Download Treating Epilepsy with newer anti-epileptic drugs

New AEDs in Pediatric Epilepsy
John M. Pellock, MD
Professor and Chairman
Division of Child Neurology
Virginia Commonwealth University
Medical College of Virginia Hospitals
Richmond, Virginia
Clinical Utility of Older and Newer AEDs:
Treatment Options
Seizure type
Partial
Simple,
Complex,
Secondarily
generalized
PHT, CBZ, PB,
GBP, TGB,
OXC, PGB, LCM
Tonicclonic
Tonic
Generalized
Infantile
spasms
Atonic
ACTH, VGB,
TGB?, LTG?,
TPM?, ZNS?
Myoclonic
PHT, CBZ,
OXC, GBP,
TGB
VPA, LTG, TPM, ZNS, FBM, LEV, RFM
Pellock JM. Epilepsy in Patients with Multiple Handicaps. In: Wyllie E (ed).
The Treatment of Epilepsy: Principles and Practice, 5th Edition.
Baltimore:Lippincott Williams and Wilkins, 2009.
Absence
ESX
Anticonvulsant Drugs Marketed in the U.S.
1912
Phenobarbital (Luminal®)
Winthrop
1993
Felbamate (Felbatol®)
Carter-Wallace
1935
Mephobarbital (Mebaral®)
Winthrop
1993
Gabapentin (Neurontin®)
Parke-Davis
1938
Phenytoin (Dilantin®)
Parke-Davis
1994
Lamotrigine (Lamitcal®)
GlaxoSmithKline
1947
Mephenytoin (Mesantoin®)
Sandoz
1996
Topiramate (Topamax®)
Ortho-McNeil
1954
Primidone (Mysoline®)
Ayerst
1997
Tigabine (Gabitril®)
Abbott
1957
Methsuximide (Celontin®)
Parke-Davis
2000
Zonisamide (Zonegran®)
Elan Pharma
1957
Ethotoin (Peganone®)
Abbott
2000
Levetiracetam (Keppra®)
UCB Pharma
1960
Ethosuximide (Zarontin®)
Parke-Davis
2000
Oxcarbazepine (Trileptal®)
Novartis
1968
Diazepam (Valium®)
Roche
2000
Pregabalin (Lyrica®)
Pfizer
1974
Carbamazepine (Tegretol®)
Ciba-Geigy
2008
Banzel (Rufinamide®)
Eisai
1975
Clonazepam (Klonopin®)
Roche
2009
Vimpat (Lacosemide®)
UCB
1978
Valproic acid (Depakene®)
Abbott
2009
Sabril (Vigabtrin®)
Lundbeck
1981
Clorazepatae (Tranxene®)
Abbott
2010
ACTH (Acthar, IS)
Questcor
Felbamate
 Efficacy

Partial, generalized, Lennox-Gastaut syndrome

Infantile spasms, myoclonic
 Adverse events

Neurotoxicity, GI, anorexia, weight loss, insomnia

Aplastic anemia, hepatotoxicity
 Advantages: children awaken, broad spectrum
 Disadvantages: titration, drug interactions,
life-threatening adverse events
Felbamate
Hepatotoxicity
 FBM 1:26,000 - 1:34,000
 VPA 1:10,000 - 1:49,000
Aplastic anemia risk
 FBM
27 - 209 :1 million
 General population
2 - 2.5 :1 million
 FBM
20x CBZ
Felbamate: Aplastic Anemia
High-Risk Profile
 Adult vs. children (<13 yr)
 Prior idiosyncratic reaction
 Prior cytopenia
 Autoimmune disease
Gabapentin
 Efficacy

Partial with /without generalization,
refractory/benign

Adjunctive, monotherapy
 Adverse events

Neurotoxicity, hyperactivity (DD)
 Advantages: fast titration, well tolerated
 Linear pK, no interactions
 Disadvantages: perception
JM Pellock, 2003
Gabapentin in Children:
Dosing vs. Levels
mg/kg/day
µg/mL
20
1-2.5
20-30
4.8 (0.8-7.9)
60-100
8-16
Initial studies: 5 to 20-30 mg/kg/day
Now: 10-20 to 60-100 mg/kg/day
Increase daily or every few days
Significant Reduction in Seizure Frequency
with Pregabalin
Median % Change from Baseline
60
French et al.
50
*
35
40
Arroyo et al.
*
51
*
43
*
37
*P≤0.01 vs placebo
Beydoun et al.
*
48
*
36
30
*
17
20
10
0
-10
1
-1
0
PBO
75
BID
150
BID
300
BID
Pregabalin Dose (mg)
PBO
50
TID
200
TID
Pregabalin Dose (mg)
PBO
300
BID
200
TID
Pregabalin Dose (mg)
The most common adverse events occurring during all controlled clinical trials for patients taking pregabalin
vs those taking a placebo were dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and
thinking abnormal (primarily difficulty with concentration/attention).
Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Arroyo et al. Epilepsia 45:20-27, 2004.
French et al. Neurology 60:1631-1637, 2003. Beydoun et al. Neurology 64:475-480, 2005.
Pregabalin Dosing Instructions
 If needed, may increase to 300 mg/day within 1 wk
 Some postherpetic neuralgia and partial-onset seizure patients may benefit
from up to 600 mg/day based on individual response and tolerability
 Dosage adjustment may be necessary in patients with renal insufficiency,
based on creatinine clearance
 Pregabalin may be taken with or without food
 Adverse events may increase with dose
Lyrica® (pregabalin) capsules CV [package insert]. New York, NY: Pfizer Inc; 2005
Lamotrigine
 Efficacy

Partial, generalized, Lennox-Gastaut syndrome
 Adverse events

Neurotoxicity, rash, insomnia

Severe rash 1:100 - 1:200
 Advantages: children awaken, broad spectrum
 Disadvantages: slow titration, dose AED
dependent, life-threatening rash/hypersensitivity
Lamotrigine for LGS: Efficacy
% Patients
50
40
36%
34%
32%
30
Seizure
20
Reduction
10
Frequency
(%)
0
-10
9%
N=78
N=89
LTG
Placebo
9%
N=75
N=89
N=60
-10%
-20
N=64
-30
All Major
Seizures
p=0.002
Drop Attacks
p=0.01
Tonic-Clonic
Seizures
p=0.03
Median change from baseline in weekly seizure counts
during treatment weeks 1-16
Motte J et al. N Engl J Med 337:1807-1812, 1997
Lamotrigine: Adjunctive Therapy for Partial
Seizures in Children Aged 2-16 Years
% of Patients with >50% Seizure Reduction
(All Partial Seizures)
p<0.001
50
% Patients
45
40
p=0.004
p=0.001
p=0.003
45%
LTG
Placebo
42%
33%
35
28%
30
25
20
15
25%
16%
10
5
3%
1%
0
Partial Seizure Frequency
1-18
7-18
Weeks
Secondary Generalized
Seizure Frequency
1-18
7-18
Weeks
Lamotrigine: Typical Absence
Seizures in Children
Maximum Dose
mg/kg/day
N
Seizure-Free
7
20
12 (60%)
15
22
18 (82%)
All patients
42
30 (71%)
Frank LM et al. Epilepsia 40:973-979, 1999
Lamotrigine Rash
 Potentially severe, life threatening

Adults: 1:1,000

Children: 1:100 - 1:200
 Overall, rash increased by VPA; rapid escalation
 Differentiate benign (10%) from serious cases
 Recommend discontinuing LTG if rash occurs
 Risk of discontinuation in patients with rash Hx:
Overall
2.8x
AED rash 3.8x
AED Rash and Pharmacogenetics
 SJS/TEN 2 to 3 x greater prevalence in Han Chinese
 With CBZ 25-33% Asian vs. 5-6% Europeans
 HLA-B 1502 allele in 59/60 Han Chinese in Taiwan
vs. 6/144 controls and 1/31 maculopapular or HSS
 SJS/TEN susceptibility locus maps tightly and
presumptively activates CD8 T lymphocyte
Questions remain:
Screen all Han Chinese? LTG? Other populations with
same/other alleles?
Miller, Ep Curr, 2008
LTG Aseptic Meningitis
 FDA Revised label 2010
 40 cases reported in 5 year period (46 million Rx)
 Symptoms: headache, fever, chills, nausea, vomiting,
stiff neck, rash, light sensitivity, drowsiness, confusion
 Most resolved after discontinuation; in I5 symptoms
returned when resumed LTG
JAMA, 2010.
Topiramate
 Efficacy

Partial, generalized, Lennox-Gastaut
syndrome, infantile spasms
 Adverse events

Neurotoxicity, cognitive (language)

Weight loss, insomnia, renal stones
 Advantages: broad spectrum
 Disadvantages: slow titration as add-on
therapy, cognitive
Topiramate – Protocol YD
50% Responders: Double-Blind vs. Baseline
% Responder
50
47%
46%
p=0.013*
p=0.027*
400 mg
(N=45)
600 mg
(N=46)
40
27%
30
20
18%
p=0.620*
10
0
Placebo
(N=45)
200 mg
(N=45)
Randomized Dose Group
*Comparison to placebo
Faught E et al. Neurology 46:1684, 1996
Cognitive Outcomes: TPM vs. VPA
 Double-blind, randomized, parallel (17 variables)
 Add-on to CBZ in epilepsy patients
Titration (mg/day/wk)
Completers
Dropouts
Mean dose (mg/day)
TPM
VPA
25 mg
24
8
251
150 mg
29
4
1,384
 VPA >TPM on verbal memory
Titration = 12 wks; maintenance = 8 wks
Aldenkamp AP et al. 2000
Topiramate: Dosing and Administration
Adjunctive therapy, 2-16 yrs, mg/kg/day
Starting dose
~1-3 nightly
Increments
1-3 every 1-2 wks
Target dose*
5-9
Monotherapy, children, 6-15 yrs
Week 1
0.5 mg/kg nightly
Week 2
0.5 mg/kg b.i.d.
Week 3
1 mg/kg b.i.d.
Target dose*
100 mg/day
If >100 mg needed, dose can be
increased weekly by 50 mg/day
*Initial evaluation point
Topiramate in Infantile Spasms:
Open-Label Studies
Study 1 (N=11):
Stabilization Outcomes*
>50% spasm
reduction
9/11 (82%)
Spasm-free
5/11 (45%)
Dose, mean (range),
mg/kg/day
Study 2 (N=21)
>50% seizure** reduction
15 (8-24)
*Glauser TA et al. Epilepsia 39:1324, 1998
**Spasms + ancillary seizures
Titration/
stabilization
5/21 (24%)
Entire study
6/21 (29%)
Spasm-free >7 days
11/21 (52%)
Dose, mean (range),
mg/kg/day
17 (4-46)
Topiramate vs. Valproate in JME:
Open-Label Randomized Study
% Patients Seizure-Free
(12-wk maintenance)
TPM (N=19)
VPA (N=9)
Observations
 Efficacy similar
 Adverse event profiles
Myoclonic
7/14 (50%)
6/9 (67%)
PGTCS
8/12 (67%)
3/4 (75%)
Absence
2/2 (100%)
1/2 (50%)
All seizures
9/19 (47%)
3/9 (33%)
Levisohn PM et al. Epilepsia 44(Suppl 9):267, 2003
different

Similar neurotoxicity
scale ratings

VPA: More systemic
toxicity
Percentage Reduction in Partial Seizures
During Treatment Period to 60 mg/kg/day
Median % Change
from Baseline
% Reduction in Weekly
Seizure Frequency
Over
Placebo
50
p=0.0002
40
30
43.3 %
p<0.0001
26.8 %
16.3 %
20
10
0
LEV
Placebo
LEV
Efficacy of Levetiracetam in
Myoclonic Seizures
 N=121; 12-65 yrs

Refractory generalized epilepsy and myoclonic seizures

LEV 3000 mg/day or placebo added to AEDs for 12 wks
Placebo
LEV
>50% seizure reduction
23.3%
58.3%
Headache
23.3%
21.6%
Treatment-limiting
adverse events
1
Noachtar S. Presented at: 26th International Epilepsy Congress;
August 29, 2005; Paris, France.
2
Adverse Events Overview
Patients, %
Infection
Somnolence
Accidental injury
Vomiting
Headache
Anorexia
Rhinitis
Hostility
Cough increased
Nervousness
Asthenia
Dizziness
Agitation
Albuminuria
Ecchymosis
Depression
LEV
(N=101)
Placebo
(N=97)
28.7
22.8
16.8
14.9
13.9
12.9
12.9
11.9
10.9
9.9
8.9
6.9
5.9
4.0
4.0
3.0
28.9
11.3
10.3
13.4
14.4
8.2
8.2
6.2
7.2
2.1
3.1
2.1
1.0
0.0
1.0
1.0
Zonisamide: Pivotal Clinical Trials
Study 2 & 3: % Responders
60
ZNS
55
50
40
35
27
30
20
7.5
10
0
>25%
>50%
>75%
>100%
Zonisamide: Progressive Myoclonic Epilepsies
 PME of Unverricht-Lundborg type (N=2):
Marked decrease in seizure frequency and
significant improvement*1
 PME of Unverricht-Lundborg type (N=7) and
Lafora Body (N=1): dramatic seizure frequency
reduction for 2-3 years*2
*Patients continued to receive BPS and benzodiazepine
TR et al. Neurology 38:928-931, 1998
2Kyllerman M et al. Epilepsy Res 29:109-114, 1998
1Henry
Zonisamide in Juvenile Myoclonic Epilepsy
 Design

Retrospective; N=15 ages 11-20 yrs

ZNS 200-500 mg/day as monotherapy (N=13)
or add-on therapy (N=2)
 Results


>50% seizure reduction in 80%
Response within 4-8 wks

Seizure-free rates:
 GTC, 69%
 Myoclonic, 62%
 Absence, 38%

Transient adverse events during titration in 3 patients (20%):
headache, weight loss, dizziness
Kothare SV et al. Epileptic Disord 6:267-270, 2004
Zonisamide: Oligohydrosis
 13 reports during 11 yrs of marketing in Japan1,2

Age: 1.6-17 yrs

Heat stroke requiring hospitalization, N=2

All cases reported during unusually hot summers

Doses: 5-15 mg/kg/day

No reported cases of decreased sweating in
US and European development program

Body temperature should be carefully monitored
in pediatric patients
1Zonegran™(zonisamide)
prescribing information, Elan Pharmaceuticals.
2Masuda Y et al. CNS Drug Reviews 4:341-360, 1998
Rufinamide
 Approved in November, 2008 as adjunctive
treatment of seizures associated with
Lennox-Gastaut syndrome
 Approval based on single pivotal trial
(orphan drug status)
 Triazole derivative; exact mechanism
of action unknown

Thought to regulate voltage dependent
sodium channels
Rufinamide for Generalized Seizures Associated
with Lennox-Gastaut Syndrome
45
40
40
30
p=0.002
31.1
p=0.0045
25
20
15
16.7
35
% Reduction
% Responders
35
42.5
45
42.5
32.7
30
p=0.0015
25
20
15
11.7
10
10.9
10
5
5
0
0
-5
Total seizures
p<0.0001
Tonic-atonic
seizures
Rufinamide
Glauser T et al. Neurology 70:1950-1958, 2008
-1.4
Total seizures
Placebo
Tonic-atonic
seizures
AEs with Incidence >5% vs. Placebo in
Subjects with Lennox-Gastaut Syndrome
Total no. patients studied*
Somnolence
Vomiting
Pyrexia
Fatigue
Decreased appetite
Nasopharyngitis
Headache
Rash
Rhinitis
Ataxia
Rufinamide, %
N=74
Placebo, %
N=64
24.3
21.6
13.5
9.5
9.5
9.5
6.8
6.8
5.4
5.4
12.5
6.3
17.2
7.8
4.7
3.1
4.7
1.6
4.7
0
*Double-blind adjunctive therapy study in LGS; includes only AEs occuring
at higher incidences with Rufinamide than placebo
Glauser T et al. Neurology 70:1950-1958, 2008
Rufinamide
 34% protein bound; Tmax 6 hr fed, 8 hr fasted; half life 8-12 hr
 Hepatic metabolism to inactive metabolite
 Mild-moderate CYP3A4 induction, reduces oral contraceptive
efficacy
 Few drug interactions (phenytoin and phenobarbital increase
clearance by ~25%)
 VPA increases RFM 16-70%, concentration dependent
 Twice daily dosing (dose 400 to 2400 mg/day in 60 kg
individual)
Hakimian S, et al. Expert Opin Pharmacother. 2007 8:1931-1940
Lacosamide in the Treatment of
Complex Partial Seizures
45
Responder Rates
40
50% Responders
75% Responders
35
39.7%**
34.1%*
30
25
22.6%
19.1%
20
13.5%
15
10
9.2%
5
0
Placebo
(n=359)
LCM 200 mg/day
(n=267)
LCM 400 mg/day
(n=466)
Percentage of patients with at least 50 or 75% reduction in seizure
frequency from baseline period to maintenance period
Intent to treat: SP667, SP754, SP755 *p<0.05; ** p<0.001
Beydoun A et al. Expert Review 9:33-42, 2009
AEs Leading to Discontinuation (≥1% of Subjects in
Lacosamide Total) during Treatment Phase (SS†)
(SP667, SP754, SP755)
AE Leading to
Discontinuation
Placebo
N=364
n (%)
LCM
200mg/day
N=270
n (%)
LCM
400mg/day
N=471
n (%)
LCM
600mg/day
N=203
n (%)
LCM
Total
N=944
n (%)
Any event
17 (4.7)
22 (8.1)
81 (17.2)
58 (28.6)
161 (17.1)
Dizziness
1 (0.3)
1 (0.4)
20 (4.2)
35 (17.2)
56 (5.9)
0
1 (0.4)
6 (1.3)
11 (5.4)
18 (1.9)
Vomiting
1 (0.3)
1 (0.4)
11 (2.3)
6 (3.0)
18 (1.9)
Diplopia
1 (0.3)
4 (1.5)
10 (2.1)
4 (2.0)
18 (1.9)
Nausea
0
1 (0.4)
8 (1.7)
8 (3.9)
17 (1.8)
Vertigo
0
3 (1.1)
4 (0.8)
5 (2.5)
12 (1.3)
Vision blurred
0
1 (0.4)
3 (0.6)
6 (3.0)
10 (1.1)
4 (1.1)
2 (0.7)
8 (1.7)
0
10 (1.1)
Coordination abnormal
Convulsion
†SS
– Safety Set: Subjects who received trial medication
Vigabatrin
 Approved January, 2009 for treatment of infantile
spasms (orphan drug status)

Only drug approved in the US for treatment of IS
 Approved January, 2009 for treatment of patients
with complex partial seizures who have not
responded to several AEDs
 Previously approved years ago in other countries
for partial seizures
Treatment Responders by
Vigabatrin Dose and Etiology
60
52%
% Responders
50
40
36%
30
27%
20
11%
10%
10
0
Low
High
(75)
(67)
Vigabatrin dose
Elterman RD et al. Neurology 57:1416-1421, 2001
10%
Tuberous Dysgenetic Postnatal Idiopathic or
cryptogenic
sclerosis
(31)
(45)
(41)
(25)
Etiology
Vigabatrin and Visual Field Defects
 Prevalence in adults ~30-50%

May be less in infants
 Concentric constriction: average peripheral
field 65° (normal 90°); central vision not affected
 Typically asymptomatic
 Earliest occurrence ~11 months
 Appears irreversible, but does not progress
 Appears idiosyncratic, not clearly dose related
Wheless JW et al. Neurotherapeutics 4:163-172, 2007