Download - Use of the New Antiepileptic Agents
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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 ofpartial-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, topiramateenhance fast inactivation
(Goldin, 2011)
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Slow inactivation
Intra-membrane sites S5 & S6 block ion
channel
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Fast Inactivation
Intracellular loop between domains III & IVblocks 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 thatinclude cytoskeletal, vesicle, and synaptic
functions in the developing brain.
The significance of this binding is an areaof current research (Hensley et al., 2011)
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Lacosamide Dosing
Adult: 50 mg twice daily; may be increasedat 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 prospectivecontrolled 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 Reduction
Group Ben-Menachem HalaszPlacebo 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 AbsentPlacebo 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 totreat status epilepticus & seizure clusters.
Bolus of 200 mg IV at rate of 60 mg/min
(Hfler et al., 2011)
Lacosamide has been used in primary
generalized epilepsy (Afra et al., 2012)
A single report described worsening ofseizures in Lennox Gastaut syndrome with
lacosamide (Cuzzola et al., 2010)
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Lacosamide Summary
Positive 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 alikely early choice for adjuvant drug
therapy of partial seizures
Future research might confirmeffectiveness for primary generalized
epilepsy & status epilepticus.
Future research might confirm greaterbenefit among patients not using sodium
channel blockers
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Rufinamide
Adjunctive therapy in the treatment ofgeneralized seizures of Lennox-Gastautsyndrome (LGS)
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Rufinamide Mechanism
Rufinamide slows sodium ion channelrecovery from the inactivated state & limits
repetitive neuronal firing
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Rufinamide Dosing
Children: Initial: 10 mg/kg/day in 2 equallydivided 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 toincreased 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 aftertherapy & 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 Stlpnagela et al. 2012)
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Rufinamide Summary
Positive
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 renalclearance
(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 Spasms
Tuberous Sclerosis Responds Best
Group % Spasm Free day 14
Vigabatrin 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)
H l Th B E l
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Hormonal Therapy Better Early
Response For Non-Tuberous
Sclerosis CasesPercent Spasm Free
Group 2 wks* 12-14 monthsHormonal 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
C O
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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 41of 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 aduration 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 LesionsNumber 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 isphenytoin
Infrequent need for serum drug levels Low protein binding
Negative
Irreversible visual field defects
White matter lesions
High cost
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Role of Vigabatrin
Vigabatrin is likely to be among the lastchoices for adjuvant treatment of partial
seizures
Vigabatrin is a good 1st
choice for infantilespasms from tuberous sclerosis (TS)
Hormonal therapy might provide more
effective early control for non-TS cases &better cognitive outcome for cryptogenic
infantile spasms
Cl b
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ClobazamAdjunctive treatment of seizures associated
with Lennox-Gastaut syndrome
Cl b M h i
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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 forGABAa subunits that mediate sedative
effects
C
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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
Cl b D i
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Clobazam Dosing
CYP2C19 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 twicedaily; after 1 week may increase to 20
mg twice daily
Cl b M t b li
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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 subsequenthydroxylation of the N-desmethyl metabolite.
Carbamazepine reduces clobazam level, &
clobazam decreases valproate (Riss et al, 2008) Many other potential drug interactions
Cl b
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Clobazam
Placebo controlled trial in 238 cases
(age 2-60 years) with Lennox-Gastautsyndrome (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 reductionshowed 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 refractorypartial seizures reported an early
improvement in seizure reduction.
Many could not tolerate the drug due tosomnolence.
Tolerance occurred; seizures re-occurred
in subjects that had improved initially
(Shimizu et al., 2003, da Silveira et al.,2006)
Cl b S
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Clobazam Summary
Positive 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 Summary
Negative High cost
High protein binding
Active metabolite & potentially significantdrug interactions
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Role of Clobazam
Clobazam is likely to be a useful drug foradjuvant 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.
E bi (R i bi )
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Ezogabine (Retigabine)
Adjuvant treatment of partial-onset seizures
E bi
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Ezogabine
Binds toKCNQ2/3
KCNQ3/5
potassiumchannels
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Ezogabine
Ezogabine binds to KCNQ2/3 & KCNQ3/5potassium 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 sodiumvoltage gated sodium & calcium channels
and increases GABA synthesis (Czuczwaret al., 2010)
Autosomal Dominant Neonatal
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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 increaseat 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 activemetabolite (NAMR) and other inactivemetabolites (eg, N-glucuronides, N-glucoside)
Linear drug kinetics (Weisenberg et al,,2011)
E ogabine Dr g Interactions
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Ezogabine Drug Interactions
No effect on oral contraceptive clearance
Lamotrigine decreases ezogabine
clearance slightly; ezogabine increases
lamotrigine clearance slightly
E bi Eff ti
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Ezogabine Effectiveness
Group Seizure ReductionPlacebo 13.1%
600 mg/d 23.4%
900 mg/d 29.3%1200 mg/d 35.2%
(Porter et al., 2007)
E bi Eff ti
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Ezogabine Effectiveness
Group Seizure ReductionPlacebo 15.9%
600 mg/d 27.9%
900 mg/d 39.9%
(Brodie et al., 2010)
E bi Eff ti
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Ezogabine Effectiveness
Group Seizure ReductionPlacebo 17.5%
1200 mg/d 44.3%
(French et al., 2011)
E bi Sid Eff tt
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Ezogabine Side Effectts
Somnolence Fatigue
Confusion
Dizziness Headache
Dysarthria
Ataxia Blurred vision
Ezogabine Summary
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Ezogabine Summary
Positive
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
R l f E bi
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Role of Ezogabine
Ezogabine is likely to be a useful drug foradjuvant therapy for refractory partial
seizures
Limiting factors are likely to be cost andoccurrence of drug related side effects
Cumulative Summary
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Cumulative Summary
Lacosamide, & 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.
Cumulative Summary
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Cumulative SummaryVigabatrin has a specialized role:
First choice therapy for infantile spasmsamong 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 laterchoices for refractory partial seizures dueto its risk of visual loss.
Cumulative Summary
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Cumulative Summary
Rufinamide 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
Pharmacokinetic Properties
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Pharmacokinetic PropertiesDrug Tmax T1/2 %PB
Lacosamide 1-2 hr 13 hr
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References Afra P, Adamolekun B. Lacosamide treatment of
juvenile myoclonic epilepsy. Seizure. 2012 Jan24.
Appleton RE, Peters ACB, Mumford JP, ShawDE. Randomized,placebo-controlled study ofvigabatrin as first-line treatment of infantile
spasms. Epilepsia. 1999;40:16271633.
Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safetyof oral lacosamide as adjunctive therapy in
adults with partial-onset seizures. Epilepsia.2007 Jul;48(7):1308-17.
References
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References Brodie M.J., W.E. Rosenfeld, B. Vazquez et al.
Rufinamide for the adjunctive treatment of partialseizures in adults and adolescents: A randomizedplacebo-controlled trial Epilepsia, 50 (2009), pp. 18991909
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