Use of the New Antiepileptic Agents Anthony Murro, M.D.

100
Use of the New Antiepileptic Agents Anthony Murro, M.D.

Transcript of Use of the New Antiepileptic Agents Anthony Murro, M.D.

Page 1: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Use of the New Antiepileptic Agents

Anthony Murro, M.D.

Page 2: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Research Support

• I currently received support for research involving biravacetam from UCB

Page 3: Use of the New Antiepileptic Agents Anthony Murro, M.D.

New Antiepileptic Agents

• Lacosamide (Vimpat)

• Rufinamide (Banzel)

• Vigabatrin (Sabril)

• Clobazam (Onfi)

• Ezogabine (Potiga)

Page 4: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide• Adjunctive therapy in the treatment of

partial-onset seizures• Functionalized amino acid

Page 5: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide - Mechanism• Lacosamide facilitates slow inactivation of

voltage gated sodium ion channels

Page 6: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide - Slow inactivation

• Membrane depolarization occurs

• A relatively slower & more sustained ion channel conformation occurs at a intra-membrane channel site

• This conformation blocks sodium ion flow

• Lacosamide enhances slow inactivation

• (Goldin, 2011)

Page 7: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Sodium Ion Channel Fast Inactivation

• Voltage gated sodium ion channel conformation occurs post-depolarization

• An intracellular protein segment (inactivating particle) binds to a docking site & blocks sodium ion flow

• Carbamazepine, felbamate, lamotrigine, phenytoin, oxcarbazepine, topiramate enhance fast inactivation

• (Goldin, 2011)

Page 8: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Slow inactivationIntra-membrane sites S5 & S6 block ion

channel

Page 9: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Fast Inactivation

Intracellular loop between domains III & IV blocks ion channel

Page 10: Use of the New Antiepileptic Agents Anthony Murro, M.D.

CRMP-2 Binding• Lacosamide also binds to a collapsin

response mediator protein-2 (CRMP-2)

Page 11: Use of the New Antiepileptic Agents Anthony Murro, M.D.

CRMP-2 Binding• This protein performs important roles that

include cytoskeletal, vesicle, and synaptic functions in the developing brain.

• The significance of this binding is an area of current research (Hensley et al., 2011)

Page 12: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Dosing

• Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day

• Maintenance dose: 200-400 mg/day

Page 13: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Metabolism

• Linear kinetics 100-800 mg/d dose

• Metabolism (CYP2C19) by de-methylation to form O-desmethyl-lacosamide (inactive)

• No significant induction/inhibition or P450 mediated interaction

(Chu et al, 2010)

Page 14: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Effectiveness• Multi-center randomized prospective

controlled trials

• > 400 patients per trial

• Age 16 years and older

• Adjunctive therapy with 1-3 anti-epileptic medications

Page 15: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Median Sz ReductionGroup Ben-Menachem Halasz

Placebo 10% 20.5%

200 mg/d 26% 35.3%

400 mg/d 39% 36.4%

600 mg/d 40% ---

(Ben-Menachem et al, 2007, Halasz et al, 2009)

Page 16: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Effectiveness

• Dose of 600 mg/day not more effective but did have increased side effect risk

• Events leading to discontinuation: Dizziness, nausea, ataxia, vomiting, nystagmus

• (Ben-Menachem et al, 2007)

Page 17: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Effect of Sodium Channel Blocker

Retrospective analysis suggests:

• Lacosamide will reduce seizure frequency even when combined with a fast sodium channel blocker (Sake et al., 2010, Stephen et al., 2011)

Page 18: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Effect of Sodium Channel Blocker

Retrospective analysis suggests:

• Lacosamide with a sodium channel blocker (e.g. phenytoin) will lead to less seizure reduction & increased side effects

• Caution: Post-hoc analysis, small samples, multiple comparisons, and potential confounding factors.

(Sake et al., 2010, Stephen et al., 2011)

Page 19: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Pooled Analysis

Median Seizure Reduction

Sodium Channel Blocker

Group Present Absent

Placebo 18.9% 28%

200 mg/d 33.3% 38%

400 mg/d 39% 62.5%

600 mg/d 42.7% 79%

Page 20: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide Case Reports• Intravenous lacosamide has been used to

treat status epilepticus & seizure clusters. Bolus of 200 mg IV at rate of 60 mg/min (Höfler et al., 2011)

• Lacosamide has been used in primary generalized epilepsy (Afra et al., 2012)

• A single report described worsening of seizures in Lennox Gastaut syndrome with lacosamide (Cuzzola et al., 2010)

Page 21: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Lacosamide SummaryPositive

• No significant drug interactions

• Common side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Low protein binding

Negative

• High cost

Page 22: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Role of Lacosamide

• The favorable profile makes lacosamide a likely early choice for adjuvant drug therapy of partial seizures

• Future research might confirm effectiveness for primary generalized epilepsy & status epilepticus.

• Future research might confirm greater benefit among patients not using sodium channel blockers

Page 23: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide• Adjunctive therapy in the treatment of

generalized seizures of Lennox-Gastaut syndrome (LGS)

Page 24: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Mechanism• Rufinamide slows sodium ion channel

recovery from the inactivated state & limits repetitive neuronal firing

Page 25: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Dosing• Children: Initial: 10 mg/kg/day in 2 equally

divided doses; increase dose by ~10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day (whichever is lower) in 2 equally divided doses

• Adults: Initial: 400-800 mg/day in 2 equally divided doses; increase dose by 400-800 mg/day every other day to a maximum dose of 3200 mg/day in 2 equally divided doses.

Page 26: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Oral Absorption• Oral absorption increases with food due to

increased solubility (33% increase overall absorption & 50% increase in peak concentration).

• Keep relationship with meals constant.

Page 27: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Metabolism

• Carboxylesterase metabolism to inactive metabolite

• Rufinamide is a weak CYP3A4 inducer

• Non-linear drug kinetics

Page 28: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Drug Levels

• Drug levels correlate with effectiveness and frequency of adverse effects

• Mean plasma level causing a 50% decrease of seizure frequency was 30 mg/l; range in studies: 5-55 mg/l.

Page 29: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Drug Interactions

• Mild increased clearance of oral contraceptives (CYP3A4 induction)

• Phenobarbital, primidone, phenytoin, carbamazepine induce carboxyesterase & significantly increase rufinamide clearance

• Valproate significantly increases rufinamide levels by 60-70%

Page 30: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Lennox Gastaut Median Seizure Reduction

Group All Seizures Tonic-atonic

Placebo 11.7% -1.4%

45 mg/kg-d 32.7% 42.5%

(Glauser et al., 2007)

Page 31: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide Partial Seizures Median Seizure Reduction

Group Seizure Reduction

Placebo -1.6%

Rufinamide* 20.4%

Dose: 1200-3200 mg/d (mean 2800 mg/d)

(Brodie et al, 2007)

Page 32: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Adverse Effects• Most common: Dizziness, fatigue,

somnolence, nausea, headache

• AED hypersensitivity syndrome (rash & fever) has occurred 1-4 weeks after therapy & more likely in children

• No significant effects on working memory, psychomotor speed, or attention

• (Wheles et al. 2010)

Page 33: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide QT shortening

• > 20 msec reduction in QT can occur but in in study population had < 300 msec

• Rufinamide should not be given to those with familial short QT syndrome potassium channelopathy

• Do not administer in situations with reduced QT interval: digoxin, hpercalcemia, hyperkalemia, acidosis

Page 34: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Myoclonic-astatic epilepsy (Doose syndrome)

• Onset age 1-6 years of age

• Myoclonic, astatic, & myoclonic-astatic Sz

• Normal development prior to seizures

• Prognosis variable: spontaneous resolution in some; prolonged non-convulsive status epilepticus, cognitive impairments & evolution to Lennox-Gastaut in others

• EEG: 2-3 Hz generalized spike wave

• MRI normal

Page 35: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Myoclonic-astatic epilepsy & Rufinamide

• In a case series, rufinamide adjunctive therapy reduced seizure frequency by >75% in 6 of 7 cases

• Seizure reduction decreased for patients followed over longer time intervals of 6-18 months (von Stülpnagela et al. 2012)

Page 36: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Rufinamide SummaryPositive

• Most side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Low protein binding

Negative

• Significant drug interactions are possible

• High cost

Page 37: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Role of Rufinamide

• Rufinamide has features similar to many of the approved drugs for Lennox-Gastaut (e.g. lamotrigine, topiramate).

• Future research might confirm the beneficial effect of rufinamide for treatment of myoclonic-astatic epilepsy.

Page 38: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin• Adjunctive treatment for infantile spasms and

adult refractory complex partial seizure

Page 39: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Mechanism

• Irreversible & competitive binding to GABA transaminase (Chu-Shore et al., 2010)

Page 40: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Mechanism

• Possibly also might stimulate GABA release

• Brain GABA increases by 40% at 2 hours post-dose

• (Chu-Shore et al., 2010)

Page 41: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin

• Linear dose relationship

• Reduces phenytoin level by 20%

• Dosage adjustment for decreased renal clearance

• (Chu-Shore et al., 2010)

Page 42: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Dosing Complex Partial Seizures

• Adults: Initial: 500 mg twice daily; increase daily dose by 500 mg at weekly intervals based on response and tolerability. Recommended dose: 3 g/day

• Children: Oral: Initial: 40 mg/kg/day divided twice daily; maintenance dosages based on patient weight

Page 43: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Dosing Infantile Spasm

• Initial dosing: 50 mg/kg/day divided twice daily; may titrate upwards by 25-50 mg/kg/day every 3 days to a maximum of 150 mg/kg/day

Page 44: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Effectiveness Complex Partial Seizures

(Dean et al., 1999)

Page 45: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Effectiveness Complex Partial Seizures

(French et al., 1996)

Page 46: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Treats Infantile SpasmsTuberous Sclerosis Responds Best

Group % Spasm Free day 14Vigabatrin low dose 11%Vigabatrin high dose 36%• Tuberous sclerosis 52%• Cryptogenic 27%• Symptomatic 10%Low: 18-36 mg/kg-d; High: 100-148 mg/kg-d(Elterman et al., 2001)

Page 47: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Hormonal Therapy Better Early Response For Non-Tuberous

Sclerosis CasesPercent Spasm Free

Group 2 wks* 12-14 months

Hormonal 73% 75%

Vigabatrin 54% 76%

• Significant difference (Lux et al., 2005)

Tuberous sclerosis cases were excluded

Page 48: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases

Outcome at 12-14 months Following Treatment

Symptomatic Vineland Adaptive Behavior Scale

Hormonal 70.8

Vigabatrin 75.9

Cryptogenic* Vineland Adaptive Behavior Scale

Hormonal 88.2**

Vigabatrin 78.9**• Significant difference (Lux et al., 2005)

Tuberous sclerosis cases were excluded

Page 49: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases

Outcome at 4 years Following Treatment

Symptomatic Vineland Adaptive Behavior Scale

Hormonal 45

Vigabatrin 50

Cryptogenic* Vineland Adaptive Behavior Scale

Hormonal 96

Vigabatrin 63

* Significant difference (Darke et al., 2005)

Tuberous sclerosis cases were excluded

Page 50: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Effectively Treats Tuberous Sclerosis

Practice Parameter: Medical Treatment of Infantile Spasms:

“Overall cessation of spasms was seen in 41 of 45 (91%) of children treated with vigabatrin, with a 100% response rate seen in five studies.”

(Mackay et al. 2004)

Page 51: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Visual Adverse Effects

• Bilateral irreversible concentric peripheral field defects occur in 30-50% of cases

• Most with defects were treated for at least 6 months; often stable after 2 years

• Defects often asymptomatic but might impair driving (Chu-Shore et al., 2010)

Page 52: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Visual Adverse Effects

• Adults: visual testing done at baseline & each 6 months

• Infants: visual testing done at baseline & test each 3 months for 18 months, then each 6 months (sedate for electroretinogram)

(Chu-Shore et al., 2010)

Page 53: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Visual Effects• Common approach is treatment for a

duration under 3 months; consider discontinuation after 6 months, if seizures are effectively controlled (Kossoff EH, 2010).

• An experimental animal study found that taurine prevented the visual adverse effect (Firas et al, 2009)

Page 54: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin White Matter Changes

• Lesions were asymptomatic & reversible

• Age: 9 months - 18 years (median 5.4 yrs)

• 8 of 23 (34%) subjects were affected

• T2/DWI scans show lesions in basal ganglia, thalamus, brainstem, & dentate nucleus (Pearl et al., 2009)

Page 55: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin White Matter Changes

Feature With Lesions Without Lesions

Number 8 subjects 15 subjects

Age 11 months 5 years

Duration 3 months 12 months

Dose 170 mg/kg-d 87 mg/kg-d

(Pearl et al., 2009)

Page 56: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin White Matter Changes

Page 57: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Vigabatrin Summary

Positive• High effectiveness for infantile spasms• Few significant drug interactions; exception is

phenytoin• Infrequent need for serum drug levels• Low protein bindingNegative• Irreversible visual field defects• White matter lesions • High cost

Page 58: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Role of Vigabatrin

• Vigabatrin is likely to be among the last choices for adjuvant treatment of partial seizures

• Vigabatrin is a good 1st choice for infantile spasms from tuberous sclerosis (TS)

• Hormonal therapy might provide more effective early control for non-TS cases & better cognitive outcome for cryptogenic infantile spasms

Page 59: Use of the New Antiepileptic Agents Anthony Murro, M.D.

ClobazamAdjunctive treatment of seizures associated

with Lennox-Gastaut syndrome

Page 60: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Mechanism• Allosteric activation of GABAa receptor

Page 61: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Mechanism• Allosteric activation of GABAa receptor

• Up-regulation GABA transporters 1 to 3 (GAT1 to GAT3)

• Clobazam has decreased affinity for GABAa subunits that mediate sedative effects

Page 62: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Dosing• ≤30 kg: Initial: 5 mg once daily for ≥1

week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily thereafter

• >30 kg: Initial: 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter

Page 63: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam DosingCYP2C19 poor metabolizers:

• ≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may increase to 10 mg twice daily

• >30 kg: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily

Page 64: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Metabolism• Hepatic via CYP3A4 and to a lesser extent via

CYP2C19 and 2B6

• N-demethylation to active metabolite [N-desmethyl] with ~20% activity of clobazam.

• CYP2C19 primarily mediates subsequent hydroxylation of the N-desmethyl metabolite.

• Carbamazepine reduces clobazam level, & clobazam decreases valproate (Riss et al, 2008)

• Many other potential drug interactions

Page 65: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam• Placebo controlled trial in 238 cases

(age 2-60 years) with Lennox-Gastaut syndrome (Ng YT et al, 2011)

• Treatment groups: placebo, 0.25 mg/kg-d, 0.5 mg/kg-d, 1.0 mg/kg-d.

• Weekly seizure rate reduction showed a dose response effect

• Side effects: somnolence, pyrexia, respiratory infections, lethargy, behavioral problems.

Page 66: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Treatment Response

Group Drop Attack Reduction

Placebo 12.1%

0.25 mg/kg-d (max 10 mg/d) 41.2%

0.5 mg/kg-d (max 20 mg/d)49.4%

1.0 mg/kg-d (max 40 mg/d)68.3%

(Ng YT et al, 2011)

Page 67: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Side Effects

• Somnolence

• Fever

• Lethargy

• Drooling

• Constipation

Page 68: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam Other Studies• Retrospective studies involving refractory

partial seizures reported an early improvement in seizure reduction.

• Many could not tolerate the drug due to somnolence.

• Tolerance occurred; seizures re-occurred in subjects that had improved initially (Shimizu et al., 2003, da Silveira et al., 2006)

Page 69: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam SummaryPositive

• High level of effectiveness for a difficult to treat seizure disorder

• Common side effects are dose dependent & easily managed with dose reduction

• Parent compound & metabolite have long half life

Page 70: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Clobazam SummaryNegative

• High cost

• High protein binding

• Active metabolite & potentially significant drug interactions

Page 71: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Role of Clobazam• Clobazam is likely to be a useful drug for

adjuvant therapy of Lennox Gastaut

• Limiting factors are likely to be cost and occurrence of drug related side effects

• Research might confirm the benefit of this drug for refractory partial seizures.

Page 72: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine (Retigabine)Adjuvant treatment of partial-onset seizures

Page 73: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine

• Binds to KCNQ2/3 KCNQ3/5 potassium channels

Page 74: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine• Ezogabine binds to KCNQ2/3 & KCNQ3/5

potassium channels at a hydrophobic pocket near channel gate

• This binding stabilizes the open KCNQ2/3 & KCNQ3/5 potassium channels

• This causes membrane hyperpolarization (Gunthorpe et al. 2012)

Page 75: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine• At high concentrations: blocks sodium

voltage gated sodium & calcium channels and increases GABA synthesis (Czuczwar et al., 2010)

Page 76: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Autosomal Dominant Neonatal Epilepsy

• Loss of function mutation KCNQ2/3

• Focal or generalized tonic-clonic seizures on day 3; seizures remit by 1 month

• 10-15% develop epilepsy

• Therapy resistant epileptic encephalopathy might occur (Kurahashi et al., 2009)

Page 77: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine Dosing

• Initial: 100 mg 3 times/day; may increase at weekly intervals in increments of ≤150 mg/day to a maintenance dose of 200-400 mg 3 times/day (maximum: 1200 mg/day)

Page 78: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine Metabolism

• No P450 metabolism• Glucuronidation via UGT1A4, UGT1A1,

UGT1A3, and UGT1A9• Acetylation via NAT2 to an N-acetyl active

metabolite (NAMR) and other inactive metabolites (eg, N-glucuronides, N-glucoside)

• Linear drug kinetics (Weisenberg et al,, 2011)

Page 79: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine Drug Interactions

• No effect on oral contraceptive clearance

• Lamotrigine decreases ezogabine clearance slightly; ezogabine increases lamotrigine clearance slightly

Page 80: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 13.1%

600 mg/d 23.4%

900 mg/d 29.3%

1200 mg/d 35.2%

(Porter et al., 2007)

Page 81: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 15.9%

600 mg/d 27.9%

900 mg/d 39.9%

(Brodie et al., 2010)

Page 82: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine EffectivenessGroup Seizure Reduction

Placebo 17.5%

1200 mg/d 44.3%

(French et al., 2011)

Page 83: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine Side Effectts

• Somnolence• Fatigue• Confusion• Dizziness• Headache• Dysarthria• Ataxia• Blurred vision

Page 84: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Ezogabine SummaryPositive

• Minimal drug interactions

• Common side effects are dose dependent & easily managed with dose reduction

• Infrequent need for serum drug levels

• Unique drug mechanism

Negative

• High cost

Ezogabine

Page 85: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Role of Ezogabine

• Ezogabine is likely to be a useful drug for adjuvant therapy for refractory partial seizures

• Limiting factors are likely to be cost and occurrence of drug related side effects

Page 86: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Cumulative SummaryLacosamide, & ezogabine are likely to be

considered early choices for adjuvant drug therapy of partial seizure because:

• Minimal drug interactions

• Novel mechanisms of action

• Relatively safe side effect profile.

Page 87: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Cumulative SummaryVigabatrin has a specialized role:• First choice therapy for infantile spasms

among those with tuberous sclerosis• Adjuvant therapy in otherwise refractory

infantile spasm cases.• ACTH may be a better choice in select

infantile cases. • Vigabatrin is likely to be among the later

choices for refractory partial seizures due to its risk of visual loss.

Page 88: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Cumulative SummaryRufinamide and clobazam have a

specialized role as adjuvant therapy for Lennox-Gastaut.

• Drug interactions are more complex with these medications.

• Side effects might limit the use of these medications in some cases

Page 89: Use of the New Antiepileptic Agents Anthony Murro, M.D.

Pharmacokinetic PropertiesDrug Tmax T1/2 %PB

Lacosamide 1-2 hr 13 hr <19%

Rufinamide 4-6 hr 6-10 hr 34%

Vigabatrin 2 hr 5-8 hr 0%

Clobazam 1-2 hr 10-30 hr 82-90%

Clobazam ** --- 36-46 hr ---

Ezogabine 1-2 hr 8-10 hr <80%

** desmethylclobazam active metabolite

(Chu et al, 2010)

Page 90: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Afra P, Adamolekun B. Lacosamide treatment of

juvenile myoclonic epilepsy. Seizure. 2012 Jan 24.

• Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomized,placebo-controlled study of vigabatrin as first-line treatment of infantile

• spasms. Epilepsia. 1999;40:1627–1633.• Ben-Menachem E, Biton V, Jatuzis D, Abou-

Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007 Jul;48(7):1308-17.

Page 91: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Brodie M.J., W.E. Rosenfeld, B. Vazquez et al.

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo-controlled trial Epilepsia, 50 (2009), pp. 1899–1909

• Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin P, Nohria V, Mansbach H; RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010 Nov 16;75(20):1817-24.

• Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6 Suppl 2:2S52–2S59.

Page 92: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N,

Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6 Suppl 2:2S52–2S59.

• Chu-Shore CJ, Thiele EA. New drugs for pediatric epilepsy. Semin Pediatr Neurol. 2010 Dec;17(4):214-23.

• Cuzzola A, Ferlazzo E, Italiano D, Calabrò RS, Bramanti P, Genton P. Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases. Epilepsy Behav. 2010 Dec;19(4):650-1

• Czuczwar P, Wojtak A, Cioczek-Czuczwar A et al. Retigabine: The newer potential antiepileptic drug Pharmacol Rep, 62 (2010), pp. 211–219

Page 93: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Darke K, Edwards SW, Hancock E, Johnson AL,

Kennedy CR, Lux AL, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP; trial steering committee on behalf of participating investigators. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial.Arch Dis Child. 2010 May;95(5):382-6.

• da Silveira MRM , Montenegro MA, Franzon RC, Guerreiro CAM, Guerreiro MM. Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy. Arq Neuropsiquiatr 2006;64(3-B):705-710

• Dean C, Mosier M, Penry K. Dose-response study of vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Epilepsia, 40 (1999), pp. 74–82

Page 94: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Elger C.E. , H. Stefan, A. Mann et al. A 24-week

multicenter, randomized, double-blind, parallel-group, dose-ranging study of Rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res, 88 (2010), pp. 255–263

• Elterman RD, Shields WD, Mansfield KA, et al; US Infantile Spasms Vigabatrin Study Group. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57:1416–1421.

• French JA, M. Mosier, S. Walker et al. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizuresVigabatrin Protocol 024 Investigative Cohort Neurology, 46 (1996), pp. 54–61

Page 95: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• French JA, Abou-Khalil BW, Leroy RF, Yacubian EM,

Shin P, Hall S, Mansbach H, Nohria V; RESTORE 1/Study 301 Investigators. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.

• Neurology. 2011 May 3;76(18):1555-63.• Firas Jammoul,, Qingping Wang, et al. Taurine

deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol. 2009 January ; 65(1): 98–107

• Glauser T, Kluger G, Sachdeo R et al. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology, 70 (2008), pp. 1950–1958

Page 96: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Goldin AL. Mechanisms of sodium channel inactivation.

Curr Opin Neurobiol. 2003 Jun;13(3):284-90. • Gunthorpe MJ, Large CH, Sankar R, The mechanism of

action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia, 1–13, 2012.

• Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, Sullivan T; SP755 Study Group.l Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia. 2009 Mar;50(3):443-53

• Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol. 2011 Jun;43(3):180-91

Page 97: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Höfler J, Unterberger I, Dobesberger J,

Kuchukhidze G, Walser G, Trinka E. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia. 2011 Oct;52(10):e148-52.

• Kossoff EH, Infantile Spasms. The Neurologist 2010;16: 69–75.

• Kurahashi H, Wang JW, Ishii A et al. Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures. Neurology, 73 (2009), pp. 1214–1217

Page 98: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Lux AL, Edwards SW, et al. The United Kingdom

Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial The Lancet Neurology. Volume 4, Issue 11, November 2005, Pages 712–717.

• M. T. Mackay, S. K. Weiss, T. Adams-Webber, et al. Practice Parameter: Medical Treatment of Infantile Spasms : Report of the American Academy of Neurology and the Child Neurology Neurology Society . 2004;62;1668

• Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011 Oct 11;77(15):1473-81.

Page 99: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Pearl PL, Vezina LG et al.,Cerebral MRI abnormalities

associated with vigabatrin therapy. Epilepsia, 50(2):184–194, 2009.

• Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86.

• Sake JK, Hebert D, Isojärvi J, Doty P, De Backer M, Davies K, Eggert-Formella A, Zackheim J. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs.

• Shimizu H, Kawasaki J, Yuasa S, Tarao Y, Kumagai S, Kanemoto K. Use of clobazam for the treatment of refractory complex partial seizures. Seizure. 2003 Jul;12(5):282-6.

Page 100: Use of the New Antiepileptic Agents Anthony Murro, M.D.

References• Stephen LJ, Kelly K, Parker P, Brodie MJ. Adjunctive

lacosamide in clinical practice: sodium blockade with a difference? Epilepsy Behav. 2011 Nov;22(3):499-504 CNS Drugs. 2010 Dec;24(12):1055-68

• von Stülpnagel C. , Coppolab G. , P. Strianoc, A. Müllera, M. Staudta, d, G. Kluger. First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome) European Journal of Paediatric Neurology 2012 Jan 20

• Weisenberg JL, Wong M. Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures. Neuropsychiatr Dis Treat. 2011;7:409-14.

• Wheless JW, Vazquez B. Rufinamide: a novel broad-spectrum antiepileptic drug. Epilepsy Curr. 2010 Jan;10(1):1-6.