Use of the New Antiepileptic Agents Anthony Murro, M.D.
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Transcript of Use of the New Antiepileptic Agents Anthony Murro, M.D.
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Use of the New Antiepileptic Agents
Anthony Murro, M.D.
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Research Support
• I currently received support for research involving biravacetam from UCB
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New Antiepileptic Agents
• Lacosamide (Vimpat)
• Rufinamide (Banzel)
• Vigabatrin (Sabril)
• Clobazam (Onfi)
• Ezogabine (Potiga)
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Lacosamide• Adjunctive therapy in the treatment of
partial-onset seizures• Functionalized amino acid
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Lacosamide - Mechanism• Lacosamide facilitates slow inactivation of
voltage gated sodium ion channels
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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)
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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)
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Slow inactivationIntra-membrane sites S5 & S6 block ion
channel
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Fast Inactivation
Intracellular loop between domains III & IV blocks ion channel
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CRMP-2 Binding• Lacosamide also binds to a collapsin
response mediator protein-2 (CRMP-2)
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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)
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Lacosamide Dosing
• Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day
• Maintenance dose: 200-400 mg/day
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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)
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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
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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)
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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)
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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)
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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)
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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%
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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)
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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
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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
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Rufinamide• Adjunctive therapy in the treatment of
generalized seizures of Lennox-Gastaut syndrome (LGS)
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Rufinamide Mechanism• Rufinamide slows sodium ion channel
recovery from the inactivated state & limits repetitive neuronal firing
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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.
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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.
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Rufinamide Metabolism
• Carboxylesterase metabolism to inactive metabolite
• Rufinamide is a weak CYP3A4 inducer
• Non-linear drug kinetics
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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.
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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%
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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)
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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)
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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)
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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
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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
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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)
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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
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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.
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Vigabatrin• Adjunctive treatment for infantile spasms and
adult refractory complex partial seizure
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Vigabatrin Mechanism
• Irreversible & competitive binding to GABA transaminase (Chu-Shore et al., 2010)
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Vigabatrin Mechanism
• Possibly also might stimulate GABA release
• Brain GABA increases by 40% at 2 hours post-dose
• (Chu-Shore et al., 2010)
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Vigabatrin
• Linear dose relationship
• Reduces phenytoin level by 20%
• Dosage adjustment for decreased renal clearance
• (Chu-Shore et al., 2010)
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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
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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
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Vigabatrin Effectiveness Complex Partial Seizures
(Dean et al., 1999)
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Vigabatrin Effectiveness Complex Partial Seizures
(French et al., 1996)
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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)
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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
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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
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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
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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)
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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)
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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)
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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)
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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)
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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)
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Vigabatrin White Matter Changes
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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
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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
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ClobazamAdjunctive treatment of seizures associated
with Lennox-Gastaut syndrome
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Clobazam Mechanism• Allosteric activation of GABAa receptor
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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
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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
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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
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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
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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.
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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)
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Clobazam Side Effects
• Somnolence
• Fever
• Lethargy
• Drooling
• Constipation
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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)
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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
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Clobazam SummaryNegative
• High cost
• High protein binding
• Active metabolite & potentially significant drug interactions
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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.
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Ezogabine (Retigabine)Adjuvant treatment of partial-onset seizures
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Ezogabine
• Binds to KCNQ2/3 KCNQ3/5 potassium channels
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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)
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Ezogabine• At high concentrations: blocks sodium
voltage gated sodium & calcium channels and increases GABA synthesis (Czuczwar et al., 2010)
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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)
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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)
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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)
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Ezogabine Drug Interactions
• No effect on oral contraceptive clearance
• Lamotrigine decreases ezogabine clearance slightly; ezogabine increases lamotrigine clearance slightly
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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)
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Ezogabine EffectivenessGroup Seizure Reduction
Placebo 15.9%
600 mg/d 27.9%
900 mg/d 39.9%
(Brodie et al., 2010)
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Ezogabine EffectivenessGroup Seizure Reduction
Placebo 17.5%
1200 mg/d 44.3%
(French et al., 2011)
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Ezogabine Side Effectts
• Somnolence• Fatigue• Confusion• Dizziness• Headache• Dysarthria• Ataxia• Blurred vision
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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
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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
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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.
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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.
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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
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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)
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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.
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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.
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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.
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• 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.