Download Drug Profiles, Efficacy, Safety, and Tolerability

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.
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