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