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New Antiepileptic Medications Drug Profiles, Efficacy, Safety, and Tolerability Evolving Epilepsy Therapy • Treatments – First-generation AEDs 1930-1980s – Second-generation AEDs 1984-2006 – Third-generation AEDs 2006-today – Orphan AEDs • Needs – Tolerability – Safety – Added efficacy Recent AEDs FDA Approval Drug Company Indication Clobazam (Onfi®) Lundbeck 2011 Adjunctive therapy for LGS in patients ≥ 2 y Eslicarbazepine (Aptiom®) Sunovion (Sepracor + Dainippon) 2013 2015 Monotherapy or adjunctive therapy for POS Lacosamide (Vimpat®) UCB Pharma 2008 2014 Monotherapy or adjunctive therapy for POS in patients ≥ 17 y Perampanel (Fycompa™) Eisai 2012 2015 Adjunctive therapy for POS and PGTC seizures in patients ≥ 12 y Retigabine/ Ezogabine (Potiga®) GSK/Valeant 2011 Adjunctive therapy for POS in patients ≥ 18 y Rufinamide (Banzel®) Eisai 2008 2013 Adjunctive therapy for LGS in patients ≥ 1 y Vigabatrin (Sabril®) Lundbeck 2009 2013 Monotherapy for infantile spasms Adjunctive therapy for CPS in patients ≥ 10 y Clobazam • Summary: 1,5-benzodiazepine (N ring position) – GABAA receptor binding (Cl flux) – Affinity for ω2 instead of ω1 subunit – Thus less sedation and tolerance than 1,4-benzodiazepines (eg, clonazepam) – T1/2 = 18 hours – Metabolized by several CYP with an active metabolite norclobazam – Indicated for adjunctive treatment of multiple seizure types in Canada, Japan; anxiety indication in United Kingdom Clobazam (cont) • Effective for drop seizures in LGSa – Ages 2 to 60; N = 238 – Doses of 0.25 and 1 mg/kg/d – Weekly titration, initial 5 to 10 mg/d – Maximum dosage 40 mg/d • FDA approved for LGS in 2011 (orphan drug approval 2008) • Approved in Europe, Canada a. Ng YT, et al. Neurology. 2011;77:1473-1481.[1] Mean Decrease in Seizure Rate, % Clobazam (cont) (95% CI, 51.5-85.1) P < .0001 80 Drop seizures 70 Total (drop and nondrop) seizures 60 (95% CI, 24.9-57.6) P = .0120 50 41.2 40 30 20 10 68.3 (95% CI, 33.4-65.4) P = .0015 49.4 65.3 (95% CI, 47.2-83.5) P < .0001 45.3 (95% CI, −3.6 to 27.8) 34.8 12.1 (95% CI, 17.2-52.5) P = .0414 (95% CI, 28.1%-62.5% P = .0044 9.3 (95% CI, −7.6 to 26.3) 0 Placebo (n = 57) Low Dosage (n = 53) Ng YT, et al. Neurology. 2011;77:1473-1481.[1] Medium Dosage (n = 58) High Dosage (n = 49) Eslicarbazepine • Demonstrated efficacy up to 1200 mg with daily dosing in 3 pivotal trials (all conducted outside United States) • Effective in monotherapy trials with up to 1600 mg/day • Chemically related; MOA same as with carbamazepine and oxcarbazepine − Forms S-licarbazepine (OXC-MHD = S + R licarbazepine) • Significant drug interactions with oral contraceptives and some other AEDs, including phenytoin • Most common adverse events were dizziness, headache, diplopia, and somnolence Stephen LJ, et al. CNS Drugs. 2011;25:89-107.[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3]; Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]; Sperling MR, et al. Epilepsia. 2015;56:546-55.[5] Eslicarbazepine Chemical Structure • Shares dibenzazepine nucleus with CBZ and OXC, but with 5carboxamide substitute Oxcarbazepine 5% • Primarily converted to S-licarbazepine • 4% converted to R-licarbazepine via oxcarbazepine Eliscarbazepine acetate R(-)-licarbazepine S(+)-licarbazepine Stephen LJ, et al. CNS Drugs. 2011;25:89-107.[2]; Elger C, et al. Epilepsia. 2007;48:497-504.[3] Eslicarbazepine Pivotal Trial Results Percent Reduction in Seizure Frequency and 50% Responder Rate 50 45 40 35 Median Relative Reduction in Seizure Frequency * * * ** 45 * 40 35 † * † † 30 % 30 % Responder Rate 50 25 25 20 20 15 15 10 10 5 5 0 0 Study 301 n = 402 Study 302 n = 393 Placebo Study 303 n = 252 ESL 400 mg Study 301 n = 402 ESL 800 mg *P < .001; †P < .05. McCormack PL, et al. CNS Drugs. 2009;23:71-79.[6] Study 302 n = 393 ESL 1200 mg Study 303 n = 252 Eslicarbazepine Phase 3 Treatment-Emergent Adverse Events Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates BIA-2093-301 BIA-2093-302 Placebo ESL 400 mg/d ESL 800 mg/d (n = 102) (n = 100) (n = 98) Placebo (n = 100) ESL 400 mg/d (n = 96) ESL 800 mg/d (n = 101) Any TEAE 31.4 44.0 50.0 68.0 78.1 83.2 Dizziness 2.0 4.0 14.3 10.0 22.9 29.7 Headache 5.9 5.0 9.2 9.0 8.3 14.9 0 2.0 7.1 4.0 8.3 14.9 2.0 6.0 9.2 17.0 15.6 16.8 Diplopia Somnolence • Other AEs (NR in 301): nausea (range 4.0-11.9), abnormal coordination (5.0-12.9), vomiting (3.0-12.9) NR = not reported. Incidence rates are for approved doses. Elger C, et al. Epilepsia. 2009;50:454-63.[7]; Ben-Menachem E, et al. Epilepsy Res. 2010;89:278-85.[8] Eslicarbazepine Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI 70 65.3% lower confidence limit of historical controls 60 50 40 30 15.6 (8.1-28.7) 20 12.8 (7.5-21.5) 10 0 mg Neurology. 2015:15:46. ESL 1600 mg JacobsonESL MP, 1200 et al. BMC Jacobson MP, et al. BMC Neurology. 2015:15:46.[4] Lacosamide • Lacosamide therapy: − Indicated as monotherapy or adjunctive therapy in the management of POS in adult patients with epilepsy • Enhancement of slow inactivation of sodium channels • Functionalized amino acid with similarity to D-serine (R)-2-acetzamido-N-benzyl-3methoxypropionamide R(+) configuration is active Molecular weight: 250.3 Water solubility: 27 mg/mL Lacosamide Pharmacokinetic Profile • Predictable and doseproportional PK profile • Tmax: 0.25 to 4 hours after oral administration • t½ ~ 13 hours (twice-a-day dosing) • Absolute bioavailability ~100% • Volume of distribution ~0.6 L/kg • Renally excreted (95%) • Low potential for drug-drug interactions Vimpat® PI 2015.[9] • Bioequivalence of oral and IV (30- and 60-minute infusions) • Low protein binding (<15%) • No food interaction has been observed • Low inter- and intra-subject variability (~ 20%) • No influence of gender or race observed Lacosamide: Median Percent Reduction in Seizure Frequency Per 28 Days: Baseline to Maintenance, Per Randomized Dose Median Reduction, % 60 50 SP667a SP754b SP755c ITT – indirect comparison of results between 3 studies 40 * 35 30 20 10 0 21 21 † † † 39 37 36 † † 40 38 LCM 400 mg/d n = 466 LCM 600 mg/d n = 202 26 10 Placebo n = 359 LCM 200 mg/d n = 267 *P < .05; †P < .01. P values based on log-transformed data from pairwise treatment using ANCOVA models. ITT = Intent to treat (randomized subjects receiving at least 1 dose of trial medication with ≥ 1 post-baseline efficacy assessment). The approved daily dose for lacosamide is up to 400 mg/day; 600 mg/d is above the FDA recommended dose. a. Ben-Menachem E, et al. Epilepsia. 2007;48:1308-17.[10]; b. Chung S, et al. Epilepsia. 2010;51:958-67.[11]; c. Halász P, et al. Epilepsia. 2009;50:443-53.[12] Lacosamide Safety and Tolerability: Pooled Pivotal Trial Data Adverse Events Occurring (≥ 10%) During the Treatment Phase Lacosamide Adverse Event (%) MedDRA Preferred Term Placebo n = 364 200 mg/d n = 270 400 mg/d n = 471 600 mg/d n = 203 Total N = 944 Dizziness 8 16 30 53 31 Headache 9 11 14 12 13 Nausea 4 7 11 17 11 Diplopia 2 6 10 16 11 Vomiting 3 6 9 16 9 Fatigue 6 7 7 15 9 Vision blurred 3 2 9 16 8 Coordination abnormal 2 4 7 15 8 Safety population, N = 1308; the approved dosage for lacosamide is up to 400 mg/d. Pooled safety data from 3 randomized, double-blind, placebo-controlled Phase 2/3 clinical trials, each trial included a 4- to 6-week titration phase followed by a 12-week maintenance phase. Safety population included adults (16-70 years of age) with POS, with or without secondary generalization, and taking 1-3 concomitant antiepileptic drugs. Chung S, et al. CNS Drugs. 2010;24:1041-1054.[13] Gil-Nagel A, et al. IEC 2009. Poster 508.[14] Lacosamide Optimizing Combination Therapy ≥ 50% Responder Rate, % ≥ 50% Responder Rate in Patients Taking ≥ 1 Concomitant Sodium-channel Blocking AEDs (ITTm Population*) 80 70 60 50 40 30 20 10 0 Pooled Phase 2/3 Trial Data ‡ † ‡ 44.3 48.6 Current Therapy + LCM 400 mg/d n = 393 Current Therapy + LCM 600 mg/d n = 142 34.8 23.1 Current Therapy + Placebo n = 337 Current Therapy + LCM 200 mg/d n = 244 *The modified ITT (ITTm) population (N = 1116) included all randomized patients receiving ≥ 1 dose of trial medication with ≥ post-baseline efficacy assessment, excluding those who discontinued during the titration phase. †P < .05; ‡ P < .01 vs placebo The approved daily dosage for lacosamide is ≤ 400 mg/day. Sake J, et al. CNS Drugs. 2010;24:1055-1068[15]; Isojarvi J, et al. ECE 2010. Poster 230.[16] Lacosamide Infusion AEs MedDRA Preferred Term Infusion duration 30 min, N = 40 n (%) Headache 3 (8) Dizziness 3 (8) Diplopia 2 (5) Nausea 2 (5) Somnolence 4 (10) Fatigue 0 (0) Abdominal pain, upper 0 (0) WBC urine positive 2 (5) Infusion reactions 3 (8) Krauss G, et al. Epilepsia. 2010;51:951-957.[17] Kaplan-Meier Predicted Exit Percentage Lacosamide Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate Lacosamide 400 mg/d 100 80 65.3% lower confidence limit of historical controls 60 40 20 0 30 32.3 Primary Assessment Secondary Assessment Patients meeting ≥ 1 exit criterion during the Lacosamide Maintenance Phase, FAS Wechsler RT, et al. Epilepsia. 2014;55:1088-1098.[18] Patients meeting ≥ 1 exit criterion, withdrawals due to a TEAE, and withdrawals due to lack of efficacy during the Lacosamide Maintenance Phase, FAS Perampanel Selective Antagonist for the AMPA Subtype of Ionotropic Glutamate Receptors Chemical Structure 5'-(2-cyanophenyl)-1'-phenyl-2,3'bipyridinyl-6'(1'H)-one Perampanel Study 306 Median Percentage Reduction in Seizure Frequency and 50% Responder Rate Perampanel 2 mg Perampanel 4 mg 30.8 (P < .001*) 35 30 23.33 (P = .003*) 25 20 15 Perampanel 8 mg 34.9 (P < .001*) 40 40 13.63 (P = ns*) 10.69 10 Responder Rate Percentage of Patients Median Percentage Change Median Percentage Change (Reduction) in Seizure (Reduction) FrequencyFrequency in Seziure Placebo 35 30 25 20 10 5 0 0 1 Median percentage reductions in seizure frequency per 28 days (ITT)– double-blind phase vs baseline * = vs placebo Krauss GL, et al. Neurology. 2012;78:1408-15.[19] 17.9 20.6 (P = NS*) 15 5 n = 184 n = 180 n = 172 n = 169 28.5 (P = .013*) n = 184 n = 180 n = 172 n = 169 Percentage of patients experiencing ≥ 50% reduction in seizure frequency (ITT) – maintenance (LOCF) period vs baseline Perampanel Treatment-Emergent Adverse Events Incidence of TEAEs (Safety Population) Patients, n (%) 4 mg/d n = 172 Placebo n = 185 2 mg/d n = 180 8 mg/d n = 169 Any AE 101 (54.6) 111 (61.7) 111 (64.5) 121 (71.6) Any TEAE 59 (31.9) 67 (37.2) 77 (44.8) 96 (56.8) Any TEAE leading to study/treatment discontinuation 7 (3.8) 12 (6.7) 5 (2.9) 12 (7.1) Any TEAE leading to dose reduction/interruption 6 (3.2) 3 (1.7) 12 (7.0) 29 (17.2) Any serious TEAE 9 (4.9) 6 (3.3) 6 (3.5) 6 (3.6) Dizziness 18 (9.7) 18 (10.0) 28 (16.3) 45 (26.6) Somnolence 12 (6.5) 22 (12.2) 16 (9.3) 27 (16.0) Headache 16 (8.6) 16 (8.9) 19 (11.0) 18 (10.7) Fatigue 5 (2.7) 8 (4.4) 13 (7.6) 9 (5.3) Upper respiratory tract infection 5 (2.7) 11 (6.1) 6 (3.5) 3 (1.8) Nasopharyngitis 3 (1.6) 7 (3.9) 9 (5.2) 3 (1.8) Gait disturbance 2 (1.1) 1 (< 1) 2 (1.2) 9 (5.3) TEAEs in ≥ 5% (any treatment group) Krauss GL, et al. Neurology. 2012;78:1408-15.[19] Perampanel for the Treatment of Refractory PGTC Seizures Perampanel (N = 81) 80 64.2 60 39.5 40 20 0 30.9 12.3 P < .0001 P = .0019 -20 -40 -38.4 -60 -80 Placebo (N = 81) -76.5 -100 Median % Change From Baseline in PGTC Seizure Frequency 50% PGTC Seizure Responder Rate French JA, et al. Neurology. 2015. [Epub ahead of print].[20] Tonic Clonic Seizure-free Rate Retigabine/Ezogabine • Novel MOA with activation of neuronal M-current mediated by KCNQ (Kv7) voltage-gated potassium channelsa • Half-life of 8 to 11 hoursa • 3x-per-day dosing (extended-release formulation in development) • Limited potential for drug-drug interactions with other AEDsb − Phenytoin and carbamazepine may increase the clearance of retigabine • Smooth muscle relaxant in rodents (bladder distention)b a. Luszczki JJ. Pharmacol Rep. 2009;61:197-216.[21]; b. Bialer M, et al. Epilepsy Res. 2009;83:1-43.[22] Retigabine Dose-Ranging Trial for POS Primary Efficacy Results Intent-to-Treat Population Change in Total Monthly Partial-seizure Frequency, % Retigabine* Placebo 600 mg/d 900 mg/d 1200 mg/d 0 -10 -20 -30 -13.1 -23.4† -40 -29.3† -35.2 -50 *P < .047 for overall difference across retigabine 300, 600, and 1200 mg/d arms †P < .001 for overall difference across all treatment arms Porter RJ, et al. Neurology. 2007;68:1197-1204.[23] Retigabine Dose-ranging Trial for Partial-Onset Seizures Adverse Events Placebo, % (n = 96) Retigabine*, % (n = 301) CNS Related Somnolence 6.3* 17.0-22.6 Confusion 5.2* 5.0-22.6 Dizziness 4.2* 8.0-17.9 10.4* 11.0-17.0 Other Headache Table shows range of incidence in all 3 dosage groups (600, 900, 1200 mg/d). Only AEs with incidence ≥ 17% at the 1200 mg/day dose are shown. *P < .05 for placebo vs the combined retigabine groups for incidence of treatment-emergent AEs. Porter RJ, et al. Neurology. 2007;68:1197-1204.[23] Retigabine Safety Concerns • Retigabine carries a black box warning for retinal abnormalities and potential vision loss − Retinal abnormalities reported > 4 yr of exposure − Seen in one-third of patients • Retigabine can cause blue skin discoloration − Reported in 10% of patients after ≥ 2 yr of exposure − Appears as blue pigmentation on/around lips, finger/toe nail beds, scattered over body − Discoloration of the palate, sclera, and conjunctiva also reported • Urinary retention − Reported in 2% of patients exposed to retigabine Potiga® PI 2015.[24] Rufinamide • Currently has orphan approval for the add-on treatment of seizures associated with LGS • Prolongs the inactive state of voltage-dependent sodium channels and limits sustained repetitive firing of sodiumdependent action potentials • Unsuccessful trials: monotherapy, pediatric POS, primary generalized epilepsy; indication for adjunctive POS not pursued • Limited potential for drug-drug interactions − Valproic acid interaction in children (increases rufinamide levels up to 70% in small children)a Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Rufinamide for Adjunctive Treatment in Lennox-Gastaut Syndrome Efficacy Tonic-atonic seizures 11.7 Reduction, % 10 1.4 0 -10 -20 -30 -32.7 -40 -42.5 -50 Rufinamide Placebo ≥ 50% Responders, % 20 Total seizures 45 40 35 30 25 20 15 10 5 0 42.5 31.1 16.7 10.9 Rufinamide Placebo Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Rufinamide Tolerability Adverse events occurring in patients treated with rufinamide vs placebo Rufinamide Short-term Therapy, % (N = 1875) Long-term Therapy, % (N = 1978) Headache 22.9 29.5 18.9 Dizziness 15.5 22.5 9.4 Fatigue 13.6 17.7 9.0 Somnolence 11.8 n/a 9.1 Nausea 11.4 n/1 7.6 Serious AEs 6.3 13.2 3.9 Adverse Event Placebo Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Rufinamide for Adjunctive Treatment of Partial Seizures 50% Responder Rate Responder Rate, % 40 30 20 10 16* 12† 14‡ 9 4.7 0 Placebo 200 mg/d 400 mg/d 800 mg/d 1600 mg/d Rufinamide *P = .027; †P = .012; ‡P = .016. Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Rufinamide Additional Studies • Monotherapy – 2 studies assessed monotherapy; neither was positive on primary end point • Partial-onset pediatric – Greater reduction in seizure frequency for placebo than rufinamide • Primary generalized tonic-clonic – Reduced frequency of generalized tonic-clonic seizures by 36.4%, compared to 25.6% for placebo, but results were not significant • As a result of these studies, an indication for POS was not pursued Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Rufinamide Dosing • Approved: rapid 1-week titration schedule – In pediatrics, an initial dosage of 10 mg/kg/d with an increase of 10 mg/kg/d every 2 days up to a target dosage of 45 mg/kg/d (maximum 3200 mg/d) – Adults are started at an initial dosage of 400 to 800 mg/d, with an increase of 400 to 800 mg every 2 days up to a maximum dosage of 3200 mg/d • Open-treatment series have shown that gradual rufinamide titration with increases every 5 to 7 days, along with reductions in ineffective concomitant AEDs, may reduce AEs seen during titration in clinical trials, such as somnolence and dizziness Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010:753-55.[25] Vigabatrin • Currently approved as monotherapy for the treatment of infantile spasms and as adjunctive therapy for adult patients with refractory complex partial seizures • MOA believed to be irreversible inhibition of γaminobutyric acid transaminase (GABA-T) • Vigabatrin requires a Risk Evaluation and Mitigation Strategy (REMS) to help manage the risk of permanent vision loss associated with use of the drug Sabril® PI 2013.[26] Krauss GL. Epilepsy Curr. 2009;9:125-129.[27] Vigabatrin Carries a Boxed Warning for Vision Loss • Vigabatrin causes permanent bilateral concentric visual field constriction in 30% to 40% of patients • Visual field defects typically occur within the first 2 years of therapy • Mild to moderately severe and irreversible peripheral field loss • Risk mitigation: registration, severe epilepsy, monitoring of favorable treatment response to justify continued therapy, perimetry testing required every 3 months Sabril® PI 2013.[16] Vigabatrin REMS Refractory Complex Partial Seizures (n = 846) Infantile Spasms (n = 1500) Other (n = 120) Exposed 308 390 53 Naive 493 992 57 Not reported 45 118 10 810 1470 117 Vigabatrin exposure Dispensed vigabatrin Total patients in registry: 2473 Total dispensed vigabatrin: 2397 Pellock JM, et al. Epilepsy Behav. 2011;22:710-717.[28] AEDs in Clinical Trials • Brivaracetam • Benzodiazepine − Nasal sprays − Sublingual (acute treatment) • YKP3089 Summary • New AED therapies are emerging for treating drug-resistant epilepsy • Novel AED mechanisms modulate sodium and potassium ion channels and AMPA receptors • Individual patients may benefit from treatment with one of several new AEDs despite not tolerating or not responding to previous AEDs Abbreviations AEs = adverse events AEDs = antiepileptic drug AMPA = α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANCOVA = analysis of covariance CI = confidence interval CPS = complex partial seizures CYP = cytochrome CBZ = carbazepine ESL = eslicarbazepine FAS = full analysis set FDA = Food and Drug Administration GABA = gamma-aminobutyric acid ITT = intent to treat IV = intravenous KCNQ = potassium voltage-gated channel, KQT-like subfamily, member 1 KM = kaplan-meier Abbreviations (cont) LCM = lacosamide LGS = Lennox-Gastaut syndrome LOCF = last observation carried forward MedDRA = Medical Dictionary for Regulatory Activities mITT = modified intent to treat MOA = mechanism of action OXC = oxcarbazepine OXC-MHD = oxcarbazepine monohydroxy derivative PK = pharmacokinetic PGTC = primary generalized tonic-clonic POS = partial-onset seizures REMS = risk evaluation and mitigation strategy TEAE = treatment-emergent adverse event WBC = white blood cell References 1. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77:1473-1481. 2. Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25:89-107. 3. Elger C, Bialer M, Cramer JA, et al. Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia. 2007;48:497-504. 4. Jacobson MP, Pazdera L, Bhatia P, et al; study 046 team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurology. 2015:15:46. 5. Sperling MR, Harvey J, Grinnell T, et al; 045 Study Team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015;56:546-555. 6. McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs. 2009;23:71-79. References (cont) 7. Elger C, Halász P, Maia J, et al; BIA-2093-301 Investigators Study Group. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-463. 8. Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89:278-285. 9. Vimpat® [package insert]. Smyrna, GA; UCB, Inc; 2015. 10. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. 11. Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partialonset seizures: a randomized controlled trial. Epilepsia. 2010;51:958-967. 12. Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453. References (cont) 13. Chung S, Ben-Menachem E, Sperling MR, et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010:24;10411054. 14. Gil-Nagel A, Biton V, Fountain N, et al. The safety and tolerability of lacosamide in randomized, double-blind, placebo-controlled phase II/III trials. Poster presented at: 28th International Epilepsy Congress; June-July 2009; Budapest, Hungary. P508. 15. Sake JK, Hebert D, Isojärvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs. 2010;24:1055-1068. 16. Isojärvi J, Hebert D, Doty P, et al. Evaluation of lacosamide efficacy and safety as adjunctive therapy in patients receiving traditional sodium channel blocking AEDs. Poster presented at: 9th European Congress on Epileptology; June-July 2010; Rhodes, Greece. P230. 17. Krauss G, Ben-Menachem E, Mameniskiene R, et al; SP757 Study Group. Intravenous lacosamide as short-term replacement for oral lacosamide in partial-onset seizures. Epilepsia. 2010;51:951-957. References (cont) 18. Wechsler RT, Li G, French J, et al; ALEX-MT Study Group. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study. Epilepsia. 2014;55:1088-1098. 19. Krauss GL, Serratosa JM, Villanueva VE, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:14081415. 20. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial. Neurology. 2015 [Epub ahead of print]. 21. Luszczki JJ. Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009;61:197-216. 22. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res. 2009;83:1-43. 23. Porter RJ, Partiot A, Sachdeo R, et al. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology. 2007;68:1197-204. References (cont) 24. Potiga® [package insert]. Research Triangle Park, NC: 2015. 25. Krauss GL, Darnley S. Rufinamide. In: Wyllie E, et al, ed. Wyllie's Treatment of Epilepsy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:753-755. 26. Sabril® [package insert]. Deerfield, IL: Lundbeck; 2013. 27. Krauss GL. Evaluating risks for vigabatrin treatment. Epilepsy Curr. 2009;9:125-129. 28. Pellock JM, Faught E, Sergott RC, et al. Registry initiated to characterize vision loss associated with vigabatrin therapy. Epilepsy Behav. 2011;22:710-717.