1. 1 “Update on Treatment of Seizures & Epilepsy” Bassel F. Shneker, MD Comprehensive Epilepsy Program The Ohio State University October 24, 2009

2. 2 Outline Definition of Seizures and Epilepsy Treatment with AEDs Newly Approved AEDs New information about AEDs –Generic AEDs –Suicidality and AEDs –Pregnancy and AEDs

3. 3 Definition of Seizures Time-limited paroxysmal events that result from abnormal, involuntary, rhythmic neuronal discharges in the brain Seizures are usually unpredictable Seizures usually brief ( < 5 minutes) and stop spontaneously Convulsion, ictus, event, spell, attack and fit are used to refer to seizures

4. 4 Right Temporal Lobe Seizure

5. 5 Etiology of Seizures Seizures are either provoked or unprovoked Provoked Seizures: Triggered by certain provoking factors in otherwise healthy brain –Metabolic abnormalities (hypoglycemia and hyperglycemia, hyponatremia, hypocalcemia) –Alcohol withdrawal –Acute neurological insult (infection, stroke, trauma) –Illicit drug intoxication and withdrawal –Prescribed medications that lower seizure threshold (theophylline, TCA) –High fever in children Unprovoked Seizures: Occur in the setting of persistent brain pathology

6. 6 Definition of Epilepsy A disease characterized by spontaneous recurrence of unprovoked seizures (at least 2) Seizures are symptoms, while epilepsy is a disease, so those terms should not be used interchangeably Epilepsy = “seizure disorder” Epilepsy is a syndromic disease Each epilepsy syndrome is determined based on; Type of seizures, age at seizure onset, family history, physical exam, EEG findings, and neuroimaging

7. 7 Etiology of Epilepsy Any process that alters the structure (macroscopic or microscopic) or the function of the brain neurons can cause epilepsy Processes that lead to structural alteration include; Congenital malformation Degenerative disease Infectious disease Trauma Tumors Vascular process In majority of patients, the etiology is proposed but not found

8. 8 Treatment of Seizures Provoked Seizures –Treatment directed to the provoking factor Unprovoked Seizures –First Seizure Usually no treatment Treatment can be initiated if risk of recurrence is high or if a second seizure could be devastating –Second Seizure Diagnosis of epilepsy is established and risk of a third Seizure is high Most physician treat at this stage In children, some may wait for a third seizure

9. 9 Treatment of Established Epilepsy First Line –Approved Anti-Epileptic Drugs (AEDs) Second Line (intractable epilepsy) –Epilepsy Surgery –Vagus Nerve Stimulation Therapy Exeprimental Treatment –AEDs –Devices Deep Brain Stimulator (DBS) Responsive Neuro Stimulator (RNS)

10. 10 Antiepileptic Drugs (AED) First GenerationSecond Generation Unconventional Carbamazepine (Tegretol) Clonazepam (Klonopin) Clorazepate (Tranxene) Ethosuximide (Zarontin) Phenobarbital Phenytoin (Dilantin) Primidone (Mysoline) Valproic acid (Depakote) Felbamate (Felbatol) Gabapentin (Neurontin) Lamotrigine (Lamictal) Levetiracetam (Keppra) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Tiagabine (Gabitril) Topiramate (Topamax) Zonisamide (Zonegran ) Adrenocorticotropic hormone (ACTH ) Acetazolamide (Diamox) Amantadine (Symmetrel) Bromides Clomiphene (Clomid) Ethotoin (Peganone) Mephenytoin (Mesantoin) Mephobarbital (Mebaral) Methsuximide (Celontin) Trimethadione (Tridione)

11. 11 What is New in AEDs World? 3 AEDs are approved in 2009 –Rufinamide (Banzel ® ) –Lacosamide (Vimpat ® ) –Vigabitrin (Sabril ® ) Discussion about generic vs. brand AEDs Suicidality and AEDs Pregnancy and AEDs

12. 12 AED Generic (Trade) Abbreviations Phenobarbital/Primidone –PB / PRM Phenytoin (Dilantin) –PHT Carbamazepine (Tegretol) –CBZ Valproic Acid (Depakote) –VPA Felbamate (Felbatol) –FBM Gabapentin (Neurontin) –GBP Lamotrigine (Lamictal) –LTG Topiramate (Topamax) –TPM Tiagabine (Gabitril) –TGB Oxcarbazepine (Trileptal) –OCBZ (OXC) Levetiracetam (Keppra) –LEV (LVT) Zonisamide (Zonegran) –ZNS Pregabalin (Lyrica) –PGB Rufinamide (Banzel) –RUF Lacosamide (Vimpat) –LCM Vigabatrin (Sabril) –VGB

13. 13 AED Therapy PBPHTCBZ VPA FBM GBP LTG FOS TPM TGB OCBZ LEV ZNS PGB LCM RUF VGB

14. 14 Generic vs. Brand AEDs Advantage –Lower cost –Increase access to treatment Disadvantage –Lower level seizures –Higher level CNS toxicity

15. 15 Generic Drug- FDA Requirements Generic drug must: –Contain same active ingredients –Identical in strength, dosage form, and route of administration –Same use indications –Bioequivalent –Same batch requirements for identity, strength, purity, and quality –Manufactured under the same strict standards of FDA's good manufacturing practice regulations required for innovator products

16. 16 Bioequivalence Requirement “A generic product has to be bioequivalent to the brand (reference) product by demonstrating the same in vivo performance” –Mainly absorption Two drugs are bioequivalent if the ratio of means of the primary PK responses such as AUC and Cmax between the two formulations of the same drug or the two drug products is within (80%, 125%) with 90% assurance.

17. 17 FDA Bioequivalence

18. 18 Questions about Generic AEDs Switch between generics Controlled vs. uncontrolled epilepsy patients Data about negative impact of generics

19. 19 Suicidality and AEDs

20. 20 FDA Alert – Results (1) Data from 199 placebo-controlled trials –43,892 total patients 27,863 drug-treated patients 16,029 placebo-treated patients Indications: –Epilepsy: 62 trials (31%) –Psychiatric Indications: 56 trials (28%) –Other Indications: 81 trials (41%) Analyzed AEDs (11): CBZ, FBM, GBP, LTG, LEV, OXC, PGB, TGB, TPM, VPA, ZNS

21. 21 FDA Alert – Results (2) IndicationDrug Patient Events per 1000 Placebo Patient Events per 1000 Risk Difference Relative Risk Epilepsy 3.51.02.53.6 Psychiatric 8.35.23.11.6 Other 2.00.81.12.3 Total 4.32.22.12.0

22. 22 FDA Alert – Results (3) Drug-treated subjects had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with placebo-treated subjects (0.22%) Risk was higher in epilepsy group compared to other groups Risk difference 2.1 per 1000 (95% CI: 0.7, 4.2) Increased risk observed throughout time periods for which data was obtained No clear pattern of risk across age groups Results generally consistent across all drugs

23. 23 FDA Alert – 12/16/2008

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25. 25

26. 26 FDA Alert, So What? “ The mean scores for the FDA alert clarity, appropriateness, and impact on clinical practice (on a scale from 1 to 10) were low, at 5.3, 4.1, and 3.6. Almost 46% did not feel the alert is going to change their practice “ Shneker, Neurology 2009 Concerns about –What to do –Patient safety from stopping AEDs

27. 27 AEDs & Pregnancy Discussion about effect of AEDs on Fetus –Malformations –Cognitive side effects Latest Information –AED Pregnancy Registry –Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study

28. 28 Background on AED Pregnancy Registry For pregnant women taking any AED For epilepsy or non-epilepsy purpose –Patients call 1-888-AED-AED4 –www.aedpregnancyregistry.org Three telephone calls –Initial (10 min), 7 months (5 min), Post-partum (5 min)

29. 29 AED Pregnancy Registry Enrollment Data www.AEDpregnancyregistry.org Winter 2009 Newsletter

30. 30 Registry Changes Procedure Preliminary Findings 6 AEDs

31. 31 What do we know now? Risk of Major Malformations –Polytherapy = ↑ risk –Specific AEDs General population = 1.6% Phenobarbital = 6.5% Valproic Acid = 10.7% August 2006 Neurology (Meador, et al.) –NEAD Study with 333 pregnancies Serious adverse outcomes (major malfs, fetal death) –CBZ (8.2%), LTG (1.0%), PHT (10.7%), VPA (20.3%)

32. 32 Lamotrigine Recent Findings AED Pregnancy Registry Data –564 infants LTG monotherapy 1st trimester –Between 1997 & March 2006 Major malformations 2.7% –vs. 1.6% unexposed 5 infants cleft lip/palate = 1:113 –vs. 1:6,160 unexposed –Relative risk LTG = 32.8 Other AED registries = 1:405

33. 33 AEDs & Neurodevelopment “ Although we’ve had a great deal of information in the past 2 years on anatomical teratogenicity from AED in utero exposure, we have had much less with regard to cognitive outcomes. Animal studies of AEDs clearly show behavioral teratogenesis at dosages less than those required to produce anatomical teratogenicity.” Meador KJ. 2006

34. 34 AEDs & Neurodevelopment Adab 2001 (UK) Additional Educational Needs VPA = 30%, CBZ = 3.2% Adab 2004 (UK) Verbal IQ lower in VPA- exposed than other AEDs Failey 2002 (FIN) Mean Verbal IQ Scores VPA 82, CBZ 96, Controls 95 Eriksson 2005 (FIN) Low intelligence VPA 19% vs. CBZ 0% NEAD Study Prospective evaluation of long term cognitive and behavioral development

35. 35 AEDs & Neurodevelopment NEAD Study –Pregnant women on monotherapy CBZ, LTG, PHT or VPA –Long-term goal = examine cognition at age 6 Planned interim analyses at 3 yrs –Mental Scale of the Bayley Scales of Infant Development –CBZ (n=73), LTG (n=84), PHT (n=48), VPA (n=53) –Children’s Mental Development Index (MDI) »Controlled (Mom’s IQ, AED levels, Sz type, etc) Meador et al. N Engl J Med 2009;360:1597-1605.

36. 36 AEDs & Neurodevelopment VPA-exposed kids significantly lower IQ scores –Dose-dependent –Conclusion “...recommendation that valproate not be used as a 1st choice drug in women of childbearing potential.” AEDMean IQ VPA92 PHT99 CBZ98 LTG101

37. 37 AEDs & Pregnancy – Take Home Messages No Safe AEDs Optimization of pre-pregnancy treatment –Monotherapy –Lowest dose Advise women to plan pregnancy Avoid VPA All childbearing age women should be on folic acid

38. 38 Acknowledgment James McAuley, PhD –Co-investigator, slides John Elliott, MPH Janet Renner Stephanie Renner