Use of the New Antiepileptic Agents

7/29/2019 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


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


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



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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)


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)



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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)



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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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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 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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600 mg/d 27.9%

900 mg/d 39.9%

(Brodie et al., 2010)

E bi Eff ti


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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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Use of the New Antiepileptic Agents