8/30/10. How to use Antiepileptic drugs properly. 3nd generation AEDs. Introduction. Introduction. Introduction. AEDs. Dr.Yotin Chinvarun M.D., Ph.D.

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1 Introduction How to use Antiepileptic drugs properly 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. Dr.Yotin Chinvarun M.D., Ph.D. 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 1 st AED Rx partial and secondarily generalized seizures 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 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 AEDs 3nd generation AEDs 1 st generation AEDs Phenytoin Carbamazepine Valproate Phenobarbital Clobazam 2 nd generation AEDs Felbamate 1993 Lamotrigine 1994 Topiramate 1996 Tiagabine 1997 Levitiracetam 1999 Oxcarbamazepine 2000 Zonisamide 2000 Pregabalin 2004 Brivaracetam Eslicarbazepine Fluorofelbamate Ganaxolone Huperzine JZP-4 Lacosamide Licarzepine Losigamone NS1209!"#$%&'(")!*+(%,'-")!./) )45%6'7&%,%8"9) :";"86%<"8%,) :%+(%,'-") :=>?@A) :#6'B"(8C;) D%;%,B%(";) E%;6C<",'-") 1

2 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 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 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 s 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

3 Oxcarbazepine 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 Advantages Lamotrigine 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 GABA Receptor Agonists 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 GABA drugs and their known sites of action Clobazam 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

4 Clonazepam 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 Had been used since 1912 s Partial onset seizure Phenobarbital 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 GABA Reuptake Inhibitors s 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

5 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 Advantages Gabapentin 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 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 Glutamate Blockers 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

6 Felbamate 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 s Topiramate 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 Levetiracetam 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 Cost of treatment Seizure type Epilepsy syndrome Pharmacokinetic profile Interactions/other medical conditions Efficacy Expected adverse effects Cost Subjective perception of treatment benefit 6

7 Early Syndromic Classification AEDs and seizure type Patients % % 13% 37% % 29% 12% 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 0 Adults (n=508)* 0 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 Valproate Felbamate Lamotrigine Topiramate Zonisamide Levetiracetam Rufinamide* Narrow-Spectrum Agents Partial onset seizures Phenytoin Carbamazepine Oxcarbazepine Gabapentin Pregabalin Tiagabine Lacosamide* Absence Ethosuximide 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 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

8 Drug Partial Secondary generalized I Tonic-clonic Absence Myoclonic!"#$%&'($) *) *) *) +) +) PHT, PB CBZ, OXC GBP, VGB, PGB,-./-0-1#!($#) *2) *) *) +) +) 3-4!.'-&#5-,(6) *) *) *) *) *)!"#$'/-./(&-4) *) *) *) 7) 8*) VPA, LTG, TPM, ZNS, LEV, (FBM) (Broad Spectrum AEDs)!.(0(6'$#) *) *) *) 7) 8*) #&"'9:;(0(6#) 7) 7) 7) *) 7) Drug Partial 2 GTCS I GTCS Absence Myoclonic <#4/-0-&#) *) *) 8*) 8*) 8*) =-/-!#$&($>)?.#@-/-4($) *) *) 8*) 7) 8 ) 4-0'&.(@($#) *) *) *) *) +/- * &'!(.-0-&#) *) *) *) 8) 8*) &(-@-/($#) *) *) 8) 8) 8) Simplifies treatment, reduces adverse effects Conversion to monotherapy from polytherapy Eliminate sedative drugs first Withdraw antiepileptic drugs slowly over several months 1'$(9-0(6#) *) *) 8*) 8*) 8*) 4#3#&(.-,#&-0) *) *) *)?+ + ';,-./-1#!($#) *) *) 85*) +) +) 46 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 47 8

9 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 Lennox-Gastaut Syndrome Best evidence: Valproate Levetiracetam (FDA indication as adjunctive tx) Clonazepam (FDA indication) Possibly effective: Zonisamide, Topiramate 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 Reasons to add vs. switch Add Switch =AB) C/9#$,#) D%',4'$(,) A'$(,) C&'$(,) Pt tolerating 1 st AED No anticipated drug interactions Pt risk averse or consequences of seizure exacerbation are high 1 st AED appropriate, provided partial control Pt not tolerating 1 st AED 1 st AED has disadvantages Drug interactions epected Pregnancy anticipated Seizure exacerbation not likely?-.&(-4) * in children of SMEI 9

10 ! 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)! 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 Combination therapy 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 CBZ, PHT, Schmidt Partial seizure or GTCS 59 patients refractory to PB or PRM monotherapy with 1-4 drugs, were given another 1-4 drugs 8 seizure-free (33%) No information 7/59 seizure-free ADR (12%), 19% had disappeared in seizure reduction 27% >75% CBZ/VPA Walker CPS (2 GTCS) 17 patients uncontrolled by either drugs, given combination CBZ/VGB Murri Partial seizure (2GTCS) 40 patients not controlled by maximal CBZ monotherapy 6/17 seizure-free No new (15%), 6/17 seizure additive toxicity reduced >50% (35%) 7 seizure-free (18%) 5 withdraw due to toxicity CBZ to VGB Tanganelli Partial seizure (2GTCS) 11 patients uncontrolled by CBZ, 5/11 seizure-free crossed over to VGB (45%), 5/14 seizure reduced >75% VGB to CBZ Tanganelli CPS (2GTCS) 14 patients not seizure-free on 6/14 patient seizurefree VGB, crossed over to CBZ (16%) Toxicity Higher than monotherapy 1 patient with CBZ had rash 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 to CBZ Walker CPS (2GTCS) Patients not seizure-free on VPA 4/25 patient seizurefree (16%), 12% had were crossed over to CBZ >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! 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! 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. 10

11 ! 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)! 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! 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 Choice of drug! 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, lowdose polytherapy should be considered! 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 11

12 Useful AED Combinations Pharmacokinetics Useful AED Combinations Pharmacodynamics 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? Choice of drug Choice of drug 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 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)! 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)! 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

13 ! 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) 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: ; Czuczwar, Epilepsy Res 2002;52:15-23, Luzsczki, Epilepsia 47:10-20, 2006; Jonker, Epilepsia 2007;48: ; 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

14 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<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

15 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 /d; Vit D /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 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 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 88 Discontinuing AEDs Progressive pathology? Avoidable precipitant? If on AED Problem with compliance or absorption? Increase dose? Change medication? If not on AED Start AED? 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)

16 Adequate sleep Avoidance of alcohol, stimulants, etc. Stress reduction specific techniques Adequate diet 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 % 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 % 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 ( %) Substantial data available, relatively good track record Lamotrigine ( %) Increased risk (5.4%) with doses > 400/day Gabapentin (0-3.2%) Topiramate (0-4.8%) Phenytoin ( %) Zonisamide, Pregabalin No substantial data on monotherapy 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 96 16

17 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 97 17