8/30/10 How to use Introduction

8/30/10
Introduction
How to use
Antiepileptic drugs properly
Dr.Yotin Chinvarun M.D., Ph.D.
• 
Modern treatment of seizures started in 1850 with the introduction of
bromides, based on the theory that epilepsy was caused by an
excessive sex drive
• 
In 1910, phenobarbital, which used to induce sleep, was found to have
anti-seizure activity and became the drug of choice for many years.
• 
A number of medications similar to phenobarbital were developed,
including primidone
Comprehensive Epilepsy and Sleep disorders Program
Pramongkutklao hospital
2
Introduction
Introduction
• 
Houston Merrit and Tracy Putnam introduced animal models for screening
multiple compounds for antiepileptic activity, published in Journal of the
American Medical Association in 1938
• 
In 1940, phenytoin (PHT) was found to be an effective drug for Rx epilepsy, and
since then it has become a major 1st AED Rx partial and secondarily generalized
seizures
• 
In 1968, carbamazepine (CBZ) was approved, initially for treatment of trigeminal
neuralgia; later, in 1974, approved for partial seizures
• 
Ethosuximide has been used since 1958 as a first-choice drug for the treatment
of absence seizures without generalized tonic-clonic seizures. Valproate was
licensed in Europe in 1960 and in the United States in 1978
• 
Until 1990s, newer AEDs with good efficacy, fewer toxic effects, better
tolerability, and no need for blood level monitoring were developed
• 
The new AEDs have been approved in the United States as add-on therapy
only, with the exception of topiramate and oxcarbazepine; lamotrigine is
approved for conversion to monotherapy
3
4
3nd generation AEDs
AEDs
1st generation AEDs
2nd generation AEDs
• 
• 
• 
Phenytoin
Carbamazepine
Valproate
• 
• 
• 
Felbamate
Lamotrigine
Topiramate
1993
1994
1996
• 
• 
Phenobarbital
Clobazam
• 
• 
• 
• 
• 
Tiagabine
Levitiracetam
Oxcarbamazepine
Zonisamide
Pregabalin
1997
1999
2000
2000
2004
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Brivaracetam
Eslicarbazepine
Fluorofelbamate
Ganaxolone
Huperzine
JZP-4
Lacosamide
Licarzepine
Losigamone
NS1209
• 
• 
• 
• 
• 
• 
• 
• 
• 
!"#$%&'(")
!*+(%,'-")
!./)0001023)45%6'7&%,%8"9)
:";"86%<"8%,)
:%+(%,'-")
:=>[email protected])
:#6'B"(8C;)
D%;%,B%(";)
E%;6C<",'-")
1
8/30/10
Antiepileptic drugs grouped according to their major mechanism of action. Some AEDs work by
acting on a combination of channels and/or some unknown mechanism of action.
Target of seizure control Rx epilepsy is achieving balance between factors influence excitatory postsynaptic
potential (EPSP) and those influence inhibitory postsynaptic potential (IPSP)
7
8
Phenytoin
Sodium Channel Blockers
•  Introduced in the treatment of epilepsy in 1938
•  Advantage
• 
Partial onset seizure
• 
2 GTCS
• 
Parenteral form and single dose daily
•  Disadvantage
Some antiepileptic drugs stabilize the inactive configuration of the sodium (Na+)
channel, preventing high-frequency neuronal firing.
• 
Adverse reactions, dose-related; ataxia, nystagmus, slurred
speech, and dizziness. High-dose phenytoin can cause
peripheral neuropathy, cerebellar atrophy, chronic side effect
cognitive impairment, gum hypertrophy, course faces, acnes
etc
• 
Significant drug interaction
9
Fosphenytoin
•  Parenteral form of phenytoin
•  Advantage
• 
Better tolerated and safety than PHT
• 
Infusion tolerance of fosphenytoin at 150 mg PE/min
compared with PHT at 50 mg/min
•  Disadvantage
• 
Cardiovascular depression and hypotension may occur but to
a lesser extent than with PHT
• 
Severe burning, itching, and/or paresthesia, mainly in
groin area, have been associated with rapid infusion
Hepatic or hemopoietic adverse reactions, like those
seen with PHT, also may occur
• 
Carbamazepine
•  Advantages
•  Partial onset seizure
•  2 GTCS
•  Disadvantages
• 
• 
• 
• 
Common side effect; dizziness, ataxia,
Severe drug eruptions are rare
Significant drug interaction
Asymptomatic elevation of liver enzymes observed
commonly during the course of therapy in 5-10% of
patients
2
8/30/10
Oxcarbazepine
Lamotrigine
Advantages
•  Broad spectrum of efficacy, favourable pharmacokinetics, Favourable
cognitive profile, fewer interactions
•  Advantage
•  Close structure similarly to Carbamazepine but better
tolerated, Fewer drug interaction
•  Partial onset seizure
•  2 GTCS
•  Partial seizure, Idiopathic generalized epilepsy alternative or adjunct
to valproate, Symptomatic generalized epilepsy, Lennox Gastaut
Syndrome
•  Combination therapy with valproate enhances antiepileptic effect
•  Very slow titration is important for better tolerability
•  Disadvantage
•  Hyponatremia in 2.5% More commonly in older patients
•  Somnolence, headache, dizziness, rash, weight gain, GI
disturbances, and alopecia most commonly ADR
•  25% cross –sensitivity with carbamazepine
•  But may aggravate myoclonic or absence seizures
Disadvantages
•  Rash, especially with valproate (sometime severe)
•  Slow titration
•  Interaction with carbamazepine
GABA Receptor Agonists
Zonisamide
•  Advantage
•  Good bioavailability, does not have the cosmetic and
pharmacokinetic problems
•  Partial seizure
•  2 GTCS
•  Long half life, can be used once daily
•  Alternative valproate for myoclonic seizure and absence
•  Disadvantage
•  Significant drug interaction, increased by approximately
30-40%, when given concomitantly with enzyme-inducing
AEDs
•  Sedation, fatigue, dizziness, ataxia, confusion, cognitive
impairment, including word finding difficulty, weight loss/
anorexia, Depression & psychosis has also been reported,
renal stone
The GABA-A receptor mediates chloride (Cl-) influx, leading to hyperpolarization of the cell
and inhibition. Antiepileptic drugs may act to enhance Cl- influx or decrease GABA
metabolism
16
Clobazam
GABA drugs and their known sites of action
•  Advantage
•  Added on partial seizure
•  Rescue therapy for aura or SPS
•  No significant clinical drug interactions
•  Disadvantage
•  Less effective
•  Sedative side effect like benzodiazepine
17
3
8/30/10
Clonazepam
Phenobarbital
Had been used since 1912
•  Advantages
•  Advantage
•  Drug of choice for myoclonic seizures
•  Adjunctive therapy in generalized convulsions and,
lesser extent, in partial epilepsies
•  Very effective in the emergency Rx status epilepticus
•  Partial onset seizure
•  2 GTCS
•  Effective in refractory seizure
•  Parenteral form and single dose daily
•  For treatment of status epilepticus
•  Low cost
•  Disadvantage
•  Sedative side effect
•  Psychiatric withdrawal also may occur, manifested as
insomnia, anxiety, psychosis, and tremor
•  Children and infants may have hypersalivation.
Occasionally, tonic seizures may be exacerbated
Primidone
•  Disadvantages
•  Sedation and hypnosis
•  Cognitive impairment
•  Significant drug interaction
GABA Reuptake Inhibitors
•  Advantages
•  Partial onset seizure
•  2 GTCS
•  Very low dose is recommended
•  Disadvantages
•  Intense sedation, dizziness, and nausea
22
Tiagabine
GABA Transaminase Inhibitor
Advantages
•  Known mode of action, toxicity mild, No enzyme induction
•  Added on partial onset seizure limited to adjunctive therapy in
refractory partial epilepsy
Disadvantages
•  Could aggravate status epilepticus if given in absence epilepsy or in
partial epilepsies with generalized spike wave
•  CNS side effect, Dizziness
•  Inducible metabolism
•  Short half life; tds dosing
•  Unknown teratogenicity
•  Not available
24
4
8/30/10
Vigabatrin
AEDs With a Potential GABA
Mechanism of Action
Advantages
•  Known mode of action, Favourable pharmacokinetics, Easy to use, Few
interactions, No enzyme induction
•  Added on Partial seizures
•  Currently rarely used
•  Useful in infantile spasms particularly in patients with tuberous sclerosis
Disadvantages
•  Sedation
•  Psychiatric effects
•  Seizure worsening in some
•  Irriversibel visual field constriction
•  Unknown teratogenicity
26
Pregabalin
Gabapentin
•  Advantage
Advantages
•  Easy to use, well tolerated, no enzyme induction, no
pharmacokinetic drug interactions
•  When to use it
–  Partial seizures
–  Early add-on
–  Useful in the elderly
Disadvantages
•  Variable absorption
•  Wide dosage range
•  tds dosing, saturation effect
•  Moderate efficacy at lower dosage
•  Highly predictable and linear pharmacokinetics,
•  Since does not bind to plasma proteins and undergoes negligible
metabolism, thereby no drug interactions expected,
•  No visual problem been reported
•  More potent than gabapentin with better bioavailability
•  Added on for partial onset seizure or 2 GTCS
•  Anxiolytic and analgesic properties could be useful in treating
patients with comorbidities
•  Disadvantage
•  Administration with food or GBP reduced Cmax
•  Most common side effects: dizziness, drowsiness and weight gain
•  Unknown teratogenicity
Valproate
Glutamate Blockers
•  Advantage
• 
• 
• 
• 
Idiopathic generalized epilepsy
Myoclonic epilepsy
Partial seizure
Parenteral form
•  Disadvantage
•  Teratogenicity
•  Side effect; weight gain, tremor, transient hair loss,
Endocrine and metabolic dysfunctions
Schematic representation of the N-methyl-D-aspartate (NMDA) receptor
30
5
8/30/10
Topiramate
Felbamate
• 
•  Advantage
•  Highly effective in severe resistance epilepsy
•  Partial-onset seizures with or without secondarily
generalized seizures (adult-monotherapy)
•  Partial and generalized seizures associated with LennoxGastaut syndrome (children-adjunctive therapy)
•  Effective in drug-resistant generalized epilepsies as adjunctive
therapy, including juvenile myoclonic epilepsy, absence and
generalized tonic-clonic seizures, and Lennox-Gastaut syndrome
• 
•  Disadvantage
•  Serious side effect: Aplastic anemia, hepatic failure
•  Significant drug interaction
•  Not available
Advantages
•  Broad spectrum of efficacy, Favourable pharmacokinetics, Few
interactions, No enzyme induction
•  Partial seizures mono/ added on therapy
•  Symptomatic generalized epilepsy
Disadvantages
•  Weight loss, hypoesthesia
•  Cognitive impairment
•  Glaucoma, ? cataract
•  Very slow titration, rapidly titration caused language difficulty
•  Unknown teratogenicity
Levetiracetam
•  Advantage
AEDs With Other Mechanisms of
Action
•  No drug interaction, well tolerate and highly effective
•  Partial seizure, alternative for idiopathic generalized
epilepsy
•  Very useful in patients with hepatic or renal insufficiency
and patients on concomitant medications
•  IV preparation is available, but Efficacy in status
epilepticus has not been established
•  Disadvantage
•  Side effects: somnolence, asthenia, infection, dizziness,
headache, depression, UTI
33
Problems faced by physicians
in clinical practice
•  Heterogeneity of epilepsy
•  Patient characteristics (children, women of childbearing
potential, elderly)
•  Medical expertise and available healthcare facilities
•  Seizure type
•  Epilepsy syndrome
•  Pharmacokinetic profile
•  Interactions/other medical conditions
•  Efficacy
•  Expected adverse effects
•  Cost of treatment
•  Cost
•  Subjective perception of treatment benefit
6
8/30/10
Early Syndromic Classification
AEDs and seizure type
•  Studies indicate at the time of diagnosis,
classification of partial or generalized seizures can
be made in half of the cases
Patients %
60
59%
50%
37%
40
60
•  With addition of EEG, 19% remain unclassified
29%
40
20
13%
0
12%
20
•  If diagnosis cannot be made, it is wise to choose a
broad-spectrum antiepileptic drug
0
Adults (n=508)*
Children (n=613)**
* Manford M et al. Arch Neurol 49:801, 1992 ; 75% !15 yrs
** Berg AT et al. Epilepsia 41:1269, 2000
AEDs and seizure type
•  Some AEDs considered "narrow spectrum", which means they
more effective at controlling seizures associated with certain
syndromes than others. For example,
–  Carbamazepine, Phenytoin, Oxcarbazepine, gabapentin and
pregabalin
•  Appropriate for partial epilepsy
•  May exacerbate some generalized seizures types such as myoclonus
and absence
• 
Board-Spectrum Agents
Narrow-Spectrum Agents
• 
• 
• 
• 
• 
• 
• 
Valproate
Felbamate
Lamotrigine
Topiramate
Zonisamide
Levetiracetam
Rufinamide*
Partial onset seizures
Phenytoin
Carbamazepine
Oxcarbazepine
Gabapentin
Pregabalin
Tiagabine
Lacosamide*
Absence
Ethosuximide
• 
•  Partial onset seizures
phenytoin*
gabapentin
carbamazepine*
phenobarbital
valproate
primidone
lamotrigine
felbamate**
Generalized onset seizures
Absence:
valproate* = ethosuximide
Myoclonic:
valproate, clonazepam
Tonic-clonic:
valproate = phenytoin
Seizures in Lennox-Gastaut Syndrome:
valproate, lamotrigine, felbamate**
topiramate
tiagabine
*
the risk of valproate-induced hepatic failure must be carefully weighed in young children
**
associated with aplastic anemia and hepatic failure
* considered by many as drugs of choice
**associated with aplastic anemia and hepatic failure
41
42
7
8/30/10
Drug
Partial Secondary
generalized
*)
*)
!"#$%&'($)
PHT, PB
CBZ, OXC
GBP, VGB, PGB
VPA, LTG, TPM, ZNS, LEV, (FBM)
(Broad Spectrum AEDs)
Drug
I° GTCS
Absence
<#4/-0-&#)
*)
Partial
2 GTCS
*)
8*)
8*)
8*)
=-/-!#$&($>)
?.#@-/-4($)
*)
*)
8*)
7)
8-)
4-0'&.(@($#)
*)
*)
*)
*)
+/- *
&'!(.-0-&#)
*)
*)
*)
8)
8*)
&([email protected]/($#)
*)
*)
8)
8)
8)
1'$(9-0(6#)
*)
*)
8*)
8*)
8*)
4#3#&(.-,#&-0)
*)
*)
*)
?+
+
';,-./-1#!($#) *)
*)
85*)
+)
+)
I° Tonic-clonic Absence Myoclonic
*)
+)
+)
,-./-0-1#!($#) *2)
*)
*)
+)
+)
3-4!.'-&#5-,(6)
*)
*)
*)
*)
*)
!"#$'/-./(&-4)
*)
*)
*)
7)
!.(0(6'$#)
*)
*)
*)
7)
8*)
#&"'9:;(0(6#)
7)
7)
7)
*)
7)
8*)
Myoclonic
•  Simplifies treatment, reduces adverse effects
•  Conversion to monotherapy from polytherapy
–  Eliminate sedative drugs first
–  Withdraw antiepileptic drugs slowly over
several months
46
•  Drugs that induce metabolism of other drugs: carbamazepine,
phenytoin, phenobarbital
Monotherapy for Partial Seizures
•  Drugs that inhibit metabolism of other drugs: valproate,
felbamate
Best evidence and FDA indication:
•  Drugs that are highly protein bound: valproate, phenytoin
Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate
Similar efficacy, likely better tolerated:
•  Other drugs may alter metabolism or protein binding of
antiepileptic drugs
Lamotrigine, Gabapentin, Levetiracetam
Also shown to be effective:
Valproate, Phenobarbital, Felbamate, Lacosamide
Limited data but commonly used:
Zonisamide, Pregabalin
47
8
8/30/10
•  Monotherapy for Generalized-Onset Tonic-Clonic
Seizures
• 
• 
Best evidence and FDA Indication:
Valproate, Topiramate
• 
Also shown to be effective:
Absence seizures
• Best evidence:
–  Ethosuximide (limited spectrum, absence only)
–  Valproate
• Also shown to be effective:
–  Lamotrigine
• 
Zonisamide, Levetiracetam
• 
Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )
• 
Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies
• 
• May be considered as second-line:
–  Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam
Myoclonic Seizures
Lennox-Gastaut Syndrome
•  Best evidence/FDA indication*:
Best evidence:
–  Topiramate, Felbamate, Clonazepam, Lamotrigine,
Rufinamide
–  Valproate
–  Levetiracetam (FDA indication as adjunctive tx)
–  Clonazepam (FDA indication)
–  * FDA approval is for adjunctive treatment for all except clonazepam
•  Also effective:
Possibly effective:
–  Valproate
–  Zonisamide, Topiramate
•  Some evidence of efficacy:
–  Zonisamide, Levetiracetam
Reasons to add vs. switch
•  Add
=AB)
–  Pt tolerating 1st AED
–  No anticipated drug
interactions
C/9#$,#)
–  Pt risk averse or
consequences of seizure
exacerbation are high
D%',4'$(,)
A'$(,)
•  Switch
– 
– 
– 
– 
– 
Pt not tolerating 1st AED
1st AED has disadvantages
Drug interactions epected
Pregnancy anticipated
Seizure exacerbation not
likely
–  1st AED appropriate,
provided partial control
C&'$(,)
?-.&(-4)
* in children of SMEI
9
8/30/10
Substitution or add-on
Substitution or add-on
! 
When patient with epilepsy does not become seizure-free on
first AED, to try one or more other drugs in monotherapy
before switching to polytherapy (Shorvon, 2000)
! 
One should not assume that all combinations have same
effectiveness (effectiveness being an outcome measure that
encompasses both efficacy and tolerability)
! 
However, doubt unfavourable reputation of polytherapy
(Deckers, 2002)
! 
In recent review of animal and clinical studies evaluating
combinations of AEDs, it appeared likely that certain
combinations offer better effectiveness than others (Deckers et
al., 2000)
Combination therapy studies
Alternative Monotherapy studies
Drugs
Author
Clinical seizure
Population
Results
ADR
Drugs
Author
Clinical seizure
Population
Results
ADR
PHT to CBZ
Hakkarainen
Adult onset seizure
26 patients not seizure free on
PHT, crossed over to CBZ
9 seizure-free (35%)
No information
PHT/CBZ
Hakkarainen
Adult onset seizure
33 patients uncontrolled by
either drugs, given combination
5/33 seizure-free with
combination (15%)
No ADR
CBZ to PHT
Hakkarainen
Adult onset seizure
24 patients not seizure free on
CBZ, crossed over to PHT
8 seizure-free (33%)
No information
CBZ/VPA
Walker
CPS (2 GTCS)
17 patients uncontrolled by
either drugs, given combination
6/17 seizure-free
(15%), 6/17 seizure
reduced >50% (35%)
No new
additive toxicity
CBZ, PHT,
PB or PRM
Schmidt
Partial seizure or GTCS
59 patients refractory to
monotherapy with 1-4 drugs,
were given another 1-4 drugs
7/59 seizure-free
(12%), 19% had
seizure reduction
>75%
ADR
disappeared in
27%
CBZ/VGB
Murri
Partial seizure (2GTCS)
40 patients not controlled by
maximal CBZ monotherapy
7 seizure-free (18%)
5 withdraw due
to toxicity
CBZ to VGB
Tanganelli
Partial seizure (2GTCS)
11 patients uncontrolled by CBZ,
crossed over to VGB
5/11 seizure-free
(45%), 5/14 seizure
reduced >75%
Toxicity Higher
than
monotherapy
CBZ/VGB
Tanganelli
Partial seizure (2GTCS)
VGB to CBZ
Tanganelli
CPS (2GTCS)
14 patients not seizure-free on
VGB, crossed over to CBZ
6/14 patient seizurefree (16%)
1 patient with
CBZ had rash
14 patients uncontrolled by
either drug alone
5/14 seizure-free
(36%), 5/14 seizure
reduced >75%
Toxicity Higher
than
monotherapy
VPA to CBZ
Walker
CPS (2GTCS)
Patients not seizure-free on VPA
were crossed over to CBZ
4/25 patient seizurefree (16%), 12% had
>50% seizure
reduction
No information
VPA/LTG
Kanner
Partial seizure
27 patients uncontrolled by
either drug alone
26% seizure-free,
59% had >50%
seizure reduction
No information
Substitution or add-on
Substitution or add-on
! 
The average percentage seizure-free rates of alternative
monotherapy and add-on therapy were similar
! 
Combination therapy achieved 25% seizure freedom in those
patients that failed on both drugs in monotherapy
! 
The success rate did vary considerably between individual
substitution studies and between individual add-on studies
! 
! 
This suggest that it is important which substitution or add-on
drug is chosen
Patients who become seizure-free on a combination of AEDs
may develop seizures again when the first AED is withdrawn
(Deckers, 2002). These examples suggest combination
therapy may be more efficacious than monotherapy
! 
Two reasons may be given for this:
! 
! 
Infra-additive toxicity of the combination which allows for higher drug
loads to be prescribed during polytherapy, thus achieving better
efficacy
Pharmacodynamic synergism which may be accomplished by
combining drugs complementary mechanisms of action.
10
8/30/10
Substitution or add-on
! 
In an observational study by Kwan and Brodie
" 
26% of 42 patients treated with second-line combination
therapy became seizure-free compared to 17% of 35
patients treated with alternative monotherapy (Kwan et al.,
2001)
" 
Failure due to adverse effects 12 and 26%, respectively
(no statistical significance)
Substitution or add-on
! 
Shorvon (2000) suggested the following strategy when a
patient does not become seizure-free
" 
On a first AED despite a maximal dose: alternative monotherapy
should be introduced incrementally at suitable dose intervals and
the first drug then withdrawn in decremental steps
" 
The second drug should titrated first to a low maintenance dose
and then, if seizures persist, dosage increased to maximal
" 
If seizures continue, re-assessed diagnosis, ? progressive lesion
or ? non-compliance
" 
If continuing seizures, other first-line drugs should be tried in
monotherapy
Substitution or add-on
Substitution or add-on
! 
Add-on therapy also has disadvantages
" 
When add-on treatment proves to be efficacious, cannot
exclude the possibility that the add-on drug have
efficacious when given as alternative monotherapy
" 
Cannot discern effects of individual drugs on efficacy or
toxicity in a polytherapy
" 
Therefore, one does not know whether first-line drug can
be withdrawn
" 
Pose problems with patients, they may not be willing to
withdraw first drug and risk losing their seizure freedom
! 
Whether aims at substitution or at add-on therapy
after a first drug has failed, usually titrate the second
drug to some level in the presence of the first drug
! 
Therefore, most pragmatic solution may be to
evaluate effectiveness of combination at this stage,
and in case of success, to gradually withdraw the
first drug
! 
This would be preferred option especially when first
drug did reduce seizure frequency to some degree
Substitution or add-on
! 
When combination not efficacious, replace the drug
that least efficacious
! 
When alternative monotherapy is not as efficacious
as the combination, the first-line drug should be
reintroduced
Choice of drug
! 
Effectiveness may differ between different combinations
" 
! 
When alternative monotherapy is efficacious but
associated with considerable adverse effects, lowdose polytherapy should be considered
LTG forms a particularly effective combination with VPA
! 
! 
Whether due to pharmacodynamic interaction, a pharmacokinetic
interaction or both unclear
LTG may combine less favourably with CBZ
! 
To consider such results when choosing an add-on drug
! 
However, due to several new AEDs, great need of more
studies studying specific combination
11
8/30/10
Useful AED Combinations
Useful AED Combinations
Pharmacokinetics
Pharmacodynamics
Problem: very little evidence in humans
# 
probably synergism
VPA + LTG
VPA + ESM (in absences)
# 
no synergism
VPA + CBZ
# 
increased toxicity
Benzodiazepines
TPM ?
+ Barbiturates
+
VPA +
LEV + TPM ?
Choice of drug
Improving efficacy was exhibited by a combination of
0XC and CBZ
Choice of drug
An addition of OXC , a sodium channel blocker, to patients currently
used TPM which processes multiple mechanisms of action was the
most effective combination
Combinations of AEDs showing different and multiple
mechanisms of action are more likely to result in synergy
than drugs sharing similar mechanism (Czuczwar, 2000)
OXC may have some other mechanisms
than blocking of Na+ channel
More patients become seizure free with the add-on combination
included a sodium channel blocker and a drug with multiple mode of
action than with other combinations (Kwan and Brodie, 2000,
Chinvarun et al, 2003)
Substitution or add-on
! 
! 
It is uncertain whether two drugs effective in combination
should also be used for substitution therapy
" 
For example, LTG a good choice as second-line monotherapy for
partial epilepsy when VPA fails as the first-line drug, given that
these drugs form a highly effective combination?
" 
LTG a less preferable choice as second-line monotherapy for
partial epilepsy when CBZ fails
" 
Need further studies
Combination of PHT and PB regarded as one of the more
effective combinations than the combinations of PHT plus CBZ
and of PB plus CBZ (Cereghino et al. ,1975)
Substitution or add-on
! 
Another participant remarked that combination of
two new AEDs much more expensive
! 
Urgent need for systematic studies on the
effectiveness of combinations of AEDs
! 
A combination is more effective than its individual
components, the drug load concept gives some
insight into the nature of this interaction
12
8/30/10
Substitution or add-on
! 
When drug load of the combination is higher than
that of the individual drugs, the higher effectiveness
may be due to
" 
" 
! 
E0#[email protected]([email protected]&('$-45?'4%&"#.-!%)
infra-additive toxicity
supra-additive efficacy (i.e. synergy)
However, polytherapy may carry unforeseen risks
" 
For example, preliminary data from the UK pregnancy
registry suggests that the combination of VPA and LTG
associated with an unexpectedly higher risk for major
congenital malformations than in patients using either
VPA or LTG alone (Barrett and Richens, 2003)
F-&('$-45?'4%&"#.-!%G5B:..#$&59&-&:9)
AEDs Combined
Outcome
Na+ blocker
+
Na+ blocker
"#
Additive efficacy or
antagonism
Na+ blocker
+
AED with multiple
actions
"#
Variable and
unpredictable
AED with multiple
actions
+
AED with multiple
actions
"#
Gabapentin
+
Any other AED
"#
Levetiracetam
+
Other AEDs
"#
Deckers, Epilepsia 2000;41:1364-74; Czuczwar, Epilepsy Res 2002;52:15-23, Luzsczki , Epilepsia 47:10-20,
2006; Jonker, Epilepsia 2007;48:412-434; Kaminski, Epilepsia 2009 (in press)
H-4!.'-&#I5J-0'&.(@($#5-$65&"#(.5,'0/($-&('$)
K7L5.#9!'$6#.5.-&#9)
F-&('$-45?'4%&"#.-!%G5?"-.0','6%$-0(,)
• 
Problem: very little evidence in humans
probably synergism
VPA + LTG
VPA + ESM (in absences)
VPA + TPM ?, LEV + TPM ?
no synergism
increased toxicity
VPA + CBZ
+ Barbiturates + Benzodiazepines
13
8/30/10
Adverse Effects of AEDs
•  Dose-related
•  Idiosyncratic
•  Teratogenic
• 
Often dose-related:
– 
– 
– 
– 
– 
Dizziness
Fatigue
Ataxia
Diplopia
Irritability
levetiracetam
–  Word-finding difficulty
topiramate
–  Weight loss/anorexia
topiramate, zonisamide, felbamate
–  Weight gain
valproate
carbamazepine, gabapentin, pregabalin
• 
Typically idiosyncratic:
–  Renal stones
topiramate, zonisamide
–  Hyponatremia
carbamazepine, oxcarbazepine
–  Aplastic anemia
felbamate, zonisamide, valproate, carbamazepine
–  Agranulocytosis
carabamazepine
–  Hepatic Failure
valproate, felbamate, lamotrigine, phenobarbital
–  Anhydrosis, heat stroke
• 
Stevens-Johnson Syndrome (SJS) and
• 
Toxic Epidermal Necrolysis (TENS)
severe life threatening allergic reaction
blisters and erosions of the skin, particularly palms/soles and mucous
membranes
fever and malaise
rare: severe risk roughly 1-10/10,000 for many AEDs
rapid titration of lamotrigine especially in combination with
valproate increases risk
topiramate
–  Acute closed-angle glaucoma
topiramate
• 
Drugs rarely associated with rash
Valproate
Gabapentin
Pregabalin
Levetiracetam
Topiramate
• 
• 
• 
• 
!!= rash rate significantly greater than average of all other AEDs (p<0.003)
""= rash rate significantly lower than average of all other AEDs (p<0.003)
!= trend towards significantly higher than average rash rate of all other AEDs
(0.003<p<0.05)
"= trend towards significantly lower than average rash rate of all other AEDs
(0.003<p<0.05)
14
8/30/10
• 
• 
• 
FDA alert 12/2007
Risk of dangerous or even fatal skin reactions (SJS and TEN) are
more common in those with HLA-B*1502
• 
This allele is almost exclusively found in Asians
–  In 10-15% of population in China, Thailand, Malaysia,
Indonesia, the Phillipines, and Taiwan
–  2-4% in India
–  <1% in Japan and Korea
• 
• 
• 
• 
• 
• 
• 
• 
59/60 Asian patients w/ SJS/TEN had this allele vs 4% of cbz
tolerant patients
Estimated absolute risk for those with the allele: 5%
Asians should be screened for the HLA-B*1502 allele before
starting treatment with carbamazepine
These patients may also be at risk with other AEDs
–  Use drugs not typically associated with rash
• 
• 
Osteoporosis
Mostly worsened by the enzyme inducers: phenytoin,
phenobarbital, primidone. Carbamazepine data equivocal.
Equivocal data with valproate, unavailable for other noninducers.
Take calcium 1000-1500/d; Vit D 400-4000/d
Depression
Can be exacerbated by levetiracetam (and less so zonisamide)
Can be helped by lamotrigine and possibly gabapentin,
pregabalin (and vagus nerve stimulator)
Migraine
Consider topiramate, valproate
Obesity
Weight loss with topiramate and zonisamide
Weight gain with valproate > gabapentin/pregabalin,
carbamazepine
•  Recent FDA alert (1/2008):
Meta-analysis of 199 placebo-controlled add-on tx trials
– 
(44,000 patients)
Suicidality with adjunct AEDs than adjunct placebo:
0.43% vs 0.22%
Extra 2.1 patients per 1000 more patients will have suicidality
4 suicides with AEDs vs 0 with placebo
“generally consistent across the 11 AEDs”
A guide not a goal
• 
Limited data
• 
Broad generalizations
• 
Individual differences
• 
Useful in:
• 
Data analysis is controversial and overall difference is very small
–  Providing initial target in patients with infrequent
seizures
• 
Further investigation is needed
–  Understanding unexpected seizures or side effects,
especially with polypharmacy
• 
• 
Clinicians should be aware of potential risk and screen for
depression/suicidality
–  Verifying compliance
www.fda.gov
88
Discontinuing AEDs
• 
• 
Seizure freedom for ! 2 years
implies overall >60% chance of successful withdrawal
• 
Favorable factors
Progressive pathology?
• 
Avoidable precipitant?
• 
If on AED
–  Control achieved easily on one drug at low dose
–  Problem with compliance or absorption?
–  No previous unsuccessful attempts at withdrawal
–  Normal neurologic status and EEG?
–  Primarily generalized seizures only?
–  Increase dose?
–  Change medication?
• 
–  Benign syndrome
If not on AED
• 
–  Start AED?
89
Consider relative risks/benefits (e.g., driving, pregnancy)
90
15
8/30/10
•  Most pregnancies in epileptic mothers produce
normal children
•  Adequate sleep
•  Fetal anomalies (up to 10% of pregnancies) are
multifactorial
•  Avoidance of alcohol, stimulants, etc.
–  Drug effects
–  Consequences of the mother s underlying diseases
–  Consequence of maternal seizures during pregnancy
•  Stress reduction — specific techniques
•  Adequate diet
•  All antiepileptic drugs carry teratogenic risks
91
Most available data on risk of AEDs comes from pregnancy
registries.
92
• 
Valproate consistently associated with poorer outcomes
MCM rate with valproate monotherapy 6.2-13.2%
across 5 registries
Most studies show dose- related increase in risk with
doses > 1000mg/day
Polytherapy regimens including valproate also
substantially increased risk of MCM
Valproate associated with lower IQs in exposed
children
• 
• 
Phenobarbital probably also poses higher risk of MCM
compared with other monotherapy regimens.
Main outcome variable of most registries are major congenital
malformations (MCM)
MCM = malformation that affects physiologic function or requires
surgery
Neural tube defects
Cardiac defects
Genitourinary defects
Oral clefts
MCMs are more common with AED exposure
MCM risk in general population 1.6-2.1%
MCM risk with AED monotherapy 4.5% (OR 2.6)
MCM risk with Polytherapy 8.6% (OR 5.1)
•  Effects on pregnancy on epilepsy
• 
MCM rate similar among other studied AEDs in
monotherapy, but not enough data to show significant difference
between them
Levetiracetam
Early data promising (0% in monotherapy, 2.7% in polytx)
Carbamazepine (2.2-3.9%)
Substantial data available, relatively good track record
Lamotrigine (1.4-4.4%)
Increased risk (5.4%) with doses > 400/day
Gabapentin (0-3.2%)
Topiramate (0-4.8%)
–  Risk of increased seizures (low if compliance maintained,
doses adjusted upward to maintain free levels)
–  Risk of seizures during delivery (impaired absorption, sleep
deprivation, exhaustion)
•  Effects of epilepsy on pregnancy
–  Genetic factors in some cases
–  Risks of convulsive seizures
–  Risks of AEDs
Phenytoin (3.2-6.7%)
Zonisamide, Pregabalin
No substantial data on monotherapy
96
16
8/30/10
•  Risk of fetal malformation is increased twofold to
threefold
• 
Breastfeeding should be encouraged unless clear risk posed
• 
Probably safe:
–  Carbamazepine
•  Prenatal diagnosis should be discussed
–  Phenytoin
•  Seizures may be deleterious to the fetus
–  Valproate
–  Lamotrigine
•  Adequate folate should be ensured
(at least 1 mg/day)
• 
Use with caution in lactating women:
–  Primidone
•  Monotherapy should be used if possible,
with the lowest effective dose
–  Phenobarbital
–  Ethosuximide
– 
97
17