Newer antiepileptic drugs (AEDs) such as eslicarbazepine, vigabatrin, lacosamide, clobazam, levetiracetam, lamotrigine, topiramate, zonisamide, oxcarbazepine have been introduced as adjunctive therapies for refractory epilepsy. These newer AEDs have fewer drug interactions and side effects than older AEDs. They target specific epilepsy syndromes in children. However, most are only used as adjunctive rather than monotherapy due to a lack of superiority trials compared to conventional AEDs. Dosing and use of the newer AEDs varies based on age, renal function

1. Newer Antiepileptics: When And How
To Use
Dr. Nishtha jain
Senior resident
Department of Neurology
GMC, Kota.

2. Introduction
Prevalence
Resistant to drug treatment in 1/3
patients
Newer AEDs
2.2/1000

3. Antiepileptic Drugs
Conventional New

4. Eslicarbazepine:
ESL
MOA
Stabilizes the inactive
state of voltage-gated
sodium channels
preventing their return
to the activated state
For partial onset
seizures
FDA Approval
2013
Aptiom

5. Dose
initiated with 400 mg every
other day for 2 weeks,
followed by 400 mg daily.
Start with
400mg OD,
increase dose
by 400mg,
maintenance
dose of 800-
1600mg OD
Renal dose adjustment
required: the doses be
reduced to 50% if CrCl<
50ml/min

6. Vigabatrin
MOA
Irreversible inhibitor
of GABA
transaminase
Infantile spasms
Add-on therapy for
refractory partial
epilepsy in adults
FDA Approval
2010
Sabril

7. 2005
2017
Vigabatrin shows better results in
patients of TSC and hormonal
treatment is better in cryptogenic
seizures.

8. Advantages Disadvantages
74% spasm cessation in
cases of infantile
spasms in TSC cases.
Good oral bioavailablity
Drug interactions are
minimal
Permanent, bilateral
concentric visual field
constriction in 30% or more
of patients
Somnolence and fatigue,
Edema,
weight gain
Peripheral neuropathy,
Myoclonic seizures and
abscence seizures
New basal ganglia, thalamic,
brainstem, and dentate
nucleus DWI or T2
hyperintense lesions

9. Pediatric dose Adult dose
-50 mg/kg/day to 150
mg/ kg/day.
-increased by 30-40
mg/ kg/day every 4-5
days
-Response time- 2
weeks
-
Stop after two
weeks
Good response
stop after 6 months
-500mg BD starting
dose
-Increase by
500mg/wk
-Max. dose 1.5 g
BD

10. 70% is excreted in the urine
Mild renal
impairment
Decrease by 25%
Moderate renal
impairment
Decrease by 50%
Severe renal
impairment
Decrease by 75%

11. Rufinamide
MOA
Prolongation of
inactive state of
sodium channels
Atonic seizures in
LGS
FDA Approval
2008
Banzel

12. Pediatric dose Adult dose
--
-200-400 mg/day
-Increase by 400-
800 mg EOD
-Max. dose
3200mg/day
10 mg/kg/day
-Increase by
10mg/kg EOD
-Max. dose
45mg/kg/day
Caution- avoid in patients with familial
short QT syndrome or in combination with
other drugs that shorten QT interval.

13. Drug interactions
Increase the serum concentration of
phenytoin by up to 21%
Valproate administration increase the serum
level of RUF by up to 70%
Diminish the efficacy and serum levels of
oral contraceptives

14. Lacosamide
MOA
Enhance slow
inactivation of
sodium channels
Adjunctive therapy for
partial seizures in
adults
FDA Approval
2009
Vimpat

15. Lancet neurol 2017
The proportion of patients predicted
to be seizure-free at 6 months was
90% taking lacosamide and 91%
taking carbamazepine-CR.

16. Advantages Disadvantages
-both an oral and
intravenous
formulation
-no dose
adjustment in mild
to moderate renal
impairment.
-no drug
interactions
-Not been studied
specifically in children
younger than 16
years of age.
-dizziness (25%) and
ataxia (6%).
-dose-dependent PR-
interval prolongation
Dose- 50mg BD, increase by 50mg BD weekly to
max. dose of 150-200mg BD

17. Perampanel
MOA
Reduces the ability of
glutamate
to activate AMPA receptors
via a non-competitive
mechanism
Partial onset and
generalised seizures
Approved by
FDA in 2012

18. Dose
Start with 2mg HS
Increase weekly by
2mg
Max.dose
12mg/day
Not established in < 12
yrs of age
Dose modification
needed in hepatic
impairment
Increase starting dose to
4mg if patient on enzyme
inducers

19. Clobazam
MOA
Enhancement of
GABAergic
neurotransmission
FDA approval 2011
for adjunctive
treatment of LGS in
patients 2 years or
older

20. Advantages Disadvantages
-low tendency to
produce sedation
-lower incidence of
loss of therapeutic
effect over time
lethargy,
somnolence,
ataxia,
aggression,
fatigue, and
insomnia
Caution : Avoid other depressant drugs or
alcohol and abrupt discontinuation of use.

21. Adult dose Pediatric dose
--
-Starting dose:
5mg/day
Dose escalation
weekly
Max. dose 20
mg/day(<30kg)
40 mg/day(>30Kg)
Starting dose:
5mg BD
Dose escalation
weekly
Max. dose-
40mg/day
Dose adjustment needed in hepatic
impairment

22. Ezogabine
MOA
Enhancement of
potassium currents
to reduce brain
excitability
Adjunctive
treatment of
partial epilepsy
FDA Approval
2011
Potiga

23. ADR Drug Interactions
- Urinary retention
-neuropsychiatric
symptoms
-dizziness and
somnolence
-QT-interval
lengthening.
-Potential for
abuse and
dependence
Carbamazepine and
phenytoin decrease
ezogabine serum
concentrations by 31%
to 34%
-inhibit renal clearance
of digoxin, leading to
increased serum digoxin
levels.
-Ethanol use can
increase serum
ezogabine levels

24. Dose
Starting dose:
100mg TDS
Increase at weekly
intervals
Max. dose 400mg
TDS
Dose adjustment in
renal impairment:
Start with 50mg TDS
Increase weekly by
50mgTDS
Max. dose- 200mg
TDS

25. Leviteracetam
MOA
inhibits high-voltage-
activated calcium
channels and also
binds SV2A which is
involved in the control
of vesicle fusion and
exocytosis
Approved for treatment of
partial epilepsy, primary
generalised tonic clonic
seizures, JME and status
epilepticus
Keppra
1999

26. Advantages Disadvantages
-No dose
adjustments
needed
-Minimum Drug
interactions
-aggression,
-emotional lability,
-oppositional
behavior, and
-psychosis.
Dose:
Adults : 500mg BD, max. dose 3000mg/day
Children : 10 mg/kg/day (divided twice daily) to
be hiked by 10-20 mg/kg every two weeks to a
maximum dose of 40-60 mg/kg/day.
.

27. Brivaracetam
FDA Approval -2016
Partial onset seizures in
adults
analogue of levetiracetam
no clinical trials in
children younger
than 16 years of
age

28. Dose
Start from 50mg BD
Max. dose 100mg BD
No adjustment in renal impairment
Hepatic Impairment: start with 25mg
BD
Max. dose 75 mg BD

29. Clinical efficacy and safety of the newer antiepileptic
drugs as adjunctive treatment in adults with
refractory partial-onset epilepsy: A meta-analysis of
randomized placebo-controlled trials

30. Topiramate
MOA
Act on voltage dependent
sodium channels,
enhancement of GABA,
decrease in glutamate
and inhibition of carbonic
anhydrase.
Adjunct in refractory
partial or generalized
epilepsy
Topamax
1996

31. ADR Dose
- Anorexia and mild
weight loss
-metabolic
acidosis,
-nephrolithiasis,
-decreased
sweating and
resultant
hyperthermia
Children: 1-3 mg/kg/day
(divided twice daily)
hiked bi-weekly to 3-8
mg/kg/day.
Adults : 25mg BD,
increased weekly by
25mg BD to max. Dose
of 200mg BD
Caution : Individuals on combination of topiramate and
valproate should be monitored for signs of
encephalopathy resulting from hyperammonemia

32. Lamotrigine
MOA
block the voltage
dependent sodium
channels
adjunct to refractory partial
and generalized epilepsy.
-absence seizure in Lennox
Gastaut syndrome
-myoclonic-astatic epilepsy.
Lamictal
1994

33. Greater overall effectiveness for focal
seizures of lamotrigine compared with
carbamazepine, oxcarbazepine, and
gabapentin
Epilepsia, 56(3):460–472, 2015
carbamazepine versus lamotrigine,
gabapentin, oxcarbazepine and topiramate,
and valproate versus lamotrigine and
topiramate

34. ADR Drug Interactions
- Steven Johnson
syndrome and
toxic epidermal
necrolysis.
-exacerbate
myoclonic seizures
in patients with
Dravet syndrome
Phenytoin
carbamazepine and
estrogen may shorten
the half life of
Lamotrigine.
-Valproate prolongs
the half life of
lamotrigine

35. Pediatric dose Adult dose
--
-Starting dose:
25mg/day
-Increase by 50mg/
week
-Maintenance dose:
200-400mg/day
Started at 1-2
mg/kg followed
by slow hiking
biweekly to 3-8
mg/kg/day

36. Oxcarbazipine
MOA
Blocks high frequency
voltage dependent
repetitive firing of sodium
channels
evidence-based effective
initial monotherapy for
children with partial-onset
seizures and focal epilepsy
Trileptal
2000

37. ADR Drug Interactions
Hyponatremia,
headache,
dizziness,
ataxia
induce the
breakdown of the
oestrogenic
component of oral
contraception
Advantage over carbamazepine- do not cause
hepatic induction nor auto induction
Dose : initial dose of 5 to 8 mg/kg/day in 2 divided
doses increasing by 5 to 8 mg/kg after 5 to 7 days up to
a maximum of 30 mg/kg.

38. Zonisamide
MOA
facilitation of dopaminergic and
serotoninergic
neurotransmission through the
blockade of T-type calcium
channels.
-prolongation of sodium channel
inactivation.
-as a weak inhibitor of carbonic
anhydrase.
progressive myoclonic
epilepsy syndromes
-second-line agent for
infantile spasms, Lennox-
Gastaut syndrome, and
juvenile myoclonic
epilepsy.
Zonegran
2000

39. ADR Dose
Somnolence,
poor appetite,
weight loss,
headache,
pruritus,
skin rash
kidney stones,
oligohydrosis
hyperthermia
problems of language
development
Pediatric dose: starting dose
is 2–4 mg/kg/day, and the
maintenance dose is 4–8
mg/kg/day; divided once or
twice daily
Adult dose : starting dose
100mg/day, increase by
100mg/week
Maintenance dose: 400mg/day
Max. dose: 600 mg/day

40. Felbamate
MOA
blocking of voltage gated
sodium channels, NMDA
and non NMDA glutamate
receptors, voltage gated
calcium receptors and
GABA.
USE
Lennox–Gastaut patients
over age 4 unresponsive
to primary antiepileptic
drugs.
Intractable partial
seizures in patients over
18 y of age
1993

41. Dose
Pediatric dose:
initial dosing of 15
mg/kg/day to be
titrated up by 15
mg/kg upto 45
mg/kg/d over a
period of three
weeks
Adult dose:
1200mg/day
Max. dose:
3600mg/day
Increase by
1200mg/week
Side effects:
Aplastic anemia
Acute liver failure

42. Pregabalin
MOA
Reduces the synaptic
release of several
neurotransmitters
increases neuronal GABA
levels
Treatment of
partial onset
seizures in adults
Lyrica
2004

43. Dose
300-600mg/day in two divided
doses
Dose adjustment needed in renal
impairment
Creatinine clearance Dose (Max)
> 60 ml/min 600 mg/D
30 – 60 ml/min 300 mg/ D
15 – 30 ml/min 150 mg/D
< 15 ml/min 75 mg/D

44. Stiripentol
MOA
Enhances the inhibitory
action of the
neurotransmitter
GABA by multiple
mechanisms
Severe Myoclonic
Epilepsy of
Infancy
DIACOMIT

45. Dose Adverse effects
-supplied in 250 mg
capsules and sachets
-target dose of 50
mg/kg in 2–3
divided doses to be
reached over 3 d
titration
anorexia,
weight loss,
insomnia,
drowsiness,
ataxia,
hypotonia
Dystonia
Transient aplastic anemia
and leukopenia

46. Ganaxolone
MOA potentiates the action of
GABA at its receptors
and directly activates the
receptor at two distinct
sites
USE Partial onset epilepsy in
adults
Infantile spasms in
children

47. Formulated in capsule, IV and
suspension forms
Dose used in trials- 1500mg/day

48. Status epilepticus
Despite increase in the prescription of newer AEDs for
SE, findings do not support an improved prognosis
following their prescription, if considered as a group.
Newer AEDs were independently related to a reduced
likelihood of return to baseline(p<0.001).
Older versus newer AEDs
(levetiracetam, pregabalin,
topiramate, lacosamide)

49. Pregnancy
In AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies was
associated with levels of seizure control similar to those that applied for the major older
AEDs carbamazepine and valproate, but with levels of seizure control superior to those
associated with use of lamotrigine and topiramate.

50. Teratogenecity

51. Newer Anticonvulsants: Lamotrigine, Topiramate and Gabapentin. Holmes et al. Birth Defects Research (Part A) 00:000000 (2012)

52. Updated ILAE evidence review of antiepileptic drug efficacy
and effectiveness as initial monotherapy for epileptic
seizures and syndromes

53. Drug Market name Price
Eslicarbezipine Eslizen Rs. 15- 400mg tab
Rs. 18- 600 mg tab
Vigabatrin Sabril Rs. 36-500mg tab
Lacosamide Lacosam Rs. 10-100mg tab
Clobazam Aedon Rs. 3-50mg tab
Rs. 6-10mg tab
Leviteracetam Levera Rs. 10-500mg tab
Lamotrigine Lametec Rs. 5- 50 mg tab.
Topiramate Topaz Rs. 10-100 mg tab
Zonisamide Zonisep Rs. 10- 100mg tab
oxcarbezipine oxetol Rs. 11- 450 mg tab

54. • Least drug- drug interactions
• Less side effects
• Useful in targeting the childhood epilepsy syndromes.
• Mostly used as adjunctive therapy.
• Lack of superiorty trials in comparison with conventional
AEDs.

55. Referrences
• Newer Antiepileptic Drugs: Evidence Based Use. Passi
G. Indian J Pediatr (October 2014) 81(10):1042–1051.
• Antiepileptic Drugs 2012: Recent Advances and Trends.
Joseph I. Sirven et al. Mayo Clin Proc. 2012;87(9):879-
889.
• Updated ILAE evidence review of antiepileptic drug
efficacy and effectiveness as initial monotherapy for
epileptic seizures and syndromes. Tracy Glauser et al.
Epilepsia:1–13, 2013.
• Newly emerging therapies for neonatal seizures. M
pressler et al. Seminars in Fetal & Neonatal Medicine 18
(2013) 216-223.