This document discusses issues related to new and generic antiepileptic drugs (AEDs). It notes that while new AEDs have been introduced, the percentage of patients with uncontrolled seizures remains around 40%. Both new "revolutionary" drugs that work via novel mechanisms and "evolutionary" drugs that improve existing ones are needed. Several new AEDs are described including retigabine, brivaracetam and eslicarbazepine. Concerns about generic AED substitution include potential differences in formulations and lack of studies on risks of switching between generics. Physician oversight is recommended when changing AED preparations.

1. New Horizons and Old Dilemmas: New AEDs and Generics Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center

2. ANTIEPILEPTIC DRUG DEVELOPMENT 1840 1860 1880 1900 1920 1940 1960 1980 2000 0 5 10 15 20 Bromide Phenobarbital Phenytoin Primidone Ethosuximide Sodium Valproate Benzodiazepines Carbamazepine Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin Oxcarbazepine Tiagabine Levetiracetam Rufinamide Lacosamide Pregabalin Retigabine Brivaracetam Eslicarbazepine Clobazam ? Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine Vigabatrin

3. SINCE 1998 2000 0 5 10 20 Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin Oxcarbazepine Tiagabine Levetiracetam Pregabalin Calendar Year Number of Licensed Antiepileptic Drugs Lamotrigine 1990 Rufinamide Lacosamide 2010 Vigabatrin

6. Compounds which are second or third generation derivatives of AEDs introduced before 1970 1 st Generation AED CarbamazepineeTegretol TM Valproic Acid Depakote TM 2 nd Generation AED Oxcarbazepine Valrocemide (SPD–493) Valnoctamide 3 rd Generation AED Eslicarbazepine Acetate (BIA 2-093) Phenobarbital T2000 Perucca et al, Lancet Neurol , 2007

7. Compounds which are second generation derivatives of AEDs introduced after 1990 Gabapentin Levetiracetam Pregabalin Brivaracetam (ucb 34714) Precursor CNS Drug Piracetam 1 st Generation AED 2 nd Generation AED Perucca et al, Lancet Neurol , 2007

10. Patients with > 50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance) Study 302 Study 301 *p<0.005 **p<0.001 % Patients 179 181 178 152 153 Placebo 600 900 Placebo 1200 RTG RTG

11. Retigabine 1200 mg/day vs Placebo: Most Common Adverse Events ( > 10% incidence) % Patients Placebo (N=152) RTG (N=153) Dizziness 14 40 Somnolence 17 31 Fatigue 8 16 Confusion 2 14 Dysarthria 2 12 Headache 18 12 Ataxia 4 12 Urinary tract infection 9 12 Tremor 4 11 Vision blurred 3 11 Nausea 7 10

14. Perampanel : Percent change in seizure frequency during maintenance phase Median % change in seizure frequency -40 -30 -20 -10 0 -50 Placebo (n=119) Perampanel 8 mg/day (n=132) Perampanel 12 mg/day (n=130) -22.86 -32.13 ( P =0.08) -39.48 ( P =0.03)

15. Treatment-emergent side effects (add-on) TEAEs, treatment-emergent adverse events Placebo Perampanel Treatment emergent Side effects % N (n=121) 8 mg (n=133) 12 mg (n=134) TEAEs leading to study or study drug withdrawal 43 6.6 6.8 19.4 Most common (≥10%) Dizziness 113 9.9 37.6 38.1 Sleepiness 63 13.2 18.0 17.2 Irritability 35 5.0 7.5 14.2 Headache 54 13.2 15.0 13.4 Fall 38 6.6 9.8 12.7 Ataxia 24 0 6.0 11.9

16. OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam (Rikelta) Eslicarbazepine Acetate (Stedesa)

19. Brivaracetam Adverse Events PBO BRV5 BRV20 BRV50 Patients (N) 54 50 52 52 Permanent study drug discontinuation 2 (3.7) 3 (6.0) 1 (1.9) 0 Patients with ≥1 AE, n (%) 29 (53.7) 26 (52.0) 29 (55.8) 28 (53.8) Total AEs 59 50 72 56 AEs reported in ≥ 5% patients Headache Somnolence Influenza Dizziness Neutropenia Fatigue 4 (7.4) 4 (7.4) 4 (7.4) 3 (5.6) 1 (1.9) 2 (3.7) 4 (8.0) 1 (2.0) 4 (8.0) 1 (2.0) 4 (8.0) 0 2 (3.8) 3 (5.8) 0 0 2 (3.8) 2 (3.8) 1 (1.9) 3 (5.8) 1 (1.9) 4 (7.7) 0 3 (5.8)

21. Change in Cholesterol after removal of Tegretol or Dilantin (First to second blood draw) Mintzer S. et al Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol. 2009 Apr;65(4):448-56. Tegretol Dilantin CONTROL

23. Results from 3 Eslicarbazepine Pivotal Trials: 50% Responder Rates Study BIA-2093-301 Study BIA-2093-302 Study BIA-2093-303 Response Rate (%) 50 45 40 35 30 25 20 15 10 5 0 McCormack PL, et al. CNS Drugs . 2009. 23(1):71-9. 800 mg and 1200 mg doses were statistically significant; 400 mg was not. PL ESL 400 mg od ESL 800 mg od ESL 1200 mg od

29. Source: WKH PHAST TRX and Sales data factored by Verispan PDDA Note: Celexa included as a reference of typical generic erosion Prescription Generic Erosion Brand TRx as Percent of Total Molecule

31. Different generics can also look different than the brand, causing confusion Tegretol Carbamazepine (Generic)

35. Drug Must Be in Solution to be Absorbed Drug in Blood Dissolution of Drug Drug in Solution Result Desired pharmacological effect achieved (seizure reduction) Solid Dosage Form

41. Position Statement Epilepsy Foundation of America Foundation Opposes Mandatory Substitution for Antiepileptic Drugs The Epilepsy Foundation has had a historical position opposing mandatory substitution of generic drugs for brand name since generics first became available because of concerns about reported breakthrough seizures in some people with epilepsy when they are switched from one version of a medication to another. Other medical organizations focused on the treatment of epilepsy have had similar positions.

42. Position Statement American Academy of Neurology (AAN) The AAN, representing over 19,000 neurologists and neuroscience professionals, has taken an active interest in the clinical, ethical and policy considerations concerning the coverage of anticonvulsant drugs for people with epilepsy. The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician ’ s approval. The FDA has allowed for significant differences between name-brand and generic drugs. This variation can be highly problematic for patients with epilepsy. Even minor differences in the composition of generic and name-brand anticonvulsant drugs for the treatment of epilepsy can result in breakthrough seizures.