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How to use Antiepileptic drugs properly

Dr.Yotin Chinvarun M.D., Ph.D.

Comprehensive Epilepsy and Sleep disorders Program Pramongkutklao hospital

Introduction

•  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

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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

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Introduction

•  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

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AEDs

1st generation AEDs •  Phenytoin •  Carbamazepine •  Valproate •  Phenobarbital •  Clobazam

2nd generation AEDs •  Felbamate 1993 •  Lamotrigine 1994 •  Topiramate 1996 •  Tiagabine 1997 •  Levitiracetam 1999 •  Oxcarbamazepine 2000 •  Zonisamide 2000 •  Pregabalin 2004

3nd generation AEDs

•  Brivaracetam •  Eslicarbazepine •  Fluorofelbamate •  Ganaxolone •  Huperzine •  JZP-4 •  Lacosamide •  Licarzepine •  Losigamone •  NS1209

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Target of seizure control Rx epilepsy is achieving balance between factors influence excitatory postsynaptic potential (EPSP) and those influence inhibitory postsynaptic potential (IPSP)

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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.

Sodium Channel Blockers

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Some antiepileptic drugs stabilize the inactive configuration of the sodium (Na+) channel, preventing high-frequency neuronal firing.

Phenytoin

•  Introduced in the treatment of epilepsy in 1938

•  Advantage •  Partial onset seizure •  2 GTCS •  Parenteral form and single dose daily

•  Disadvantage •  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

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

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Oxcarbazepine

•  Advantage •  Close structure similarly to Carbamazepine but better

tolerated, Fewer drug interaction •  Partial onset seizure •  2 GTCS

•  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

Lamotrigine

Advantages •  Broad spectrum of efficacy, favourable pharmacokinetics, Favourable

cognitive profile, fewer interactions •  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

Disadvantages •  Rash, especially with valproate (sometime severe) •  Slow titration •  Interaction with carbamazepine

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

GABA Receptor Agonists

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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

GABA drugs and their known sites of action

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Clobazam

•  Advantage •  Added on partial seizure •  Rescue therapy for aura or SPS •  No significant clinical drug interactions

•  Disadvantage •  Less effective •  Sedative side effect like benzodiazepine

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Clonazepam

•  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

•  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

Phenobarbital

Had been used since 1912 •  Advantages

•  Partial onset seizure •  2 GTCS •  Effective in refractory seizure •  Parenteral form and single dose daily •  For treatment of status epilepticus •  Low cost

•  Disadvantages •  Sedation and hypnosis •  Cognitive impairment •  Significant drug interaction

Primidone

•  Advantages •  Partial onset seizure •  2 GTCS •  Very low dose is recommended

•  Disadvantages •  Intense sedation, dizziness, and nausea

GABA Reuptake Inhibitors

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Tiagabine

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

GABA Transaminase Inhibitor

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Vigabatrin

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

AEDs With a Potential GABA Mechanism of Action

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Gabapentin

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 •  Unknown teratogenicity

Pregabalin

•  Advantage •  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

Valproate

•  Advantage •  Idiopathic generalized epilepsy •  Myoclonic epilepsy •  Partial seizure •  Parenteral form

•  Disadvantage •  Teratogenicity •  Side effect; weight gain, tremor, transient hair loss,

Endocrine and metabolic dysfunctions

Glutamate Blockers

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Schematic representation of the N-methyl-D-aspartate (NMDA) receptor

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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 Lennox-

Gastaut syndrome (children-adjunctive therapy)

•  Disadvantage •  Serious side effect: Aplastic anemia, hepatic failure •  Significant drug interaction •  Not available

Topiramate •  Advantages

•  Broad spectrum of efficacy, Favourable pharmacokinetics, Few interactions, No enzyme induction

•  Partial seizures mono/ added on therapy •  Symptomatic generalized epilepsy •  Effective in drug-resistant generalized epilepsies as adjunctive

therapy, including juvenile myoclonic epilepsy, absence and generalized tonic-clonic seizures, and Lennox-Gastaut syndrome

•  Disadvantages •  Weight loss, hypoesthesia •  Cognitive impairment •  Glaucoma, ? cataract •  Very slow titration, rapidly titration caused language difficulty •  Unknown teratogenicity

AEDs With Other Mechanisms of Action

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Levetiracetam

•  Advantage •  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

Problems faced by physicians in clinical practice

•  Heterogeneity of epilepsy

•  Patient characteristics (children, women of childbearing potential, elderly)

•  Medical expertise and available healthcare facilities

•  Cost of treatment

•  Subjective perception of treatment benefit

•  Seizure type •  Epilepsy syndrome •  Pharmacokinetic profile •  Interactions/other medical conditions •  Efficacy •  Expected adverse effects •  Cost

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Early Syndromic Classification

0

20

40

60

Patie

nts

%

* Manford M et al. Arch Neurol 49:801, 1992 ; 75% !15 yrs ** Berg AT et al. Epilepsia 41:1269, 2000

50%

13%

37%

0

20

40

60

59%

29%

12%

Adults (n=508)* Children (n=613)**

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

•  With addition of EEG, 19% remain unclassified

•  If diagnosis cannot be made, it is wise to choose a broad-spectrum antiepileptic drug

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

•  Valproate •  Felbamate •  Lamotrigine •  Topiramate •  Zonisamide •  Levetiracetam •  Rufinamide*

Narrow-Spectrum Agents

Partial onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide*

Absence Ethosuximide

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•  Partial onset seizures phenytoin* gabapentin

carbamazepine* phenobarbital

valproate primidone

lamotrigine felbamate**

topiramate

tiagabine * considered by many as drugs of choice **associated with aplastic anemia and hepatic failure

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•  Generalized onset seizures Absence: valproate* = ethosuximide Myoclonic: valproate, clonazepam Tonic-clonic: valproate = phenytoin

Seizures in Lennox-Gastaut Syndrome: valproate, lamotrigine, felbamate**

* the risk of valproate-induced hepatic failure must be carefully weighed in young children ** associated with aplastic anemia and hepatic failure

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(Broad Spectrum AEDs)

PHT, PB CBZ, OXC GBP, VGB, PGB

VPA, LTG, TPM, ZNS, LEV, (FBM)

Drug Partial Secondary generalized

I° Tonic-clonic Absence Myoclonic

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Drug Partial 2 GTCS I° GTCS Absence Myoclonic

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•  Simplifies treatment, reduces adverse effects

•  Conversion to monotherapy from polytherapy –  Eliminate sedative drugs first –  Withdraw antiepileptic drugs slowly over

several months

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•  Drugs that induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital

•  Drugs that inhibit metabolism of other drugs: valproate, felbamate

•  Drugs that are highly protein bound: valproate, phenytoin

•  Other drugs may alter metabolism or protein binding of antiepileptic drugs

Monotherapy for Partial Seizures

Best evidence and FDA indication: Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate

Similar efficacy, likely better tolerated:

Lamotrigine, Gabapentin, Levetiracetam

Also shown to be effective:

Valproate, Phenobarbital, Felbamate, Lacosamide

Limited data but commonly used:

Zonisamide, Pregabalin

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•  Monotherapy for Generalized-Onset Tonic-Clonic Seizures

•  Best evidence and FDA Indication: •  Valproate, Topiramate

•  Also shown to be effective:

•  Zonisamide, Levetiracetam

•  Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )

•  Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies

• 

Absence seizures

• Best evidence: –  Ethosuximide (limited spectrum, absence only) –  Valproate

• Also shown to be effective:

–  Lamotrigine

• May be considered as second-line:

–  Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam

Myoclonic Seizures

Best evidence:

–  Valproate –  Levetiracetam (FDA indication as adjunctive tx) –  Clonazepam (FDA indication)

Possibly effective: –  Zonisamide, Topiramate

Lennox-Gastaut Syndrome

•  Best evidence/FDA indication*: –  Topiramate, Felbamate, Clonazepam, Lamotrigine,

Rufinamide –  * FDA approval is for adjunctive treatment for all except clonazepam

•  Also effective: –  Valproate

•  Some evidence of efficacy: –  Zonisamide, Levetiracetam

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Reasons to add vs. switch

•  Add

–  Pt tolerating 1st AED –  No anticipated drug

interactions –  Pt risk averse or

consequences of seizure exacerbation are high

–  1st AED appropriate, provided partial control

•  Switch

–  Pt not tolerating 1st AED –  1st AED has disadvantages –  Drug interactions epected –  Pregnancy anticipated –  Seizure exacerbation not

likely

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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)

!  However, doubt unfavourable reputation of polytherapy (Deckers, 2002)

Substitution or add-on

!  One should not assume that all combinations have same effectiveness (effectiveness being an outcome measure that encompasses both efficacy and tolerability)

!  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)

Alternative Monotherapy studies 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

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, 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 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

VGB to CBZ Tanganelli CPS (2GTCS) 14 patients not seizure-free on VGB, crossed over to CBZ

6/14 patient seizure-free (16%)

1 patient with CBZ had rash

VPA to CBZ Walker CPS (2GTCS) Patients not seizure-free on VPA were crossed over to CBZ

4/25 patient seizure-free (16%), 12% had >50% seizure reduction

No information

Combination therapy studies Drugs Author Clinical seizure Population Results ADR

PHT/CBZ Hakkarainen Adult onset seizure 33 patients uncontrolled by either drugs, given combination

5/33 seizure-free with combination (15%)

No ADR

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/VGB Murri Partial seizure (2GTCS) 40 patients not controlled by maximal CBZ monotherapy

7 seizure-free (18%) 5 withdraw due to toxicity

CBZ/VGB Tanganelli Partial seizure (2GTCS) 14 patients uncontrolled by either drug alone

5/14 seizure-free (36%), 5/14 seizure reduced >75%

Toxicity Higher than monotherapy

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

!  The average percentage seizure-free rates of alternative monotherapy and add-on therapy were similar

!  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

Substitution or add-on

!  Combination therapy achieved 25% seizure freedom in those patients that failed on both drugs in monotherapy

!  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.

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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

!  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

Substitution or add-on

!  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

!  When alternative monotherapy is efficacious but associated with considerable adverse effects, low-dose polytherapy should be considered

Choice of drug

!  Effectiveness may differ between different combinations

"  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

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Useful AED Combinations Pharmacokinetics

Problem: very little evidence in humans

#  probably synergism VPA + LTG VPA + ESM (in absences)

#  no synergism VPA + CBZ

#  increased toxicity + Barbiturates +

Benzodiazepines VPA + TPM ?

LEV + TPM ?

Useful AED Combinations Pharmacodynamics

Improving efficacy was exhibited by a combination of 0XC and CBZ

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

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

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)

Choice of drug

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

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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 "  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)

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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)

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 "#

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•  Problem: very little evidence in humans

probably synergism VPA + LTG VPA + ESM (in absences)

VPA + TPM ?, LEV + TPM ?

no synergism VPA + CBZ

increased toxicity + Barbiturates + Benzodiazepines

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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

topiramate –  Acute closed-angle glaucoma

topiramate

•  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

•  Drugs rarely associated with rash Valproate Gabapentin Pregabalin Levetiracetam Topiramate

•  !!= rash rate significantly greater than average of all other AEDs (p

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•  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 –  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”

•  Data analysis is controversial and overall difference is very small

•  Further investigation is needed

•  Clinicians should be aware of potential risk and screen for •  depression/suicidality

www.fda.gov 88

A guide not a goal •  Limited data •  Broad generalizations •  Individual differences •  Useful in:

–  Providing initial target in patients with infrequent seizures

–  Understanding unexpected seizures or side effects, especially with polypharmacy

–  Verifying compliance

89

•  Progressive pathology? •  Avoidable precipitant? •  If on AED

–  Problem with compliance or absorption? –  Increase dose? –  Change medication?

•  If not on AED

–  Start AED?

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Discontinuing AEDs

•  Seizure freedom for ! 2 years implies overall >60% chance of successful withdrawal

•  Favorable factors –  Control achieved easily on one drug at low dose –  No previous unsuccessful attempts at withdrawal –  Normal neurologic status and EEG? –  Primarily generalized seizures only? –  “Benign” syndrome

•  Consider relative risks/benefits (e.g., driving, pregnancy)

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•  Adequate sleep

•  Avoidance of alcohol, stimulants, etc.

•  Stress reduction — specific techniques

•  Adequate diet

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•  Most pregnancies in epileptic mothers produce normal children

•  Fetal anomalies (up to 10% of pregnancies) are multifactorial –  Drug effects –  Consequences of the mother’s underlying diseases –  Consequence of maternal seizures during pregnancy

•  All antiepileptic drugs carry teratogenic risks

Most available data on risk of AEDs comes from pregnancy registries.

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)

•  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.

•  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%) Phenytoin (3.2-6.7%) Zonisamide, Pregabalin

No substantial data on monotherapy

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•  Effects on pregnancy on epilepsy –  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

8/30/10

17

97

•  Risk of fetal malformation is increased twofold to threefold

•  Prenatal diagnosis should be discussed

•  Seizures may be deleterious to the fetus

•  Adequate folate should be ensured (at least 1 mg/day)

•  Monotherapy should be used if possible, with the lowest effective dose

•  Breastfeeding should be encouraged unless clear risk posed

•  Probably safe: –  Carbamazepine –  Phenytoin –  Valproate –  Lamotrigine

•  “Use with caution” in lactating women: –  Primidone –  Phenobarbital –  Ethosuximide –