1. New Antiepileptic Medications
Drug Profiles, Efficacy, Safety, and Tolerability

2. Evolving Epilepsy Therapy
Treatments
First-generation AEDs s
Second-generation AEDs
Third-generation AEDs
2006-today
Orphan AEDs
Needs
Tolerability
Safety
Added efficacy
Content Slide Layout: TEXT

3. Recent AEDs Drug Company FDA Approval 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
Adjunctive therapy for POS and PGTC seizures in patients ≥ 12 y
Retigabine/
Ezogabine (Potiga®)
GSK/Valeant
Adjunctive therapy for POS in patients ≥ 18 y
Rufinamide (Banzel®)
Adjunctive therapy for LGS in patients ≥ 1 y
Vigabatrin (Sabril®)
2009
Monotherapy for infantile spasms
Adjunctive therapy for CPS in patients ≥ 10 y

4. 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

5. 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: [1]

6. Mean Decrease in Seizure Rate, %
Clobazam (cont)
Mean Decrease in Seizure Rate, %
(95% CI, −3.6 to 27.8)
(95% CI, −7.6 to 26.3)
(95% CI, )
P = .0414
(95% CI, )
P < .0001
(95% CI, )
P = .0015
Ng YT, et al. Neurology. 2011;77: [1]

7. 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: [2]; Elger C, et al. Epilepsia. 2007;48: [3]; Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]; Sperling MR, et al. Epilepsia. 2015;56: [5]

8. Eliscarbazepine acetate
Eslicarbazepine
Chemical Structure 5%
Oxcarbazepine
Eliscarbazepine acetate
R(-)-licarbazepine
S(+)-licarbazepine
Shares dibenzazepine nucleus with CBZ and OXC, but with 5- carboxamide substitute
Primarily converted to S-licarbazepine
4% converted to R-licarbazepine via oxcarbazepine
Stephen LJ, et al. CNS Drugs. 2011;25: [2]; Elger C, et al. Epilepsia. 2007;48: [3]

9. Median Relative Reduction in Seizure Frequency
Eslicarbazepine Pivotal Trial Results
Percent Reduction in Seizure Frequency and 50% Responder Rate
Median Relative Reduction in Seizure Frequency
Responder Rate 50 50 * * * 45 45 † 40 * 40 *
* * † 35 35 † 30 30 % % 25 25 20 20 15 15 10 10 5 5
Study 301
Study 302
Study 303
Study 301
Study 302
Study 303
n = 402
n = 393
n = 252
n = 402
n = 393
n = 252
Placebo
ESL 400 mg
ESL 800 mg
ESL 1200 mg
*P < .001; †P < .05.
McCormack PL, et al. CNS Drugs. 2009;23:71-79.[6]

10. Eslicarbazepine Phase 3 Treatment-Emergent Adverse Events
Treatment-Emergent Adverse Events With ≥ 10% Incidence Rates
BIA
BIA
Placebo
(n = 102)
ESL 400 mg/d
(n = 100)
ESL 800 mg/d
(n = 98)
(n = 96)
(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
Diplopia
7.1
Somnolence
6.0
17.0
15.6
16.8
Other AEs (NR in 301): nausea (range ), abnormal coordination ( ), vomiting ( )
NR = not reported.
Incidence rates are for approved doses.
Elger C, et al. Epilepsia. 2009;50: [7]; Ben-Menachem E, et al. Epilepsy Res. 2010;89: [8] 10

11. Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI
Eslicarbazepine Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate
65.3% lower confidence limit of historical controls
15.6
( )
Cumulative Exit Rate at 112 Days (KM Estimate), %; 95% CI
12.8
( )
Jacobson MP, et al. BMC Neurology. 2015:15:46.
Jacobson MP, et al. BMC Neurology. 2015:15:46.[4]

12. (R)-2-acetzamido-N-benzyl-3-methoxypropionamide
Lacosamide
(R)-2-acetzamido-N-benzyl-3-methoxypropionamide
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(+) configuration is active Molecular weight: 250.3
Water solubility: 27 mg/mL

13. Lacosamide Pharmacokinetic Profile
Predictable and dose- proportional 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
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
Vimpat® PI 2015.[9]

14. ITT – indirect comparison of results
Lacosamide: Median Percent Reduction in Seizure Frequency Per 28 Days:
Baseline to Maintenance, Per Randomized Dose
n = 359 n = n = n = 202
ITT – indirect comparison of results
between 3 studies
Median Reduction, % 21 37 38 † 10 26 39 40 36 * 35 20 30 50 60
SP667a
SP755c
SP754b
Placebo LCM 200 mg/d LCM 400 mg/d LCM 600 mg/d
*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: [10]; b. Chung S, et al. Epilepsia. 2010;51: [11]; c. Halász P, et al. Epilepsia. 2009;50: [12]

15. Lacosamide Safety and Tolerability: Pooled Pivotal Trial Data Adverse Events Occurring (≥ 10%) During the Treatment Phase
Adverse Event (%)
MedDRA Preferred Term
Placebo n = 364
Lacosamide
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 17
Diplopia 2 6 10
Vomiting 3
Fatigue 15
Vision blurred
Coordination abnormal
The most common adverse events (AEs) seen in the lacosamide pivotal trials are listed on the slide.
The most frequent treatment-emergent adverse events (TEAEs) occurring in lacosamide-treated patients during the treatment phase (i.e., titration plus maintenance) were:1
dizziness (31% of lacosamide-treated patients versus 8% of placebo-treated patients)
headache (13% versus 9%)
nausea (11% versus 4%)
diplopia (11% versus 2%).
Most of the reported AEs were mild to moderate in intensity.2
The incidence of severe AEs (SAEs) was 10.4% for all lacosamide-treated patients versus 4.7% of placebo-treated patients.2
The most frequently reported drug-associated SAE was dizziness (3.7%), which occurred at a higher incidence in patients randomised to the lacosamide 600 mg/day† group (9.4%). The incidence of severe dizziness was similar in patients in the lacosamide 200 mg/day (1.9%) and 400 mg/day (2.3%) groups.2
• The maximum recommended daily dose for lacosamide is up to 400 mg/day.
Source:
1. 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 (12): 1041–1054.
2. Gil-Nagel A, Biton V, Fountain NB, et al. The safety and tolerability of lacosamide in randomized, double-blind, placebo-controlled phase II/III clinical trials. Poster presented at the 28th International Epilepsy Congress, Budapest 2009.
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: [13] Gil-Nagel A, et al. IEC Poster 508.[14]

16. Pooled Phase 2/3 Trial Data
Lacosamide Optimizing Combination Therapy ≥ 50% Responder Rate in Patients Taking ≥ 1 Concomitant Sodium-channel Blocking AEDs (ITTm Population*)
Pooled Phase 2/3 Trial Data
≥ 50% Responder Rate, % ‡
n = 337
n = 244
n = 393
n = 142 ‡ †
Overall, 82% (1,077/1,308; safety population) of patients were using at least one concomitant traditional sodium-channel blocking AED.1 In both the pooled pivotal trial population and in the group of patients treated with traditional sodium-channel blocking AEDs, patients treated with lacosamide 200–600 mg/day showed higher ≥50% responder rates compared to placebo-treated patients (lacosamide 400 mg/day and 600 mg/day, p<0.01).1
The median percent reduction in seizure frequency per 28 days was significantly greater for the lacosamide 200–600 mg/day treatment groups compared with placebo-treated patients in both the pooled pivotal trial population and in the group of patients treated with concomitant traditional sodium-channel blocking AEDs.1
Source:
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 (12): 1055–1068.
*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: [15]; Isojarvi J, et al. ECE Poster 230.[16]

17. Infusion duration 30 min, N = 40 n (%)
Lacosamide Infusion
AEs
MedDRA
Preferred Term
Infusion duration 30 min, N = 40 n (%)
Headache
3 (8)
Dizziness
Diplopia
2 (5)
Nausea
Somnolence
4 (10)
Fatigue
0 (0)
Abdominal pain, upper
WBC urine positive
Infusion reactions
Adverse event rates were low and consistent with that seen with oral lacosamide.
Importantly, AEs do not increase with shorter infusion durations
From Krauss AAN 2008.
Krauss G, et al. Epilepsia. 2010;51: [17]

18. Lacosamide Monotherapy Conversion Trial Kaplan–Meier-Estimated 112-Day Exit Rate
65.3% lower confidence limit of historical controls
Kaplan-Meier Predicted Exit Percentage
Patients meeting ≥ 1 exit criterion during the Lacosamide Maintenance Phase, FAS
Patients meeting ≥ 1 exit criterion, withdrawals due to a TEAE, and withdrawals due to lack of efficacy during the Lacosamide Maintenance Phase, FAS
Wechsler RT, et al. Epilepsia. 2014;55: [18]

19. 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one
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

20. Perampanel Study 306
Median Percentage Reduction in Seizure Frequency and 50% Responder Rate
Placebo
Perampanel 2 mg
Perampanel 4 mg
Perampanel 8 mg
(P < .001*)
(P = .013*)
Median Percentage Change (Reduction) in Seizure Frequency
Percentage of Patients
(P = NS*)
n = 184
n = 180
n = 172
n = 169
Median percentage reductions in seizure frequency per 28 days (ITT)– double-blind phase vs baseline
Percentage of patients experiencing ≥ 50% reduction in seizure frequency (ITT) – maintenance (LOCF) period vs baseline
* = vs placebo
Krauss GL, et al. Neurology. 2012;78: [19]

21. Perampanel Treatment-Emergent Adverse Events
Incidence of TEAEs (Safety Population)
Patients, n (%)
Placebo
n = 185
2 mg/d
n = 180
4 mg/d
n = 172
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)
TEAEs in ≥ 5% (any treatment group)
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
11 (6.1)
3 (1.8)
Nasopharyngitis
3 (1.6)
7 (3.9)
9 (5.2)
Gait disturbance
2 (1.1)
1 (< 1)
2 (1.2)
Krauss GL, et al. Neurology. 2012;78: [19]

22. Perampanel for the Treatment of Refractory PGTC Seizures
French JA, et al. Neurology [Epub ahead of print].[20]

23. 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: [21]; b. Bialer M, et al. Epilepsy Res. 2009;83:1-43.[22]

24. Retigabine Dose-Ranging Trial for POS Primary Efficacy Results
Intent-to-Treat Population
Partial-seizure Frequency, %
Change in Total Monthly
Retigabine*
*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: [23]

25. Retigabine Dose-ranging Trial for Partial-Onset Seizures Adverse Events
Placebo, %
(n = 96)
Retigabine*, %
(n = 301)
CNS Related
Somnolence
6.3*
Confusion
5.2*
Dizziness
4.2*
Other
Headache
10.4*
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: [23]

26. 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]

27. 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 sodium- dependent 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: [25]

28. Rufinamide for Adjunctive Treatment in Lennox-Gastaut Syndrome
Efficacy
Tonic-atonic seizures
Total seizures
Reduction, %
≥ 50% Responders, %
Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: [25]

29. Rufinamide Tolerability
Adverse events occurring in patients treated with rufinamide vs placebo
Adverse Event
Rufinamide
Placebo
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
Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: [25]

30. Rufinamide for Adjunctive Treatment of Partial Seizures 50% Responder Rate
14‡ 9
4.7
16*
12† 10 20 30 40
Placebo
200 mg/d
400 mg/d
800 mg/d
1600 mg/d
Responder Rate, %
Rufinamide
*P = .027; †P = .012; ‡P = .016.
Krauss GL, et al. Wyllie's Treatment of Epilepsy: Principles and Practice. 2010: [25]

31. 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: [25]

32. 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: [25]

33. 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 γ- aminobutyric 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: [27]

34. 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]

35. Refractory Complex Partial Seizures
Vigabatrin REMS
Refractory Complex Partial Seizures
(n = 846)
Infantile Spasms
(n = 1500)
Other
(n = 120)
Vigabatrin exposure
Exposed
308
390 53
Naive
493
992 57
Not reported 45
118 10
Dispensed vigabatrin
810
1470
117
Total patients in registry: 2473
Total dispensed vigabatrin: 2397
Pellock JM, et al. Epilepsy Behav. 2011;22: [28]

36. AEDs in Clinical Trials
Brivaracetam
Benzodiazepine
Nasal sprays
Sublingual (acute treatment)
YKP3089

37. 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

38. 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

39. 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

40. References
1. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77: Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25: 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: 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: 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: McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs. 2009;23:71-79.

41. References (cont)
7. Elger C, Halász P, Maia J, et al; BIA 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: Ben-Menachem E, Gabbai AA, Hufnagel A, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89: Vimpat® [package insert]. Smyrna, GA; UCB, Inc; 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: Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51: 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:

42. 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; 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. P 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: 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. P 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:

43. References (cont)
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44. References (cont)
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