or treatment resistant epilepsy: Failure of 3 or more compatible AEDs at adequate dosages with 3 or more seizures/ month.

Definitions Long-term: refers to ≥48 weeks of therapy. Efficacy: ability of that medication to produce seizure freedom. Tolerability: involves the “incidence, severity, and impact” of AED-related adverse effects. Effectiveness: encompasses both AED efficacy and tolerability, as reflected in retention on treatment. ILAE treatment guidelines 2006

Long-term: refers to ≥48 weeks of therapy.

Efficacy: ability of that medication to produce seizure freedom.

Tolerability: involves the “incidence, severity, and impact” of AED-related adverse effects.

Effectiveness: encompasses both AED efficacy and tolerability, as reflected in retention on treatment.

Pharmacology

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

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

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

Lamotrigine

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

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

New onset absence seizures Class II study involving 45 children. LTG (2-15 mg/kg/d) Vs Placebo. Study duration: 4 weeks. Seizure free: LTG (64%), placebo (21%). Discontinuation: Nil Frank LM et al. Epilepsia 1999; 40: 973-9

Class II study involving 45 children.

LTG (2-15 mg/kg/d) Vs Placebo.

Study duration: 4 weeks.

Seizure free: LTG (64%), placebo (21%).

Discontinuation: Nil

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

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

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

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

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

Summary Effective: Initial monotherapy in new onset partial seizures in adults (Level A). Initial monotherapy in new onset partial seizures in children (Level A). Initial monotherapy in new onset partial seizures in elderly (Level A). Initial monotherapy in new onset GTCS in adults (Level C). Monotherapy in new onset absence seizures (Level B). Monotherapy in refractory partial epilepsy in adult (Level A). AAN and AES practice parameters 2004.

Effective:

Initial monotherapy in new onset partial seizures in adults (Level A).

Initial monotherapy in new onset partial seizures in children (Level A).

Initial monotherapy in new onset partial seizures in elderly (Level A).

Initial monotherapy in new onset GTCS in adults (Level C).

Monotherapy in new onset absence seizures (Level B).

Monotherapy in refractory partial epilepsy in adult (Level A).

Summary 7. Add-on in refractory partial epilepsy in adults and children (Level A). 8. Lennox-Gastaut syndrome- at 50-400 mg/d (Level A). But may worsen myoclonic seizures. Effective dose: 300-500 mg/d in enzyme induced pts, 150 mg/d in pts on VPA. Better response at higher doses, but less tolerated. There is risk of serious rash in children. AAN and AES practice parameters 2004.

7. Add-on in refractory partial epilepsy in adults and children (Level A).

8. Lennox-Gastaut syndrome- at 50-400 mg/d (Level A). But may worsen myoclonic seizures.

Effective dose: 300-500 mg/d in enzyme induced pts, 150 mg/d in pts on VPA.

Better response at higher doses, but less tolerated.

There is risk of serious rash in children.

Topiramate

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

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)

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

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

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)

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

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

Summary Effective: Add-on therapy in refractory partial seizures in adults. Add-on in refractory partial epilepsy in children (125-400 mg/d). Monotherapy in refractory partial seizure Idiopathic refractory GTCS with or without other seizure types (at 6 mg/kg/d). Lennox- Gastaut syndrome: at 6 mg/kg/d. AAN and AES practice parameters 2004.

Effective:

Add-on therapy in refractory partial seizures in adults.

Add-on in refractory partial epilepsy in children (125-400 mg/d).

Monotherapy in refractory partial seizure

Idiopathic refractory GTCS with or without other seizure types (at 6 mg/kg/d).

Lennox- Gastaut syndrome: at 6 mg/kg/d.

Summary Effective dose: 300-1000 mg/d. Better response at higher doses, but less tolerated. Slow titration will reduce side effects. Hypohidrosis has been noted in children. AAN and AES practice parameters 2004.

Effective dose: 300-1000 mg/d.

Better response at higher doses, but less tolerated.

Slow titration will reduce side effects.

Hypohidrosis has been noted in children.

Oxcarbazepine

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)

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)

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)

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

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)

Summary Effective: Monotherapy in new onset partial/ generalized epilepsy. Monotherapy in refractory partial epilepsy. Add-on therapy in refractory partial epilepsy in adults. Add-on in refractory partial epilepsy in children (30-46 mg/kg/d). Effective dose: 600-2400 mg/d, better response at higher doses, but less tolerated. AAN and AES practice parameters 2004.

Effective:

Monotherapy in new onset partial/ generalized epilepsy.

Monotherapy in refractory partial epilepsy.

Add-on therapy in refractory partial epilepsy in adults.

Add-on in refractory partial epilepsy in children (30-46 mg/kg/d).

Effective dose: 600-2400 mg/d, better response at higher doses, but less tolerated.

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

Gabapentin All studies are Class I evidence unless specified otherwise.

New onset epilepsy GBP (300, 900, 1800 mg/d) Vs CBZ (600 mg/d). 275 adults and adolescents with partial or generalized epilepsy. Exit point: 3 SPS/CPS or 1 GTCS or 1 SE. Time to exit was the outcome measured. GBP (900, 1800 mg/d) and CBZ equally efficacious. GBP (300 mg/d) was inferior. Discontinuation: CBZ (24%), GBP (13.5%). Chadwick DW et al. Neurology 1998; 51: 1282-8

GBP (300, 900, 1800 mg/d) Vs CBZ (600 mg/d).

275 adults and adolescents with partial or generalized epilepsy.

Exit point: 3 SPS/CPS or 1 GTCS or 1 SE.

Time to exit was the outcome measured.

GBP (900, 1800 mg/d) and CBZ equally efficacious. GBP (300 mg/d) was inferior.

Discontinuation: CBZ (24%), GBP (13.5%).

Refractory partial epilepsy- adjunctive therapy 4 Class I studies in adults; dose of 600-1800 mg/d. Responder rate of 8.4- 26.4%. Best results with higher dose (1800 mg/d). Discontinuation rate: 3- 11.5% Slower titration led to better tolerability. No therapeutic blood level range could be established. Anhut H et al. Epilepsia 1994; 35: 795-801 Fischer RS et al. Neurology 2001; 56: 743-8

4 Class I studies in adults; dose of 600-1800 mg/d.

Responder rate of 8.4- 26.4%.

Best results with higher dose (1800 mg/d).

Discontinuation rate: 3- 11.5%

Slower titration led to better tolerability.

No therapeutic blood level range could be established.

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)

Summary Effective: Monotherapy in new onset partial/generalized epilepsy. Add-on in refractory partial epilepsy in adults. Add-on in refractory partial epilepsy in children (23-35 mg/kg/d). Ineffective in: Absence seizures. Refractory generalized epilepsy (primary/ secondary). Lennox-Gastaut syndrome: May worsen myoclonic seizures. Effective dose: 600-1800 mg/d. AAN and AES practice parameters 2004.

Effective:

Monotherapy in new onset partial/generalized epilepsy.

Add-on in refractory partial epilepsy in adults.

Add-on in refractory partial epilepsy in children (23-35 mg/kg/d).

Ineffective in:

Absence seizures.

Refractory generalized epilepsy (primary/ secondary).

Lennox-Gastaut syndrome: May worsen myoclonic seizures.

Effective dose: 600-1800 mg/d.

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

Tiagabine Currently not available in India

Refractory partial seizures- adjunctive therapy 2 Class I and 1 Class II studies. Doses tested: 16-56 mg/d. 50% responder rate: 20-36% Median seizure reduction: 12-36% Better response with higher doses. No difference between b.i.d and q.i.d dosage. Discontinuation rate: 8-20 % (placebo= 8-9%). Sachdeo RC et al. Arch Neurol 1997; 54: 595-601 Uthman DM et al. Arch Neurol 1998; 55: 56-62

2 Class I and 1 Class II studies.

Doses tested: 16-56 mg/d.

50% responder rate: 20-36%

Median seizure reduction: 12-36%

Better response with higher doses.

No difference between b.i.d and q.i.d dosage.

Discontinuation rate: 8-20 % (placebo= 8-9%).

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

Summary Effective: Add-on therapy in refractory partial epilepsy Effective dose: 16-56 mg/d. Better response at higher doses, but less tolerated. AAN and AES practice parameters 2004.

Effective:

Add-on therapy in refractory partial epilepsy

Effective dose: 16-56 mg/d.

Better response at higher doses, but less tolerated.

Zonisamide

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

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

Levetiracetam

Refractory partial epilepsy- adjunctive therapy 3 studies have Class I evidence. Doses tested: 1000- 3000 mg/d. 50% responder rate: 1000 mg/d (22-33%), 2000 mg/d (31-34%), 3000 mg/d (39.8%), placebo (10-17%). Seizure free rate: Max. with higher doses (8% with 3000 mg/d). Discontinuation rate: 7-13% (placebo 5-8%). Unrelated to dose. Cereghino JJ et al. Neurology 2000; 55: 236-42 Shorvon SD et al. Epilepsia 2000; 41: 1179-86

3 studies have Class I evidence.

Doses tested: 1000- 3000 mg/d.

50% responder rate: 1000 mg/d (22-33%), 2000 mg/d (31-34%), 3000 mg/d (39.8%), placebo (10-17%).

Seizure free rate: Max. with higher doses (8% with 3000 mg/d).

Discontinuation rate: 7-13% (placebo 5-8%). Unrelated to dose.

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

Summary Effective: Add-on therapy in refractory partial epilepsy Effective dose: 1000-3000 mg/d. No increment in response at higher doses. AAN and AES practice parameters 2004.

Effective:

Add-on therapy in refractory partial epilepsy

Effective dose: 1000-3000 mg/d.

No increment in response at higher doses.

Vigabatrin Effective: Initial monotherapy in new onset partial seizures in adults, children. Initial monotherapy in new onset adult GTCS. Add-on therapy in pts with refractory partial epilepsy. Infantile spasms. Concentric visual field abnormalities in 40% of pts, probably irreversible. Hence consensus is to not to recommend this drug. Marson AG et al. Epilepsia 1997; 38; 859-80. Kalviainen R et al. Neurology 1999; 53: 922-6

Effective:

Initial monotherapy in new onset partial seizures in adults, children.

Initial monotherapy in new onset adult GTCS.

Add-on therapy in pts with refractory partial epilepsy.

Infantile spasms.

Concentric visual field abnormalities in 40% of pts, probably irreversible.

Hence consensus is to not to recommend this drug.

Clobazam Antiepileptic activity has been discovered recently. Has equivalent efficacy to CBZ and PHT as monotherapy for childhood epilepsy. Effective in febrile seizures at dose of 0.75 mg/kg in 2 divided doses for 2-3 days. Effective dose: 10-30 mg/d. Common adverse effects: sedation, ataxia, somnolence, irritability, depression, weight gain. Tolerance may develop. Canadian study group for childhood epilepsy. Epilepsia 1998; 39: 952-9 GEMIND. Indian Epilepsy Association 2008.

Antiepileptic activity has been discovered recently.

Has equivalent efficacy to CBZ and PHT as monotherapy for childhood epilepsy.

Effective in febrile seizures at dose of 0.75 mg/kg in 2 divided doses for 2-3 days.

Effective dose: 10-30 mg/d.

Common adverse effects: sedation, ataxia, somnolence, irritability, depression, weight gain.

Tolerance may develop.

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

Recommendations

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)

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

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

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

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

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

Elderly New onset partial seizures: LTG and GBP are effective as initial monotherapy (Level A). Other option is TPM (Level D). Other seizure types: recommendations for adult population to be followed. ILAE treatment guidelines 2006

New onset partial seizures: LTG and GBP are effective as initial monotherapy (Level A). Other option is TPM (Level D).

Other seizure types: recommendations for adult population to be followed.

Status epilepticus None of the published guidelines incorporate newer AEDs in the management of status epilepticus. Established status epilepticus: Fosphenytoin infusion at a dose of 15−20 mg phenytoin equivalents (PE)/kg at a rate of 50-100 mg PE/minute. NICE Guidelines 2004

None of the published guidelines incorporate newer AEDs in the management of status epilepticus.

Established status epilepticus:

Fosphenytoin infusion at a dose of 15−20 mg phenytoin equivalents (PE)/kg at a rate of 50-100 mg PE/minute.

Newer AEDs and Teratogenicity All AEDs fall under FDA category C or D. Category C: Teratogenicity proven in animals, human risk not known. eg All newer AEDs Category D: Teratogenicity proven in both animals and humans. Eg PHT, CBZ, VPA. Selection of AED in pregnancy is decided by risk: benefit ratio for seizure control. AAN and AES practice parameters 2004.

All AEDs fall under FDA category C or D.

Category C: Teratogenicity proven in animals, human risk not known. eg All newer AEDs

Category D: Teratogenicity proven in both animals and humans. Eg PHT, CBZ, VPA.

Selection of AED in pregnancy is decided by risk: benefit ratio for seizure control.

Pitfalls No recent guidelines. Evidence derived from very few studies. No data on epileptic syndromes. Newer drugs- yet to be incorporated. Most study populations were heterogenous, with patients having different seizure types. Confusing use of terms; mixed seizure types, GTCS.

No recent guidelines.

Evidence derived from very few studies.

No data on epileptic syndromes.

Newer drugs- yet to be incorporated.

Most study populations were heterogenous, with patients having different seizure types.

Confusing use of terms; mixed seizure types, GTCS.

Pitfalls Numerous contradicting statements in the AAN document. Inconsistencies in recommendations between AAN and ILAE. Extrapolates efficacy in adults to that in children. ILAE guidelines covers only a limited spectrum of epilepsy syndromes. However, this is the best that we have at present. Panayiotopoulos CP et el. Epilepsia 2004; 45; 1646-52.

Numerous contradicting statements in the AAN document.

Inconsistencies in recommendations between AAN and ILAE.

Extrapolates efficacy in adults to that in children.

ILAE guidelines covers only a limited spectrum of epilepsy syndromes.

However, this is the best that we have at present.

Conclusions Alarming paucity of well conducted trials for obtaining evidence. Newer drugs are as effective as the older drugs in new onset and refractory epilepsy. May not be superior. May be better tolerated. Start low and go slow to improve tolerability. Recommendations are inadequate for many common clinical situations.

Alarming paucity of well conducted trials for obtaining evidence.

Newer drugs are as effective as the older drugs in new onset and refractory epilepsy. May not be superior.

May be better tolerated.

Start low and go slow to improve tolerability.

Recommendations are inadequate for many common clinical situations.

Issues that need to be addressed Need for update of these recommendations Standardized trial design and inclusion criteria. Adequately powered to demonstrate true non-inferiority. No trials yet of newer drugs in IGE syndromes. Studies on extended release preparations. No literature on cost-benefit analysis related to these issues.

Need for update of these recommendations

Standardized trial design and inclusion criteria.

Adequately powered to demonstrate true non-inferiority.

No trials yet of newer drugs in IGE syndromes.

Studies on extended release preparations.

No literature on cost-benefit analysis related to these issues.

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

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