New AEDs in Pediatric Epilepsy John M. Pellock, MD Professor and Chairman Division of Child...
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Transcript of New AEDs in Pediatric Epilepsy John M. Pellock, MD Professor and Chairman Division of Child...
New AEDs in Pediatric Epilepsy
John M. Pellock, MDProfessor and Chairman
Division of Child NeurologyVirginia Commonwealth University
Medical College of Virginia HospitalsRichmond, Virginia
Clinical Utility of Older and Newer AEDs: Treatment Options
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.
VPA, LTG, TPM, ZNS, FBM, LEV, RFM
Seizure type
Partial GeneralizedInfantilespasms
Simple,Complex,
Secondarilygeneralized
PHT, CBZ, PB, GBP, TGB,
OXC, PGB, LCM
Tonic-clonic
Tonic Atonic Myoclonic Absence
PHT, CBZ,OXC, GBP,
TGBESX
ACTH, VGB,TGB?, LTG?,TPM?, ZNS?
Anticonvulsant Drugs Marketed in the U.S.
1912 Phenobarbital (Luminal®) Winthrop
1935 Mephobarbital (Mebaral®) Winthrop
1938 Phenytoin (Dilantin®) Parke-Davis
1947 Mephenytoin (Mesantoin®) Sandoz
1954 Primidone (Mysoline®) Ayerst
1957 Methsuximide (Celontin®) Parke-Davis
1957 Ethotoin (Peganone®) Abbott
1960 Ethosuximide (Zarontin®) Parke-Davis
1968 Diazepam (Valium®) Roche
1974 Carbamazepine (Tegretol®) Ciba-Geigy
1975 Clonazepam (Klonopin®) Roche
1978 Valproic acid (Depakene®) Abbott
1981 Clorazepatae (Tranxene®) Abbott
1993 Felbamate (Felbatol®) Carter-Wallace
1993 Gabapentin (Neurontin®) Parke-Davis
1994 Lamotrigine (Lamitcal®) GlaxoSmithKline
1996 Topiramate (Topamax®) Ortho-McNeil
1997 Tigabine (Gabitril®) Abbott
2000 Zonisamide (Zonegran®) Elan Pharma
2000 Levetiracetam (Keppra®) UCB Pharma
2000 Oxcarbazepine (Trileptal®) Novartis
2000 Pregabalin (Lyrica®) Pfizer
2008 Banzel (Rufinamide®) Eisai
2009 Vimpat (Lacosemide®) UCB
2009 Sabril (Vigabtrin®) Lundbeck
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 AnemiaHigh-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
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.
Med
ian
% C
han
ge
fro
m B
asel
ine
French et al. Arroyo et al. Beydoun et al.
-10
0
10
20
30
40
50
60
50TID
200TID
Pregabalin Dose (mg)
75BID
150BID
300BID
Pregabalin Dose (mg)
*
200TID
300BID
Pregabalin Dose (mg)
*
*
*
*
*
*
0
35 37
51
-1
17
43
1
36
48
PBO PBO PBO
*P≤0.01 vs placebo
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).
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 AEDdependent, life-threatening rash / hypersensitivity
Motte J et al. N Engl J Med 337:1807-1812, 1997
Lamotrigine for LGS: Efficacy
Median change from baseline in weekly seizure counts during treatment weeks 1-16
N=78 N=89 N=75 N=89 N=60
N=64
% Patients
36%34%32%
-10%
9%9%
-30
-20
-10
0
10
20
30
40
50
All MajorSeizures
Drop Attacks Tonic-ClonicSeizures
Seizure Reduction Frequency
(%)
LTGPlacebo
p=0.002 p=0.01
p=0.03
Lamotrigine: Adjunctive Therapy for Partial Seizures in Children Aged 2-16 Years
Partial Seizure Frequency Secondary Generalized
1-18 7-18 Seizure Frequency
Weeks 1-18 7-18
Weeks
% of Patients with >50% Seizure Reduction (All Partial Seizures)
33%
28%
42%45%
1%3%
25%
16%
0
5
10
15
20
25
30
35
40
45
50
% P
ati
en
ts
LTGPlacebo
p<0.001 p=0.001p=0.004 p=0.003
Lamotrigine: Typical Absence Seizures in Children
Frank LM et al. Epilepsia 40:973-979, 1999
Maximum Dosemg/kg/day N Seizure-Free
7 20 12 (60%)
15 22 18 (82%)
All patients 42 30 (71%)
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
0
10
20
30
40
50
18%
27%
47% 46%
Placebo 200 mg 400 mg 600 mg (N=45) (N=45) (N=45) (N=46)
Randomized Dose Group
p=0.620* p=0.013* p=0.027*
% R
esp
on
der
Faught E et al. Neurology 46:1684, 1996
Topiramate – Protocol YD50% Responders: Double-Blind vs. Baseline
*Comparison to placebo
Cognitive Outcomes: TPM vs. VPA
Aldenkamp AP et al. 2000
Double-blind, randomized, parallel (17 variables) Add-on to CBZ in epilepsy patients
TPM VPA
Titration (mg/day/wk) 25 mg 150 mg
Completers 24 29
Dropouts 8 4
Mean dose (mg/day) 251 1,384
VPA >TPM on verbal memory
Titration = 12 wks; maintenance = 8 wks
Topiramate: Dosing and Administration
*Initial evaluation point
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
Topiramate in Infantile Spasms: Open-Label Studies
*Glauser TA et al. Epilepsia 39:1324, 1998**Spasms + ancillary seizures
Study 1 (N=11):Stabilization Outcomes*
>50% spasm reduction 9/11 (82%)
Spasm-free 5/11 (45%)
Dose, mean (range), mg/kg/day 15 (8-24)
Study 2 (N=21)
>50% seizure** reduction
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
Levisohn PM et al. Epilepsia 44(Suppl 9):267, 2003
% Patients Seizure-Free (12-wk maintenance)
TPM (N=19) VPA (N=9)
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%)
Observations
Efficacy similar
Adverse event profiles different Similar neurotoxicity
scale ratings VPA: More systemic
toxicity
Percentage Reduction in Partial SeizuresDuring Treatment Period to 60 mg/kg/day
0
10
20
30
40
50
Median % Change from Baseline
Over Placebo
p=0.0002 p<0.0001
% R
edu
ctio
n i
n W
eekl
y S
eizu
re F
req
uen
cy
LEV Placebo LEV
26.8 %
16.3 %
43.3 %
Efficacy of Levetiracetam in Myoclonic Seizures
Noachtar S. Presented at: 26th International Epilepsy Congress; August 29, 2005; Paris, France.
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
2
Adverse Events OverviewPatients, %
LEV(N=101)
Placebo(N=97)
Infection 28.7 28.9Somnolence 22.8 11.3Accidental injury 16.8 10.3Vomiting 14.9 13.4Headache 13.9 14.4Anorexia 12.9 8.2Rhinitis 12.9 8.2Hostility 11.9 6.2Cough increased 10.9 7.2Nervousness 9.9 2.1Asthenia 8.9 3.1Dizziness 6.9 2.1Agitation 5.9 1.0Albuminuria 4.0 0.0Ecchymosis 4.0 1.0Depression 3.0 1.0
7.5
27
35
55
0
10
20
30
40
50
60 ZNS
Zonisamide: Pivotal Clinical Trials%
of
Pat
ien
ts
Study 2 & 3: % Responders
>25% >50% >75%
% Reduction in Seizures
>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 1Henry TR et al. Neurology 38:928-931, 1998 2Kyllerman M et al. Epilepsy Res 29:109-114, 1998
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
Glauser T et al. Neurology 70:1950-1958, 2008
Rufinamide for Generalized Seizures Associated with Lennox-Gastaut Syndrome
31.1
42.5
10.9
16.7
0
5
10
15
20
25
30
35
40
45
Total seizures Tonic-atonicseizures
% R
esp
on
der
s
Rufinamide Placebo
32.7
42.5
11.7
-1.4-5
0
5
10
15
20
25
30
35
40
45
Total seizures Tonic-atonicseizures
% R
edu
ctio
n
p=0.0045
p=0.002
p=0.0015
p<0.0001
Glauser T et al. Neurology 70:1950-1958, 2008
*Double-blind adjunctive therapy study in LGS; includes only AEs occuring at higher incidences with Rufinamide than placebo
AEs with Incidence >5% vs. Placebo in Subjects with Lennox-Gastaut Syndrome
Rufinamide, % Placebo, %Total no. patients studied* N=74 N=64
Somnolence 24.3 12.5
Vomiting 21.6 6.3
Pyrexia 13.5 17.2
Fatigue 9.5 7.8
Decreased appetite 9.5 4.7
Nasopharyngitis 9.5 3.1
Headache 6.8 4.7
Rash 6.8 1.6
Rhinitis 5.4 4.7
Ataxia 5.4 0
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
Beydoun A et al. Expert Review 9:33-42, 2009
Percentage of patients with at least 50 or 75% reduction in seizurefrequency from baseline period to maintenance periodIntent to treat: SP667, SP754, SP755 *p<0.05; ** p<0.001
39.7%**
34.1%*
22.6%19.1%
13.5%
9.2%
0
5
10
15
20
25
30
35
40
45R
esp
on
de
r R
ates
50% Responders75% Responders
Placebo(n=359)
LCM 200 mg/day(n=267)
LCM 400 mg/day(n=466)
AEs Leading to Discontinuation (≥1% of Subjects in Lacosamide Total) during Treatment Phase (SS†)
(SP667, SP754, SP755)
AE Leading to Discontinuation
Placebo
N=364n (%)
LCM200mg/day
N=270n (%)
LCM400mg/day
N=471n (%)
LCM600mg/day
N=203n (%)
LCMTotal
N=944n (%)
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)
Coordination abnormal 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)
Convulsion 4 (1.1) 2 (0.7) 8 (1.7) 0 10 (1.1)†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
Elterman RD et al. Neurology 57:1416-1421, 2001
Treatment Responders by Vigabatrin Dose and Etiology
27%
10%10%
52%
36%
11%
0
10
20
30
40
50
60
Low
(75)
High
(67)
Tuberoussclerosis
(25)
Dysgenetic
(31)
Postnatal
(41)
Idiopathic orcryptogenic
(45)
Vigabatrin dose Etiology
% R
es
po
nd
ers
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