Newer antiepileptic drugs

NEWER ANTIEPILEPTIC DRUGS
DR. PIYUSH OJHA
DM RESIDENT
DEPARTMENT OF NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

Ideal Properties for an Antiepileptic Drug :-
• Broad spectrum activity against all seizure types
• High Efficacy
• Good tolerability
• No risk of allergic or idiosyncratic reactions (including
teratogenicity)
• Low interaction potential
• Favorable pharmacokinetics ( linear kinetics, half life
compatible with once or twice daily dosage)

Ideal Properties for an Antiepileptic Drug :-
• No tolerance to antiepileptic effects
• No withdrawal seizures
• No need for intensive laboratory monitoring
• Availability of convenient formulations (pediatric and
parenteral )
• Low cost

“Older” Anti-Epileptic drugs
Phenobarbital 1912
Phenytoin 1938
Primidone 1952
Ethosuximide 1960
Carbamazepine 1974
Valproate 1978

• Despite a broad range of AEDs currently available,
about 30 % of patients with epilepsy are
uncontrolled with available treatment and a further
25 % suffer from manifestation of drug toxicity.
An introduction to Antiepileptic drug. Epilepsia 2005; 46 (Suppl 4): 31-37

Newer Antiepileptic drugs
• Equally effective as older AEDs
• Better tolerated than older AEDs
• Most have fewer interactions with other medications
than older AEDs
• Expensive compared to older drugs.

Newer Antiepileptic drugs
• Felbamate 1993
• Gabapentin 1993
• Lamotrigine 1994
• Topiramate 1996
• Tiagabine 1998
• Levetiracetam 1999
• Oxcarbazepine 2000
• Zonisamide 2000
• Pregabalin 2005
• Lacosamide 2008
• Eslicarbazepine 2009
• Retigabine 2011

FELBAMATE
• FDA approval on 30th July 1993.
• Mechanism of action – Sodium channel blockade,
potentiation of GABA a mediated inhibition and antagonism
of NMDA mediated responses.
• Primary Indications –
- Not indicated as a First line agent.
- Add-on treatment of Lennox-Gestaut Syndrome and
partial and secondary generalised seizure refractory to
other agents.

• Usual preparations – Tablet 400,600 mg; syrup 600mg/5ml
• Usual dosages –
Initial 1200mg/day (adults); 15mg/kg (children)
Maintenace : 1200-3600mg/day (adults);
15- 80mg/kg/day (children)
• Dosing frequency – 2-4 times/day
FELBAMATE

• Oral Bioavailability – 90 % (not affected by food)
• Time to Peak Levels – 1-6 hours
• Half life – 20 hours approx
• Reference range – 30-60 mg/L
• Significant drug interactions –
increases Phenytoin, valproate levels
lowers carbamazepine and steroid levels
valproate decreases rate of Felbamate elimination.
FELBAMATE

• Common/ important adverse effects –
Hepatotoxicity and Aplastic anemia are rare but serious
(due to Toxic Metabolite ATROPALDEHYDE).
others- insomnia, headache, weight loss, mood and
behavioural changes, ataxia, visual disturbances, Rash.
FELBAMATE

• Elimination - hydroxylation and then conjugation (60%) and
renal excretion in unchanged form (40%).
So dose modification is required in hepatic and renal
diseases.
• Comment – Highly effective in severe refractory cases, but
use limited by hepatic and haematological toxicity.
FELBAMATE

• Based on the 2006 expert panel consensus, Felbamate should
be regarded as a highly efficacious AED in patients refractory
to first line agents. Patients considered unsuitable for
candidates for Felbamate therapy include those with new
onset epilepsy, history of haematological or hepatic
dysfunction or autoimmune diseases. They also concluded
that it has a risk-benefit ratio profile that allows it to use in
selected patients with refractory epilepsy.
• A similar opinion was also reached in 1999 by join AAN and
American Epilepsy Society practice advisory.
FELBAMATE
Pelleck JM et al. Felbamate :consensus of current clinical experience. Epilepsy
Res 2006;71:89-101

GABAPENTIN
• FDA approval on 31ST December 1993.
• Mechanism of action – Modulates neurotransmitter release
by binding to α2-δ subunit of voltage gated Ca channels. This
closes N and P/Q pre-synaptic calcium channels, diminishing
excessive neuronal activity and neurotransmitter release
- Adjunctive therapy or monotherapy of partial or
secondary generalized seizures.
- also used in Neuropathic Pain, postherpetic neuralgia,
and diabetic neuropathy.

• Usual preparations – Tablet 100,300,400,600,800 mg;
Syrup 250mg/5ml
Initial 300-900 mg/day
Maintenace : 900-3600mg/day
GABAPENTIN

• Oral Bioavailability – <65 % (decreases with increasing dose)
(60% with 300mg dose, 40% with 600mg dose, and
about 35% at a steady state dose of 1600 mg TDS i.e.
non linear increase in serum levels with increasing dosage)
• Time to Peak Levels – 2-3hours
• Half life – approx 5 hours
• Reference range – 2-20mg/L
• Significant drug interactions –
No significant interaction btw Gabapentin and other AEDs
Antacid containing Aluminium or Magnesium hydroxide can
reduce Gabapentin absorption by abt 20%.
GABAPENTIN

drowsiness (24.4%), dizziness (20.3%), ataxia (17%),
headache (15%), tremor, diplopia, nausea, vomiting,
non-pitting pedal edema, weight gain
GABAPENTIN

• Elimination – renal excretion in unchanged form.
• Comment –
Gabapentin is effective in focal epilepsy but may aggravate
generalized epilepsy.
Main advantage is good tolerability.
Main disadvantage is modest efficacy, particularly in
severe cases, and spectrum of efficacy restricted to partial
epilepsies
GABAPENTIN

GABAPENTIN
• In SANAD study in patients with partial epilepsy, Gabapentin
was inferior to Lamotrigine in time to treatment failure
(defined as stopping the randomly assigned drug due to
inadequate seizure control, intolerable side effects or the
addition of other AEDs) and inferior to carbamazepine in time
to 12 month remission.
The SANAD study of effectiveness of carbamazepine, gabapentin,
Lamotrigine, oxcarbazepine or Topiramate for treatment of Partial
epilepsy :an unblinded randomised controlled trial
LANCET 2007;369;1000-1015

GABAPENTIN
• In another study comparing Gabapentin with carbamazepine,
Carbamazepine demonstrated superior efficacy but at the
cost of more frequent adverse effects.
A double blind trial of gabapentin monotherapy for newly diagnosed
partial seizures. Chadwick et al . Neurology 1998;51;1282-1288
• Compared to Lamotrigine, Gabapentin may show decreased
effectiveness but has advantage of lacking potential for any
serious adverse effects.
Gabapentin vs Lamotrigine monotherapy ; a double blind trial in newly
diagnosed epilepsy : EPILEPSIA 2002;43;993-1000

LAMOTRIGINE
• Mechanism of action – blockade of voltage dependent sodium
and calcium channels.
- Adjunctive therapy and monotherapy of partial
seizures (with or without secondary generalization)
and primary GTCS.
- also useful for other generalized epilepsy syndromes,
including Lennox-Gastaut Syndrome, mostly as
adjunctive therapy.

• Usual preparations – Tablet 25,50,100,150,200 mg;
Initial 100-200 mg/day (>12 yrs of age)
LAMOTRIGINE

• Oral Bioavailability – >95 %
• Time to Peak Levels – 1-3hours
• Reference range – 2.5-15mg/L
• Elimination – primary by conjugation with glucuronic acid in
Liver.
dizziness, diplopia,ataxia, blurred vision, somnolence,
insomnia, headache, nausea, asthenia, skin rash(5.9%)
(including serious cutaneous reactions )
lower with a low starting dose and with a slow dose
escalation.
LAMOTRIGINE

LAMOTRIGINE
• Lamotrigine associated rash is typically maculopapular or
erythematous, pruritic and has the characteristics of delayed
hypersensitivity reaction, appearing within first 4 weeks of
initiating treatment and resolving rapidly within drug
withdrawl. Rarely, rash may be more severe (erythema
multiforme) and progress to dsquamation with involvement
of mucous membrane (Stevens-Johnson Syndrome)

LAMOTRIGINE
• Sporadic cases of multiorgan failure have also been reported
attributed to lamotrigine.
Multisystem adverse reaction to Lamotrigine ; Shaub et al;
Lancet 1994, 344;481
• Isolated cases of Pseudolymphoma, agranulocytosis,
neutropenia and hepatotoxicity have also been reported.
Drug-induced pseudolymphoma secondary to Lamotrigine ;
Pathak P et al ; Neurology 1998; 50;1509-1510

LAMOTRIGINE
Significant drug interactions –
Serum Lamotrigine levels are reduced by enzyme inducing
AEDs (Phenytoin, carbamazepine, phenobarbital).
Absorption is not altered by presence of food.
Serum Lamotrigine levels are increased by Valproic acid as
Valproate reduces rate of Lamotrigine elimination . (approx
doubled half life). It explains the increased incidence of rash
seen after starting add-on Lamotrigine in patiets reveiving
Valproate.
While the pharmacokinetics of other AEDs is not altered when
Lamotrigine is added or withdrawn to the regimen.

• Comment –
- A very useful drug which can be used as 1st or 2nd line
monotherapy, or as adjunctive therapy in treatment of
partial seizures and occasionaly in generalised epilepsy
syndromes.
- safe in pregnancy.
- Main advantage is relative broad spectrum efficacy against
multiple seizure types and good tolerability, particularly
when used as monotherapy.
- Main disadvantage is need for slow-dose escalation. Highly
variable pharmacokinetics in relation to physiological
factors (pregnancy) and drug interactions.
LAMOTRIGINE

TOPIRAMATE
• Mechanism of action
- blockade of voltage dependent Na and Ca channels
- potentiation of GABA mediated inhibition at GABA A receptors,
- reduction of excitatory action of Glutamate via AMPA receptors,
- inhibition of carbonic anhydrase.
- Adjunctive therapy or monotherapy of partial
and secondary GTCS.
- also useful for Lennox-Gastaut Syndrome and primary
generalised tonic clonic seizures.

• Usual preparations – Tablet 25,50,100,200 mg;
Initial - 25 mg/day
Maintenance - 100-500 mg/day (>12 yrs of age)
• Dosing frequency –2 times/day
TOPIRAMATE

• Oral Bioavailability – approx 100%.
• Elimination – partly by renal excretion and partly by oxidative
metabolism.
dizziness, ataxia, somnolence, paraesthesia, tremor,
somnolence, cognitive dysfunction, confusion, agitation,
amnesia, depression, headache, nausea, diarrhoea,
diplopia, weight loss.
TOPIRAMATE

TOPIRAMATE
Serum Topiramate levels are reduced by enzyme inducing
AEDs (Phenytoin, carbamazepine, phenobarbital).
Topiramate may increase serum Phenytoin levels.
Ingestion with food delays absorption by approx 2 hours but
maximal plasma concentrations are unchanged for a given oral
dose.

• Comment –
- A very useful drug with relatively broad spectrum efficacy.
- Safe in pregnancy.
- Main advantage is high responder rates.
- Main disadvantage is CNS adverse effects.
- Dose reduction required in renal diseases.
TOPIRAMATE

TIAGABINE
• Mechanism of action – Inhibition of GABA reuptake by
depressing GABA transporter GAT-1 which removes
synaptically released GABA into neurons and glial cells
and thus potentiates GABA mediated neuronal inhibition.
- Adjunctive therapy for partial seizures, with or
without secondary generalization.

• Usual preparations – Tablet 2.5,5,10 and 15 mg
Starting dose - 5 mg/day, which may be increased
by weekly increment of 5 mg/day
Maintenance - 15-30 mg/day
TIAGABINE

• Time to Peak Levels – 0.5- 2.3 hours
• Reference range – 0.02-0.2 mg/L
• Elimination – Primarily by oxidative metabolism mediated by
cytochrome CYP3A4.
dizziness, asthenia, nervousness, tremor,
attention/ concentration difficulties, depressed mood,
language problems (difficulty in finding words or inititating
speech) , seizure exacerbations (myoclonic and
absence seizures, Non-convulsive status epilepticus)
TIAGABINE

TIAGABINE
Serum Topiramate levels are reduced by enzyme inducing
AEDs by promoting its clearance.
Tiagabine does not affect metabolism of coadministered AED.
Food delays the absorption but does not change the total
amount absorbed.
The pharmacokinetics of Tiagabine is unaffected in patients
with renal impairment
Patients with hepatic impairment have higher and more
prolonged concentrations of Tiagabine and more neurological
adverse effects.

• Comment –
- A valuable drug for the adjunctive treatment of refractory
partial epilepsy with or without secondary generalization.
- Its use in unclassied epilepsy and generalized epilepsies is
to be avoided.
- Main advantage is that mechanism of action distinct from
that of other AEDs and clearly demonstrated efficacy in
partial seizures.
- Main disadvantage is short half life necessitating multiple
daily dosing, need for slow dose titration, CNS adverse
effects, and efficacy spectrum related to partial seizures.
- Dose modification not needed in Renal diseases but to be
done in hepatic disorders.
TIAGABINE

LEVETIRACETAM
• First approved in USA in 1999 as adjunctive treatment in
patients with partial-onset seizures.
• A pyrrolidine derivative that differs from all other currently
approved AED in its chemical structure, pharmacological
profile and mechanism of action and as a consequence posses
unique pharmacological properties.
• Mechanism of action – Binds to Synaptic Vesicle 2A (SV2A)
protein. Precise mechanism by which this binding acts is
unknown but is likely to involve inhibition of
neurotransmitter release from nerve end terminals.
Doesnot involve any of the three main AED mechanism (blockade of
sodium or T type Ca channels or enhancement of GABA ergic
neurotransmission)

LEVETIRACETAM
- First- line and adjunctive therapy of partial-onset
seizures.
- Adjunctive and, possibly, first line therapy of GTCS and
Myoclonic seizures associated with idiopathic
generalized epilepsies.

• Usual preparations –
Immediate Release Tablets 250,500,750,1000 mg
Extended release tablets – 500,750 mg
oral solution- 100mg/ml
Intravenous Preparation – 500mg/ 5ml (given as 15-min infusion)
Adults :1000-3000 mg/day. T/t may be started with 500 or 1000
mg/day and increased to target dose by increments of 500 or 1000
mg every 1-2 weeks
Children : 20-60 mg/kg/day. T/t may be started with 10-20mg/kg/day
and adjusted according to response , by increments of 10-20
mg/kg/day every 2 weeks
• Dosing frequency –2 times/day
LEVETIRACETAM

• Time to Peak Levels – 0.5-2 hours
• Half life – approx 6-8 hours
• Elimination – Primarily by renal excretion in unchanged form
(66%).
dizziness, ataxia, somnolence (10%), asthenia, infection,
nervousness, irritability, behavioural and Psychiatric
disorders (12.9% vs 6.2% of placebo patients), suicidal
behaviour (0.5% versus 0%in placebo)
LEVETIRACETAM
A systematic review of behavioural effects of Levetiracetam in adults
with Epilepsy : Epilepsy behav 2003; 4; 124-132

LEVETIRACETAM
Serum Levetiracetam levels are reduced by enzyme inducing
AEDs (Phenytoin, carbamazepine, phenobarbital) by about
20-30 %.
Levetiracetam doesnot induce or inhibit drug metabolizing
enzymes.
Administration with food doesnot reduce the extent but
decreases the rate of absorption.

LEVETIRACETAM
• Renal impairment reduces clearance of Levetiracetam and its
metabolites.
• Compared to subjects with normal renal function,
levetiracetam clearance is reduced on an average by 40% with
a creatinine clearance (CLcr) of 50-80 ml/min, by 50% with
Clcr of 30-50 ml/min, and by 60% with CLcr < 30%.
Clinical Pharacokinetics of Levetiracetam : Clin Pharmacokinet
2004;43;707-724

LEVETIRACETAM
• Dose reduction in relation to degree to renal impairment are
recommended as follows :
Renal function Creatinine Clearance
(ml/min/1.73 sq m)
Dose administered
twice daily (mg)
Normal 80 500-1500
Mild 50-80 500-100
Moderate 30-50 250-750
Severe <30 250-500
2004;43;707-724

LEVETIRACETAM
• For a patient with renal failure on hemodialysis, a dose of
500-1000 mg/day is recommended, with a supplemental dose
of 250-500 after a dialysis treatment
2004;43;707-724

LEVETIRACETAM
• Hepatic impairment :
• Mild to moderate (Child-pugh class A or B) hepatic
impairment donot alter the clearance and no dose alterations
are required in these patients.
• However, Levetiracetam clearance is reduced in severe
hepatic failure (Child-Pugh class C), most likely due to
concomitant renal insufficiency.
• Adjustments in dose should be made on renal rather than
hepatic function.
Pharacokinetics of Levetiracetam in patients with moderate to severe
liver cirrhosis: Clin Pharmaco ther 2005;77;529-541

• Comment –
- A valuable antiepileptic drug for both first line use and
adjunctive therapy.
- Main advantage is Relatively broad spectrum activity, good
tolerability, and lack of clinically significant drug
interactions.
- Main disadvantage is efficacy in some generalized seizure
types and epilepsy syndrome unproven. Behavioural and
psychiatric adverse effects
- dose reduction required in renal diseases.
LEVETIRACETAM

OXCARBAZEPINE
• Mechanism of action – Blockade of voltage gated Na channels
and N and P type calcium channels.
- Adjunctive therapy or monotherapy for partial and
secondary generalized seizures.
- Also useful to treat primary generalized tonic clonic
seizures not associated with absence and myoclonic
seizures.
-

• Usual preparations – Tablet 150,300, 600 mg
oral suspension – 60mg/ml
Starting dose - 300 mg/day (5mg/kg/day), which may
be increased by weekly increment of
300 mg/week
Maintenance - 900-1800 mg/day (20-45 mg/kg/day)
• Dosing frequency – 2 times/day
OXCARBAZEPINE

• Oral Bioavailability – > 95 %.
• Time to Peak Levels – 4- 6 hours
• Half life – approx 5 hours (of MHD)
• Elimination – Ketoreduction to MHD (monohydroxycarbazepine) ,
which is then cleared in urine in unchanged form and
as a glucuronide conjugate. Toxic effects due to
epoxide etabolite (as with Carbamazepine) are
hence avoided.
Dizziness, diplopia, ataxia, somnolence, headache, fatigue,
rash, hyponatremia, gastrointestinal disturbances
OXCARBAZEPINE

OXCARBAZEPINE
Serum Oxcarbazepine levels are reduced by enzyme inducing
AEDs by promoting its clearance.
Oxcarbazepine may increase the levels of phenytoin and
Phenobarbital.
oral bioavailability is not affected by food intake.
Drug interactions and auto induction of own metabolism are
less marked because it is a weak enzyme inducer

• Comment –
- A useful drug for the treatment of partial and secondary
generalized seizures, with some advantages over
Carbamzepine.
- Main advantage is that it is better tolerated and has fewer
interactions than carbamazepine. Risk of hepatotoxicity is
estimated to be lower than carbamazepine.
- Main disadvantage is efficacy spectrum restricted to
partial epilepsies. Higher incidence of hyponatremia
compared with carbamazepine.
- Not indicated for absence, myoclonic and other types of
generalized seizures other than tonic-clonic seizures and
indeed may exacerbate them.
OXCARBAZEPINE

ZONISAMIDE
• Was approved in USA (2000) and Europe(2005).
• Mechanism of action – Multiple including blockade of voltage
gated Na channels, blockade of T-type calcium channels,
potentiation of GABAergic transmission and inhibition of
Carbonic anhydrase.
- Adjunctive therapy for partial and secondary
generalized seizures.
- May also be used as adjunctive therapy in primary
generalized seizures.
- Myoclonic Epilepsies (Uncontrolled studies)

• Usual preparations – Capsules 25,50, 100 mg
Starting dose - 50 mg/day initially, increased to 100
mg/day after 1 week and 200mg/day after a further 2
weeks. Further dose increments by 100mg/day may be
indicated at intervals of 1-2 weeks, according to clinical
response.
ZONISAMIDE

• Oral Bioavailability – ~ 100%.
• Time to Peak Levels – 2- 6 hours
• Elimination – partly by renal excretion, partly by metabolism
mediated by CYP3A4, N-Acetyltransferase and glucuronyl
transferase.
ZONISAMIDE

ZONISAMIDE
Serum Zonisamide levels are reduced by enzyme inducing
AEDs.
Administration with food doesnot reduce the extent but
decreases the rate of absorption.
Zonisamide doesnot induce or inhibit drug metabolizing
enzymes.

• Since both Zonisamide and Topiramate exhibit carbonic
anhydrase inhibitory activity, possibility of an increase in the
incidence of renal stones has been raised.
• No renal calculi were identified in 59 patients exposed to both
Zonisamide and Topiramate for upto 135 weeks in the US and
European clinical trials, while one case of Nephrolithiasis was
reported during postmarketing surveillance in the USA.
Zonisamide and renal calculi in patients with Epilepsy : how big an issue?
Wroe S. : Curr MedRes Opin 2007;23;1765-1773

ZONISAMIDE
Dizziness, somnolence (18% vs placebo), diplopia, ataxia,
headache, attention and concentration difficulties, memory
impairment, agitation, irritability, confusion, depression,
anorexia, Weight loss, Nephrolithiasis (1.2-1.4%), skin rashes
(including Stevens Jonhnson Syndrome), blood dyscrasias and
hypersensitivity reaction.
Teratogenicity has been reported in animal studies.
(cardiovascular defects, skeletal abnormalities and fetal
death)
Reproduction studies of Zonisamide in animals ; Terada Y et al; Jpn
Pharmaco Ther; 1987; 15; 4399-4416

• Comment –
- A useful AED drug with a probable broad spectrum of
efficacy
- Main advantage is long term clinical experience
(Japan) and suggestive evidence of broad spectrum
efficacy.
- Main disadvantage is CNS adverse effects.
- No proven safety in Pregnancy, so should be avoided.
ZONISAMIDE

PREGABALIN
• Was approved by Eurpean Medicines Agency (EMEA) in July
2004 and US FDA in June 2005.
• Mechanism of action –Binds to the α2- δ subunit of voltage
gated calcium channels, causing decreased calcium influx at
nerve terminals and reduced excitatory neurotransmitter
release . No effect on GABA pathways.
- Adjunctive therapy for partial seizure with or without
secondary generalization.
- also used in Neuropathic pain, Fibromyalgia and
generalized anxiety disorders.

• Usual preparations – Capsules 50, 75,100,150,200,300 mg
Starting dose - 150 mg/day
PREGABALIN

• Half life – 5-7 hours
• Elimination –Renal excretion in unchanged form.
So dose should be reduced by 50% in patients with CLcr
between 30-60 ml/min compared to those with CLcr >
60ml/min . And a further reduction of dose by 50 % for each
additional 50 % decrease in Clcr.
PREGABALIN

PREGABALIN
Pregabalin may potentiate the effects of other CNS
depressants on cognition and motor coordination.
Pregabalin is devoid of any enzyme-inducing or inhibiting
activity on drug metabolizing enzymes and is not itself
significantly metabolized. So drug interactions are unlikely.

PREGABALIN
Dizziness (28.9%) , somnolence (20.8%), ataxia, asthenia,
weight gain (10.4% vs 1.4% in placebo),
visual disturbances, attention and concentration
difficulties, tremor and peripheral edema

• Comment –
- A useful AED drug for management of Refractory Partial
onset seizures.
- Main advantage is robust efficacy, predictable
pharmacokinetics, lack of drug interactions and activity in
neuropathic pain, Fibromyalgia and Generalized Anxiety
Disorders.
- Main disadvantage is spectrum of efficacy limited to
partial eplipsies, CNS adverse effects and propensity to
cause weight gain.
- No data on Pregabalin adminstration in Pregnancy.
- Studies in Generalized epilepsies are under way.
PREGABALIN

LACOSAMIDE
• Recently been licensed for clinical use (2008).
• Mechanism of action – Enhances slow inactivation of
voltage- gated sodium channels resulting in stabilization of
hyperexcitable neuronal membranes ; may interact with
Collapsin response mediated protein 2 (CRMP-2)
(involved in signal transduction of Neurotrophic factors ---under research)
- Adjunctive therapy for refractory partial-onset seizure
with or without secondary generalization in adults
with epilepsy.

Tablets - 50, 100,150,200 mg
Syrup – 15 mg/ml
Intravenous solution – 10 mg/ml
Starting dose - 100 mg/day
LACOSAMIDE

• Time to Peak Levels – 0.5-4 hours following oral dose.
• Elimination – Partly by Renal excretion in unchanged form in
urine (40%) and partly by metabolism
(primarily demethylation) follwed by excretion.
No dose reduction required in Mild to Moderate Renal or
Hepatic dysfunction but dose reduction required in severe cases
LACOSAMIDE

LACOSAMIDE
Enzyme inducing AEDs reduce serum Lacosamide levels by
approx 25 %.
No significant effect of food intake on Pharmacokinetics of
Lacosamide.
Lacosamide doesnot alter metabolism of coadministered AEDs.

LACOSAMIDE
Dizziness , headache, nausea, diplopia, Tremor, nausea,
vomiting
Initial concerns were regarding QTc prolongation – but found
to have no effect on QTc at 800mg/day.
Lacosamide demonstrated no potential for QTc prolongation
Epilepsia 2007;48 (suppl 7)
Asymptomatic PR prolongation has been observed but no 2nd
or 3rd degree Heart block has been observed.
Lacosamide in diabetic neuropathic pain trials ; Euro J Neurol 2008; 15 (Suppl 3)

• Comment –
- A potentially valuable AED as an adjunctive therapy in the
management of Partial-onset seizures with or without
secondary generalization in adults with epilepsy.
- Main advantage is well documented efficacy, lack of
clinically important drug interactions and availability of
Intravenous formulation.
- Main disadvantage is limited clinical experience, CNS
and gastrointestinal adverse effects.
- May also be used in Neuropathic Pain at doses of
400mg/day.
LACOSAMIDE
Lacosamide safety and efficacy in painful distal diabetic neuropathy ;
Neurology ; 66:( Suppl 2 ) 318-319

ESLICARBAZEPINE ACETATE
• One of the latest AED to be licensed for clinical use (2009).
• Mechanism of action –
Blockade of voltage gated sodium channels resulting in
stabilization of hyper-excitable neuronal membranes.
- Adjunctive therapy for partial seizures.
(potential additional indications are under assessment)

Tablets – 400, 600 and 800 mg
Syrup – 50 mg/ml
800 – 1200mg/day (tentative dose range)
• Dosing frequency – once daily

• Time to Peak Levels – 2-3 hours following oral dose.
• Elimination – Hydrolyzed rapidly to Eslicarbazepine, which is
excreted in urine in free and conjugated form. Minor
metabolites include (R)-licarbazepine, oxcarbazepine and
their conjugates.

Enzyme inducing AEDs reduce serum Eslicarbazepine levels.
Eslicarbazepine acetate decreases the levels of OCPs.

Dizziness , blurred vision, headache, nausea, diplopia,
nausea, vomiting, visual disturbances

• Comment –
- Potentially a useful AED, but more data are needed to
establish its place in the current therapy.
- Main advantage is usually well tolerated, once daily dosing
- Main disadvantage is limited clinical experience, efficacy
spectrum probably restricted to partial epilepsies.

RETIGABINE
• Recently been approved by FDA (2011).
• Mechanism of action – Activation of voltage gated neuronal
Potassium channels [KCNQ (kv7)], resulting in enhanced
M-current, and thereby stabilization of resting membrane
potential. (under research)
- Adjunctive therapy for refractory partial-onset seizure.

Tablets - 50, 100,200,300 and 400 mg
600-1200 mg/day. Treatment started at 300mg/day
and increased at weekly intervals by 150mg/day upto desired
target dose.
RETIGABINE

• Time to Peak Levels – 0.6-1.5 hours.
• Elimination – Partly by Renal excretion in unchanged form in
urine (20-30%) and partly by metabolism
(50-65% ) followed by excretion.
No dose reduction required in Mild to Moderate Renal or
Hepatic dysfunction but dose reduction required in severe cases
RETIGABINE

RETIGABINE
Retigabine increases Lamotrigine levels by about 20%.
Enzyme inducing AEDs reduce serum Lacosamide levels by
approx 30 %.
No significant effect of food intake on Pharmacokinetics of
Lacosamide.

RETIGABINE
Dizziness , somnolence, fatigue, confusion, dysarthria,
confusion, tremor, urinary hesitancy/retention.

• Comment –
- A potentially valuable AED as an adjunctive therapy in the
management of refractory Partial-onset seizures.
- Studies are required to assess potential efficacy in other
seizure types.
- Main advantage is clearly defined dose related efficacy,
low interaction potential.
- Main disadvantage is need for gradual titration and for
frequent dosing, CNS adverse effects and limited clinical
experience.
RETIGABINE

ANTIEPLILEPTIC DRUGS IN EARLY
CLINICAL DEVELOPMENT

2-DEOXY-D-GLUCOSE
• Differs from normal Glucose by lacking an Oxygen atom at 2
position.
• MOA- intake into cells is not followed by metabolism-leading
to inhibition of Glycolysis – supposed to decrease
epileptogenesis.
• Effective in various animal models.
• Drug interaction, efficacy and adverse effects are presently
unknown.
Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute
Seizures in Adult Rats :Xiao-Yuan Lian, Firdous A. Khan, and Janet L. Stringer The
Journal of Neuroscience, 31 October 2007, 27(44): 12007-
12011; doi: 10.1523/JNEUROSCI.3163-07.2007

FLUOROFELBAMATE
• Analogue of Felbamate, devoid of toxic metabolite
(Atropaldehyde).
• So designed to emulate clinical efficacy of Felbamate without
its safety concerns ( aplastic anemia and hepatotoxicity)
• Exact MOA is unknown, but appears to decrease responses to
GABA, kainate and NMDA and to decrease voltage dependent
sodium currents.
• Shown to have greater potency than Felbamate in
experimental models
unknown.
Seizure. 2002 Oct;11(7):423-30.Anticonvulsant and antiepileptogenic effects of
fluorofelbamate in experimental status epilepticus.Mazarati AM, Sofia
RD, Wasterlain CG

GANAXOLONE
• A neurosteroid, synthetic analogue of allopregnalone, a
metabolite of Progesterone.
• Potent positive modulator of GABA-A receptors.
• Effective in various experimental Models
• Preliminary trials have not shown any significant drug
interactions.
• Might be useful in Generalized as well as partial epilepsy and
also in Infantile Spasms.
• Adverse effects – sedation, dizziness, headache, GI
disturbances , fatigue
Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18.Clinical evaluation of
ganaxolone in pediatric and adolescent patients with refractory epilepsy.Pieribone
VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O

JZP-4
• Structural analogue of Lamotrigine with better
pharmacokinetic and safety profiles compared to Lamotrigine.
• Potent sodium and high voltage calcium channel blocker.
• Co adminstration of valproic acid did not result in any
significant change in JZP-4 pharmacokinetics.
unknown.
Pharmacol Biochem Behav. 2008 Jun;89(4):523-34 In vivo pharmacological effects
of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and
antidepressant activity. Foreman MM et al

SELETRACETEM
• An analogue of Levetiracetam.
• Is approximately 10 fold more potent than Levetiracetam in
some experimental models.
• Drug interaction, efficacy are presently unknown.
• Well tolerated
• Most frequently encountered adverse effect is somnolence,
dizziness, euphoria and nausea.
J Neuro Sci 2005;238 : Matagne et al : Seletracetam (UCB 44212)

YKP3089
• A novel compound with broad spectrum anticonvulsant
activity.
• MOA is unknown
• Effective in all kinds of experimental models.
unknown.
Epilepsy Res. 2007 Jan;73(1):1-52. Progress report on new antiepileptic drugs: a
summary of the Eigth Eilat Conference (EILAT VIII). Bialer M, Johannessen
SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T.

REFERENCES
• The treatment of Epilepsy 3rd Edition : Simon Shorovon, Emilio
Perucca & Jerome Engel Jr
• Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in
Models of Acute Seizures in Adult Rats :Xiao-Yuan
Lian, Firdous A. Khan, and Janet L. Stringer The Journal of
Neuroscience, 31 October 2007, 27(44): 12007-
12011; doi: 10.1523/JNEUROSCI.3163-07.2007
• Seizure. 2002 Oct;11(7):423-30.Anticonvulsant and
antiepileptogenic effects of fluorofelbamate in experimental
status epilepticus.Mazarati AM, Sofia RD, Wasterlain CG

• Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18.Clinical
evaluation of ganaxolone in pediatric and adolescent patients
with refractory epilepsy.Pieribone VA, Tsai J, Soufflet C, Rey
E, Shaw K, Giller E, Dulac O
• Pharmacol Biochem Behav. 2008 Jun;89(4):523-34 In vivo
pharmacological effects of JZP-4, a novel anticonvulsant, in
models for anticonvulsant, antimania and antidepressant
activity. Foreman MM et al
• J Neuro Sci 2005;238 : Matagne et al : Seletracetam (UCB
44212)
• Epilepsy Res. 2007 Jan;73(1):1-52. Epub 2006 Dec 8.Progress
report on new antiepileptic drugs: a summary of the Eigth
Eilat Conference (EILAT VIII).Bialer M, Johannessen
SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T.

• Pelleck JM et al. Felbamate :consensus of current clinical
experience. Epilepsy Res 2006;71:89-101
• The SANAD study of effectiveness of carbamazepine,
gabapentin, Lamotrigine, oxcarbazepine or Topiramate for
treatment of Partial epilepsy :an unblinded randomised
controlled trial ;LANCET 2007;369;1000-1015
• A double blind trial of gabapentin monotherapy for newly
diagnosed partial seizures. Chadwick et al . Neurology
1998;51;1282-1288
• Gabapentin vs Lamotrigine monotherapy ; a double blind trial
in newly diagnosed epilepsy : EPILEPSIA 2002;43;993-1000

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