AEDs

1. AEDs Martin del Campo MD UHN Toronto, Ont.

2. Disclosures • Speakers Bureau • Ad-boards: • UCB Canada • Boehringer-Ingelheim

3. Outline • Review the new AEDs including Lacosamide • Canadian experience with Lacosamide • Example cases

4. Old vs New

5. The Bad News • At the last visit • 423 patients were on a single AED (68% seizure-free) • 53 patients took 2 AED’s (23% seizure-free) • 5 patients were on 3 AED’s (none were seizure-free) Kwan, P. and Brodie, M. NEJM 2000; 342: 314-319

6. Lamotrigine (Lamictal) • Good “broad spectrum” AED • BID dosing (soon to be OD) • Useful as mood stabilizer • Metabolism inhibited by VPA • Insomnia • Skin rash - SJS

7. Lamotrigine (Lamictal) • 5/564 incidence of oral clefts (3 palate, 2 lip) in North American registry • 4/1623 had oral cleft in other registries • Non-teratogenic in doses <200 mg/day (2.6% mono, 10.8% with VPA) Holmes LB et al. Birth Defects Research (Part A); 2006; v76:5

8. Gabapentin (Neurontin) • Structural analog of GABA • Weak AED (30% responder rate) • Mode of action unknown • Excreted unchanged in urine • No drug interactions • Quick titration • Dizziness, fatigue

9. Topiramate (Topamax) • Various mechanisms of action • Minimally protein-bound • Plasma levels ‘d by PHT, CBZ and VPA • Partial renal excretion • Responder rate 30-50% in partial onset or primarily generalized convulsive Sz’s • Useful in Lennox-Gastaut and infantile spasms • Weight loss, renal stones, oligohydrosis, hallucinations, cognitive impairment • Rare acute narrow-angle glaucoma.

10. Vigabatrin (Sabril) • Another GABA look-alike • Designed as a GABA transaminase inhibitor • Excreted unchanged in urine • GABA levels elevated 120 hrs after single dose • Responder rates inferior to CBZ • Decreases PHT and CBZ levels • 20-30% incidence of visual field constriction

11. Clobazam (Frisium) • 1,5 benzodiazepine • Active metabolite: desmethylclobazam • GABAa agonist • Efficacy in myoclonic and absence status • Usually used as adjunct for partial Sz’s with or without generalization • Tachyphylaxis • Sometimes difficult to taper down

12. Oxcarbazepine (Trileptal) • CBZ analogue • Converted to MHD, active metabolite • Renal excretion • Traditional AED’s induce its metabolism • 25% of pts with CBZ hypersensitivity will react to OXC • No reports of aplastic anemia • hypoNa especially in older pts

13. Oxcarbazepine (Trileptal) • 50-60% responder rate • 12% Sz-free • Indicated as monotherapy • Not on ODB or LU

14. Levetiracetam (Keppra) • Plasma half-life: 6 to 8 hours in adults • Steady state: after 2 days of BID dosing • Renal elimination • 66% eliminated as unchanged drug • Correlated with creatinine clearance

15. Levetiracetam (Keppra) • No interaction with other AEDs included in placebo-controlled clinical studies in patients with epilepsy1 • No interaction with phenytoin2 and valproic acid3 confirmed by clinical pharmacokinetic studies 1. Keppra® Product Monograph 2. Browne TR et al. J Clin Pharmacol 2000;40:590-5. 3. Coupez R et al. Epilepsia 2003;44(2):171-8.

16. 45 40 35 30 25 20 15 10 5 0 Responder Rate % of patients with 50% reduction in Sz frequency * *p<0.001 vs. placebo % of Patients 42.1 16.7 Placebo(n=105) LEV 3000 mg/day(n=181) Ben-Menachem et al. Epilepsia 2000;41:1276-83.

17. AEDs: Molecular and Cellular Mechanisms  Phenytoin, Carbamazepine • Block voltage-dependent sodium channels at high firing frequencies  Barbiturates • Prolong GABA-mediated chloride channel openings • Some blockade of voltage-dependent sodium channels  Benzodiazepines • Increase frequency of GABA-mediated chloride channel openings

18. AEDs: Molecular and Cellular Mechanisms  Gabapentin • Increases neuronal GABA concentration • Enhances GABA mediated inhibition  Lamotrigine • Blocks voltage-dependent sodium channels at high firing frequencies • May interfere with pathologic glutamate release

19. AEDs: Molecular and Cellular Mechanisms  Ethosuximide • Blocks low threshold, “transient” (T-type) calcium channels in thalamic neurons  Valproate • May enhance GABA transmission in specific circuits • Blocks voltage-dependent sodium channels  Vigabatrin • Irreversibly inhibits GABA-transaminase

20. AEDs: Molecular and Cellular Mechanisms  Topiramate • Blocks voltage-dependent sodium channels at high firing frequencies • Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines) • Antagonizes glutamate action at AMPA/kainate receptor subtype • Inhibition of carbonic anydrase

21. AEDs: Molecular and Cellular Mechanisms  Levetiracetam • Binding of reversible saturable specific binding site • Reduces high-voltage- activated Ca2+ currents • Reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators  Oxcarbazepine • Blocks voltage-dependent sodium channels at high firing frequencies • Exerts effect on K+ channels

22. Lacosamide:Metabolism and Elimination • About 95% of dose excreted in urine • 40% as unchanged lacosamide • ~30% as O-desmethyl metabolite (no known pharmacological activity) • CYP2C19 enzyme responsible for O-desmethyl metabolite • No clinical difference in pharmacokinetics in poor vs. extensive metabolizers for CYP2C19 • No clinical relevant changes in pharmacokinetics with omeprazole (CYP2C19 inhibitor) • t½: ~13 hours (steady-state achieved in 3 days) • Low intra- and inter-subject variability EU SmPC; Doty 2007

23. Pharmacokinetics of Lacosamide: Special Patient Populations and Drug-Drug Interaction • Mild and moderate renal impairment: No dose adjustment needed • Maximum dose of 300mg/day recommended for patients with severe renal impairment (CLCR ≤30 mL/min) or end-stage renal disease. • Supplement of up to 50% of the divided daily dose directly after the end of hemodialysis is recommended. • In all patients with renal and/or hepatic impairment, dose titration should be performed with caution. • Low potential for drug-drug interactions • No clinical relevant changes in the plasma concentrations of concomitant AED’s (carbamazepine, valproic acid, phenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine or zonisamide). • No clinical relevant interaction with digoxin, metformin, omeprazole (CYP2C19 inhibitor), or ethinyl estradiol + levonorgestrel-containing oral contraceptives. • Caution should be exercised when VIMPAT is given with other drugs that prolong the PR interval (eg. carbamazepine, pregabalin, lamotrigine or beta-blockers), and in patients treated with class I anti-arrhythmic drugsas further PR prolongation is possible. UCB data on file;Canadian Product Monograph.

24. Pivotal trials: Patient demographics and baseline characteristics (ITT) AED=antiepileptic drug; BMI=body mass index ITT= all patients with ≥1 post-baseline efficacy assessment • 1294 patients received trial medication and had ≥1 post-baseline efficacy assessment (ITT) • Mean age: 38.6 years • 51.1% female • 91.7% Caucasian • BMI: 26.8 kg/m2 • Time since diagnosis 23.7 years • Lifetime use of AEDs • 32.2% tried 4 to 6 • 45.2% tried 7 or more • Number of concomitant AEDs • 1 AED: 15.5% • 2 AEDs: 62.4% • 3 AEDs: 22.0% UCB data on file

25. Pivotal trials: Seizure freedom during maintenance (Pooled data) Seizure-free rates for completers Median change in percentage of seizure-free days during maintenance phase Median increase (%) Seizure-free patients (%) Lacosamide Lacosamide

26. Rosenfeld study: ≥50% responder rate N=370 70 60 50 40 30 20 10 0 Patients responding (%) >0−6 >6−12 >12−18 >18−24 >24−30 >30 Treatmentperiod Months Percentages were based on the number of patients in each modal dose group with an evaluable responder status during the relative time interval. Responders were defined as patients who experienced ≥50% reduction in seizure frequency during the time interval from baseline (where baseline was from the previous trial). A month was defined as 28 days.

27. § Pivotal Trials Pooled Results: ≥ 50% Responder Rate During Maintenance By Dose (ITT) *P <.05; ** P <.001 versus placebo ** ** * N = 1294 Patients Responding (%) n = 359 n = 267 n = 466 n = 202 ITT = all randomized patients receiving ≥1 dose of trial medication with ≥1 post-baseline efficacy assessment,; §Lacosamide is approved up to a dose of 400 mg/day Chung AES 2008

28. Pooled Pivotal Trials:Most Common AEs During Titration and Maintenance* * Safety population, N = 1308.

29. Lacosamide in Canada

30. Lacosamide in Canada

31. Lacosamide in Canada

32. Lacosamide in Canada

33. Lacosamide in Canada

34. Case 1 • 22 y.o. woman with 6 month h/o episodes of unresponsiveness, associated with lip smacking, lasting 2-3 min., occurring 2-4/month. • Lives with boyfriend. • No consistent contraception • EEG shows left temporal spikes • MRI shows left mesial temporal sclerosis

35. Mesial Temporal Sclerosis

36. Case 1Issues • Young female in childbearing age • Compliance • Cosmetic side effects • Weight control • Long-term side effects • Birth control • Risk to baby

37. Case 1options • Lamictal • Tegretol • Trileptal • Surgery • Nothing

38. Case 2 • 65 y.o. man with high blood pressure, irregular heart beat, high cholesterol and a recent stroke. • Reports 3 episodes of head turning to the left and involuntary jerking of the left arm and face lasting 1 min. • On several drugs for control of his various conditions including warfarin

39. Case 2issues • Multiple drugs • Compliance • Side effects • Interactions • Organ failure

40. Case 2options • Neurontin • Keppra • Lacosamide • Surgery?

41. Case 3 • Twenty-one y.o. man, obese, with a 6 year history of several Grand Mal seizures per year. On Epival but does not always take it (drowsy, hand tremor) • Sister has seizures too

42. Case 3issues • Non-compliance • Side effects • Strong potential for social issues • Depression • Inability to buy drugs

43. Case 3options • Tegretol • Dilantin • Lamictal • Topamax • Keppra • Surgery?

44. Case 4 • 45 y.o lady, single, works as a town librarian in St. Joseph’s Island, gives a history of temporal lobe seizures since mid-teens. They used to occur every week but as she got older, they happen 3-4 times/ y. • Has always been on Tegretol, 4 pills/day. Higher doses make her see double and get dizzy

45. Case 4issues • Social and geographic isolation • Can’t drive • Can’t find a job in the city • Can’t access specialty care easily • Has read about other drugs but local GP says “this is as good as she’ll ever be”

46. Case 4options • Lacosamide • Tegretol CR • Trileptal • Lamictal • Keppra • Topamax • Surgery?

47. Summary • Numerous pharmacological choices • Newer AEDs have less potential for drug-drug interaction • Choose AED according to patient profile • If no success, consider surgery

48. Thank You