Anti Epileptic Drugs, New Vs. Old

1. What’s New In Antiepileptic
Drugs

2. ILAE Classification of Seizures
Seizures
Partial
Generalized
Simple Partial
Absence
Complex Partial
Myoclonic
Secondarily
Generalized
Atonic
Tonic
Tonic-Clonic
C-Slide 2

3. Complex Partial Seizures
 Impaired consciousness
 Clinical manifestations
vary with site of origin
and degree of spread
– Presence and nature of
aura
Seizures
Partial
Generalized
– Automatisms
– Other motor activity
 Duration typically < 2
minutes
Complex Partial
C-Slide 3

4. AED Choice by Seizure Type
Partial
Simple
Complex
Secondary
generalized
Generalized
Tonicclonic
Tonic
Myoclonic
PHT, CBZ, PB,
GBP, TGB, LVT,
OCBZ
Atonic
Infantile
Spasms
ACTH
TPM?
TGB?
VGB?
VPA, LTG, TPM, (FBM)
ZNS
Absence
ESX

5. 1st Generation AEDs
• Vast Clinical Experience
• Incomplete Efficacy
• Unfavorable Kinetics (M-M, protein binding)
• Narrow Therapeutic Range
– Small window between efficacy & toxicity
• Adverse CNS Effects
• Adverse Non-CNS Effects
• Drug-Interactions

6. Idiosyncratic Adverse
Effects of AEDs
 Hematologic damage
– Marrow aplasia, agranulocytosis
– Early symptoms: abnormal bleeding, acute onset of fever,
symptoms of anemia
– Laboratory monitoring probably not helpful in early detection
– Felbamate aplastic anemia approx. 1:5,000 treated patients
– Patient education
P-Slide 6

7. Long-Term Adverse
Effects of AEDs
 Endocrine/Metabolic Effects
•
Osteomalacia, osteoporosis
• Carbamazepine
• Phenobarbital
• Phenytoin
• Oxcarbazepine
• Valproate
•
Folate (anemia, teratogenesis)
• Phenobarbital
• Phenytoin
• Carbamazepine
• Valproate
•
P-Slide 7
Altered connective tissue metabolism or
growth (facial coarsening, hirsutism, gingival
hyperplasia or contractures)
• Phenytoin
• Phenobarbital
 Neurologic
• Neuropathy
• Cerebellar syndrome phenytoin
 Sexual Dysfunction - 3060%
• Phenytoin
• Carbamazepine
• Phenobarbital
• Primidone

8. Stevens-Johnson
Syndrome

9. Gingival Hyperplasia
Induced
by Phenytoin
New Eng J Med. 2000:342:325.
P-Slide 9

10. After Withdrawal of
Phenytoin
New Eng J Med. 2000:342:325.
P-Slide 10

11. Trabecular Bone
http://www.merck.com
P-Slide 11

12. AED Hypersensitivity
Syndrome
 Characterized by rash, systemic
involvement
 Arene oxide intermediates - aromatic
ring
 Lack of epoxide hydrolase
 Cross-reactivity
P-Slide 12
–
–
–
–
Phenytoin
Carbamazepine
Phenobarbital
Oxcarbazepine

13. Influence on Hepatic
Metabolism
• 1st Generation antiepileptic drugs
– Inducers
• Phenobarbital
• Phenytoin
• Carbamazepine
– Inhibitor
• Valproate
• Therefore, affect the kinetics and dynamics of nonCNS drugs as well…

14. DO WE NEED MORE NEW
ANTIEPILEPTIC DRUGS?
• Problem with conventional AEDs:
– Seizure control
• Newly diagnosed well treated
• Still 40% with therapy resistance
• New AEDs over last 20 years are slowly
changing this equation!

15. The Ideal AED Therapy:
• Improved efficacy → no seizures
• Few side effects → no new problems in
patient’s daily life
• Easy dosing scheduling → no chance for
dosing mistakes
• Minimal drug interactions → no need to
adjust other medicines
• Expense not prohibitive → cost will not
prevent taking the AED
• Maximizing quality of life

16. New Versus Standard AEDs
• Equal efficacy
• Differentiated by
– Adverse events
– Drug interactions
– Pharmacokinetics profiles

17. How do we make progress?
• Revolutionary Drugs
– Drugs that work with new mechanisms never tried
before
– Expectation: They will control seizures that
existing drugs can’t control
• Evolutionary Drugs
– Improve on existing drugs
– Expectation: We can eliminate some of the
problems/side effects of good drugs, without
reducing their effect on seizures

18. Number of Licensed Antiepileptic Drugs
ANTIEPILEPTIC DRUG
DEVELOPMENT
?
20
Pregabalin
Zonisamide
Levetiracetam
Oxcarbazepine
Tiagabine
15
Fosphenytoin
Topiramate
Lamotrigine
Gabapentin
10
Felbamate
Sodium Valproate
Carbamazepine
Ethosuximide
5
Phenobarbital
Phenytoin
Benzodiazepines
Primidone
Bromide
0
1840
Retigabine
Rufinamide
Lacosamide
Brivaracetam
1860
1880
1900
1920
1940
Calendar Year
1960
1980
2000

19. Number of Licensed Antiepileptic Drugs
SINCE 1998
20
Pregabalin
10
Zonisamide
Levetiracetam
Tiagabine Oxcarbazepine
Topiramate
5
Fosphenytoin
Lamotrigine
Gabapentin
Felbamate
0
1990
2000
Calendar Year

20. AED Choice by Seizure Type
Partial
Simple
Complex
Secondary
generalized
Generalized
Tonicclonic
Tonic
Myoclonic
PHT, CBZ, PB,
GBP, TGB, LVT,
OCBZ
Atonic
Infantile
Spasms
ACTH
TPM?
TGB?
VGB?
VPA, LTG, TPM, (FBM)
ZNS
Absence
ESX

21. Gabapentin
• Mechanism
– designed, yet unknown
• Dose (900 to 4800 mg/day [TID to QID])
• Side Effects
– fatigue, dizziness, ataxia
• Drug Interactions
– None with AEDs [only Antacids]
• Renal Elimination - CrCl
• Clinical Pearl
– non-Epilepsy uses

22. Lamotrigine
• Mechanism
– Na+ Channels, Glutamate
• Dose (100 to 500 mg/day [QD or BID])
• Side Effects
– Sedation, Diplopia, Ataxia, Nausea - Rash
• Drug Interactions
• “one way street”
• Contraceptives
• Clinical Pearl
• Slow taper - (esp. VPA)
• Incidence of severe rash may by overestimated
• Pediatric approval

23. Topiramate
• Mechanisms - many
– Na+ Channels, Glutamate, GABA, CAI
• Dose (200 to 400 mg/day [BID - QDrenal])
• Side Effects
• Sedation, Difficulty Concentrating, Kidney Stones, Glaucoma
• Drug Interactions
– “one way street”
• Clinical Pearl
– ceiling dose, fluids, visual changes, use outside of
epilepsy

24. Tiagabine
• Mechanism
– Blocks re-uptake of pre-synaptic GABA
• Dose (32 to 56 mg/day [BID to QID])
• Side Effects
– Fatigue, Dizziness, Weakness
• Drug Interactions
– “one-way street”
• Clinical Pearl
• different mechanism of action
• take with food to decrease side effects (same AUC)

25. Oxcarbazepine
• Mechanism - Na+ Channels
• Dose
• Adjunctive (600 to 1,200 mg/day [BID])
• Mono (up to 2,400 mg/day)
• Side Effects
• Dizziness, Somnolence, Diplopia, N/V, Ataxia
• Drug Interactions
• Inhibit/Induce - OCs, PHT
• Clinical Pearl
• Prodrug (OCBZ to MHD)

26. Levetiracetam
• Mechanism
– SV 2 inhibitor
• Dose: (1,000 to 3,000 mg/day [BID])
• Side Effects
– Somnolence, Asthenia, Infection, Dizziness
• Drug Interactions
– PK
• None with AEDs, probenecid - metabolite
– PD ?
• Clinical Pearl
– Adjust dose for renal function

27. Zonisamide
• Mechanism
– Na+ and T-calcium channels, CAI
• Dose: 100 to 600 mg/day (BID or QD)
• Side Effects:
– somnolence, dizziness, nausea, headache,
agitation/irritation, kidney stones, weight loss
• Drug Interactions
• No effect on others
• Clinical Pearl
• Appr. Japan & Korea ‘89, Sulfonamide
• Use outside of epilepsy

28. What’s really new
• Two new drugs
– Revolutionary
• lacosamide
• rufinamide
• Four drugs in late trials
– Evolutionary
• brivaracetam
• Eslicarbazepine
– Revolutionary:
• Carisbamate
• Retigabine

29. Lacosamide
• Works on sodium channels, like
Carbamazepine and Phenytoin
• However, It selectively enhances slow
inactivation of sodium channels, whereas the
older drugs work on fast inactivation
• Approved in Europe and USA

30. Double-Blind Placebo-Controlled Add-on Trial
of Lacosamide (LCS) in Refractory Partial
Epilepsy: 50% Responder Rates (n=418)
% Patients
41%*
38%*
33%
(* P<0.05
vs PL)
22%
Placebo
LCS 200mg
LCS 400mg
LCS 600mg
Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive
Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

31. RUFINAMIDE
• Also works on sodium channels with new
mechanism
• Approved in Europe for treatment of a severe
form of epilepsy (Lennox-Gastaut syndrome)
– “Orphan drug”
• In Front of FDA for Lennox-Gastaut and
Partial seizures

32. Rufinamide AEs With Incidence
≥3% vs Placebo: All Treated
Subjects With Epilepsy (Doubleblind Only)
Rufinamide
N (%)
Placebo
N (%)
1465
635
1180 (80.5)
497 (78.3)
36 (17)
16 (8.1)
Vomiting
35 (16.5)
14 (7.1)
Headache
34 (16.0)
16 (8.1)
Nausea
16 (7.5)
7 (3.6)
Ataxia
10 (4.7)
1 (0.5)
Diplopia
10 (4.7)
1 (0.5
Subjects
Subjects with an AE
Somnolence

33. BRIVARACETAM
• Similar mechanism to Levetiracetam but much
stronger in animal models
• Also has sodium channel blocking activity
• FDA trials underway

34. Efficacy of Brivaracetam (5, 20 and 50
mg/day) Add-on Treatment in Refractory
Partial-Onset Epilepsy
RESPONDER RATES
p = 0.001
55.8%
60
8.0%
4/50
p = 0.047
32.0%
40
7.7%
4/52
7.7%
4/52
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
% Patients
% Respondents
10
p = 0.002
44.2%
50
30
20
SEIZURE-FREEDOM RATES
16.7%
1.9%
1/54
10
0
PBO
(n=54)
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
ITT population: n=208; 110M, 98F; age range 16–65 y
0
PBO
(n=54)

35. Eslicarbazepine
• A “third generation” Carbamazepine
• Improves on second generation
– Less effect on sodium
– Smoother release may produce less side effects
• Hopefully will work equally as well
• Ready to submit to FDA

36. •
•
•
•
Summary of 2nd Generation
AEDs
Safer
More expensive
May help with intractable partial seizures
Less drug interactions
• Not profoundly more potent

37. ILAE Summary Guidelines
Seizure type or
epilepsy syndrome
Class I
Studies
Class II
Studies
Class III
Studies
Level of efficacy and effectiveness evidence
(in alphabetic order)
Adults with partial-onset
seizures
2
1
30
Level A: CBZ, PHT
Level B: VPA
Level C: GBP, LTG, OXC, PB, TPM, VGB
Children with partial-onset
Seizures
1
0
17
Level A: OXC
Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
Elderly adults with partialonset seizures
1
1
2
Level A: GBP,
Level B: None
Level C: CBZ
Adults with generalized
onset tonic–clonic seizures
0
0
23
Level A: None
Level B: None
Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA
Children with generalized
onset tonic–clonic seizures
0
0
14
Level A: None
Level B: None
Level C: CBZ, PB, PHT, TPM, VPA
Children with absence
Seizures
0
0
6
Level A: None
Level B: None
Level C: ESM, LTG, VPA
BECTS
0
0
2
Level A: None
Level B: None
Level C: CBZ, VPA
JME
0
0
0
Levels A, B, C: None
LTG
Reference: Epilepsia 2006:47; 1094-1120.

38. Summary of AAN evidence-based
guidelines level A or B
recommendations
AED
Newly Diagnosed
Monotherapy
Partial/mixed
Newly Diagnosed
Absence
Gabapentin
Yes*
No
Lamotrigine
Yes*
Yes*
Topiramate
Yes
No
Tiagabine
No
No
*Not FDA approved for this indication
Reference: Neurology 2004, 62:1252-1260.
C-Slide 38

39. Summary of AAN evidence-based
guidelines level A or B
recommendations
AED
Newly Diagnosed
Monotherapy
Partial/mixed
Newly Diagnosed
Absence
Oxcarbazepine
Yes
No
Levetiracetam
No
No
Zonisamide
No
No
*Not FDA approved for this indication
Reference: Neurology 2004, 62:1252-1260.
C-Slide 39

40. Summary of AAN evidencebased guidelines level A or B
recommendation
AED
Partial
adjunctive
adult
Partial
Monotherapy
Primary
generalized
Symptomatic
generalized
Pediatric
partial
Gabapentin
Yes
No
No
No
Yes
Yes
Yes
Yes*(only
absence)
Yes
Yes
Yes
No
No
No
No
Lamotrigine
Levetiracetam
* Not FDA approved for this indication
References:
Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.
C-Slide 40

41. Summary of AAN evidencebased guidelines level A or B
recommendation
AED
Partial
adjunctive
adult
Partial
Monotherapy
Primary
generalized
Symptomatic
generalized
Pediatric
partial
Oxcarbazepin
e
Yes
Yes
No
No
Yes
Tiagabine
Yes
No
No
No
No
Topiramate
Yes
Yes*
Yes
Yes
Yes
Zonisamide
Yes
No
No
No
No
* Not FDA approved for this indication
References:
Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.
C-Slide 41

42. Summary of ILAE guidelines on
therapeutic drug levels
C-Slide 42

43. LEVEL OF KNOWLEDGE AT TIME OF APPROVAL
What we
know
What we don’t know

44. THANK YOU !!!