K.B. Das

Master Class Nov 2012

What is their role?

Update on Newer AEDs

Young Epilepsy

Learning objectives

To understand the role of newer AEDs in

managing epilepsy

Discuss some newer drugs

Assumptions

Newer drugs are more efficacious

They have novel modes of action

Their side effects are less

Drug interactions are less

They are more cost effective

Drug-resistant Epilepsy (ILAE 2010)

‘Failure of adequate trials of two tolerated,

appropriate chosen and used AED schedules

(where as monotherapy or in combination)

to achieve seizure freedom’

Previously : intractable, refractory, difficult epilepsy

Cumulative probability of being seizure-free by time from start of treatment and number of antiepileptic drug regimens

Brodie ,Neurology 2012 ,78:1548

Lucky 7 !

Zonisamide 2005

Japan 1989, US 2000

Broad spectrum

Indications

Adjunctive therapy in the treatment of partial

seizures, with or without secondary

generalisation in adult patients (>18 yrs)

Monotherapy in the treatment of partial

seizures, with or without secondary

generalisation, in adults with newly diagnosed

epilepsy

Mechanism

The mechanism of action of zonisamide is not

fully elucidated

It appears to act on voltage-sensitive sodium

and calcium channels

Zonisamide also has a modulatory effect on

GABA-mediated neuronal inhibition

Dosing

1-2 - 5-8 mg/kg/day ; build up 2 weekly

Adults:100mg/day – 200 mg/day – 300-

500mg/day

Can be given OD for focal sz

Steady state 13 days

Half life 105 hrs

Zonegran

Effectiveness

Placebo Zonisamide

Sz reduction 16% 51%

Very common (>1 in 10)

Somnolence , dizziness ,loss of appetite

Agitation, irritability, confusion, depression, ataxia,memory impairment,

diplopia and decreased blood bicarbonate levels.

Common (1/10 - 1/100)

Weight decreased

Ecchymosis ,Rash ,Hypersensitivity (including cases of Stevens-Johnson syndrome )

Abdominal pain

Anxiety, Insomnia

Psychotic disorder

Nephrolithiasis

Nausea, Constipation ,Diarrhoea ,Dyspepsia

Pruritis ,Alopecia

Fatigue

Influenza-like illness

Pyrexia

Peripheral oedema

Side Effects

Caution Unexplained Rash

Serious rashes can occur including cases of Stevens-

Johnson syndrome.

Sulphonamide reactions

Serious immune based adverse reactions include rash, allergic

reaction and major haematological disturbances including

aplastic anaemia, which very rarely can be fatal.

Cases of agranulocytosis, thrombocytopenia, leukopenia,

aplastic anaemia, pancytopenia and leucocytosis have been

reported.

Pancreatitis

Rhabdomyolysis

Heat stroke

Kidney stones

Renal stones have occurred in patients treated with zonisamide.

It should be used with caution in patients who have risk factors for

nephrolithiasis, including prior stone formation, a family history of

nephrolithiasis and hypercalcuria.

Metabolic acidosis

Hyperchloraemic, non-anion gap, metabolic acidosis is caused by renal

bicarbonate loss due to the inhibitory effect of zonisamide on carbonic

anhydrase.

The risk of zonisamide induced metabolic acidosis appears to be more

frequent and severe in younger patients.

If metabolic acidosis develops and persists, consideration should be given to

reducing the dose or discontinuing it as osteopenia may develop.

Should be used with caution in patients being treated concomitantly with

carbonic anhydrase inhibitors such as topiramate.

Rufinamide 2007 (Orphan )

Used to treat patients aged 4 years or older

who have Lennox-Gastaut syndrome

Tablets (100 mg, 200 mg or 400 mg)

Oral suspension (40 mg/ml)

Adults with focal sz 20 % reduction

( in those not on Carbamazepine)

Inovelon

Mechanism

Rufinamide modulates the activity of sodium

channels, prolonging their inactive state

Dosing

Use in children four years of age or older and less than 30 kg

Patients <30 kg not receiving valproate:

Treatment should be initiated at a daily dose of 200 mg

Increase by 200 mg/day increments, as frequently as every two days, up to a

maximum recommended dose of 1000 mg/day

Patients <30 kg also receiving valproate:

As valproate significantly decreases clearance of rufinamide, a lower maximum dose

of Rufinamide is recommended for patients <30 kg being co-administered

valproate.

Treatment should be initiated at a daily dose of 200 mgs

The dose may be increased by 200 mg/day, to the maximum recommended dose

of 600 mg/day.

Use in adults, adolescents and children four years of age or older of 30 kg or over

Treatment should be initiated at a daily dose of 400 mg

The dose may be increased by 400 mg/day increments, as frequently as every two

days, up to max 1-8-3.2gm/day.

Side effects

>1 in 10 patients

somnolence

headache

vomiting

dizziness

nausea

fatigue

Status epilepticus

Status epilepticus cases have been observed during clinical development

studies, under rufinamide whereas no such cases have been observed under

placebo.

These events led to rufinamide discontinuation in 20 % of the cases.

Central Nervous System reactions

Dizziness, somnolence, ataxia and gait disturbances can occur, which could

increase the occurrence of accidental falls.

Hypersensitivity reactions

Fever and rash associated with other organ system involvement. Other

associated manifestations included lymphadenopathy, liver function tests

abnormalities, and haematuria.

QT shortening

Rufinamide produced a decrease in QTc interval proportional to

concentration.

Caution

Interactions

No clinically relevant pharmacokinetic effects

on carbamazepine, lamotrigine, phenytoin, or

sodium valproate

No effect on OCP

Stiripentol 2007 (Orphan)

It is available as capsules and sachets (250

and 500 mg)

Start 10mg/kg/day in 2-3 doses

The normal dose is 50 mg per kg/day,

divided into two or three doses

Add on therapy for Dravet

( with Valproate + Clobazam)

Also tried in drug resistant epilepsy

Diacomit

Stiripentol in SMEI

Side effects Seen >1 in 10 patients:

loss of appetite

weight loss

insomnia

drowsiness

hypotonia

dystonia

behaviour

Monitor FBC,LFT/6 monthly, growth

Need to monitor drug levels, adjust dose

Pregablin

The active substance, pregabalin, is a gamma-

aminobutyric acid analogue ((S)-3-

(aminomethyl)-5-methylhexanoic acid).

Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in

the central nervous system

Indications

Is indicated as adjunctive therapy in adults

with partial seizures with or without secondary

generalisation

In the treatment of peripheral and central

neuropathic pain in adults

Generalised Anxiety Disorder in adults

Dosing

Pregabalin treatment can be started with a

dose of 150 mg per day given as two or three

divided doses.

Based on individual patient response and

tolerability, the dose may be increased to 300

mg per day after 1 week.

The maximum dose of 600 mg per day may be

achieved after an additional week.

Lyrica

Side effects

Dizziness

Somnolence

Weight gain (Diabetic)

Hypersensitivity

Blurred vision

Renal failure

CCF

Benefits

No interactions with other drugs

No interactions with OCP

Lacosamide 2008

Adjunctive treatment of focal seizures >16yrs

Selectively enhance slow inactivation of Na

channels ( others act on fast inactivation)

Start 50 mg /day , increase to 100 mg bd , max

200 mg bd

IV formulation available

Vimpat

Indications

It is indicated as adjunctive therapy in the

treatment of partial-onset seizures with or

without secondary generalisation in adult and

adolescent (16-18 years) patients with

epilepsy.

Solution for infusion:

Is an alternative for patients when oral

administration is temporarily not feasible.

Dosing

The recommended starting dose is 50 mg

twice a day which should be increased to an

initial therapeutic dose of 100 mg twice a day

after one week.

Depending on response and tolerability, the

maintenance dose can be further increased by

50 mg twice a day every week, to a maximum

recommended daily dose of 400 mg

(200 mg twice a day)

Efficacy

Placebo Lacosamide

200mg

Lacosamide

400mg

Lacosamide

600mg

50% reduction

in the number

of seizures

23% 34% 40% 40% +

Side effects

Very common(1/10) :dizziness ,headache ,

diplopia, nausea

Common(1/100): depression, conduction

defects, CNS, GIT

Not sedative

Caution Dizziness

Treatment with lacosamide has been associated with dizziness

which could increase the occurrence of accidental injury or

falls.

Cardiac Rhythm and Conduction

Prolongations in PR interval with lacosamide have been

observed in clinical studies. Lacosamide should be used with

caution in patients with known conduction problems or severe

cardiac disease such as a history of myocardial infarction or

heart failure.

Second degree or higher AV block has been reported in post-

marketing experience.

In the placebo-controlled trials of lacosamide in epilepsy

patients, atrial fibrillation or flutter were not reported;

however both have been reported in open-label epilepsy

trials and in post-marketing experience

Interactions

No interaction with CMZ, Valproate

concentrations

Enzyme inducers reduce Lacosamide levels

No significant interaction with OCP

Eslicarbazepine Acetate 2009

Eslicarbazepine acetate is a third generation of a family of antiepileptic drugs (AEDs), which includes carbamazepine (first generation) and oxcarbazepine (second generation)

Eslicarbazepine is thought to work by blocking ‘voltage-gated sodium channels’

Less hyponatraemia (1%), rash(1.1%) and

CNS side effects

It is used to treat adults with partial-onset seizures with or without secondary generalisation

(Children- trial on)

Tab 200 mg, 400 mg, 600 mg and 800 mg

Start at 400 mg once a day, before increasing it to 800 mg once a day after one or two weeks.

Zebinix

Efficacy

Placebo Eslicarbazepine

400mg

Eslicarbazepine

800mg

Eslicarbazepine

1200mg

50% Sz

reduction

19% 21% 34% 36%

Carbamazepine & Oxcarbazepine

CMZ reduces Eslicarbazepine levels by 32%

CMZ levels unchanged

Increased diplopia, ataxia, dizziness

Concomitant use with Oxcarbazepine is not

recommended because this may cause

overexposure to the active metabolites

Side effects

The most common side effects (>in 10) are

dizziness and somnolence

It must not be used in people with second or

third degree atrioventricular block

Retigabine 2011

It is indicated as adjunctive treatment of partial

onset seizures with or without secondary

generalisation in adults >18 years

Mechanism

In vitro studies indicate that retigabine acts

primarily through opening neuronal potassium

channels (KCNQ2 [Kv7.2] and KCNQ3

[Kv7.3]).

This stabilises the resting membrane potential

and controls the sub-threshold electrical

excitability in neurons, thus preventing the

initiation of epileptiform action potential bursts.

The mechanism of action of retigabine (ezogabine)

Dosing

Tablets: 50 mg; 100 mg;

200 mg; 300 mg; 400 mg

The maximum total daily starting dose is 300

mg (100 mg three times daily)

Thereafter, the total daily dose is increased by

a maximum of 150 mg every week

Effective maintenance dose : 600 - 1,200

mg/day

Trobalt

Side Effects

Dizziness

Somnolence

Fatigue

Dysuria

Urinary hesitation

Haematuria

Chromaturia

CNS

Weight gain

GIT

Very common Common

Caution

Urinary retention

Urinary retention, dysuria and urinary hesitation were reported in

controlled clinical studies with retigabine, generally within the first 8

weeks of treatment

QT interval

Retigabine titrated to 1,200 mg/day produced a QT-prolonging

effect

Monitor ECG

Psychiatric disorders

Confusional state, psychotic disorders and hallucinations were

reported in controlled clinical studies with retigabine.

These effects generally occurred within the first 8 weeks of

treatment, and frequently led to treatment withdrawal in affected

patients

Perampanel 2012

Perampanel is the first highly selective, non-

competitive AMPA receptor antagonist.

It inhibits post-synaptic AMPA receptor

activation by agonists, and selectively inhibits

the transmission of seizures by blocking the

effects of glutamate.

Dosing

• Starting Dose

• Treatment should be initiated at a dose of

2 mg/day

• Maintenance Dose

• The dose may be increased based on clinical response and tolerability by increments of 2 mg/day to a maintenance dose of

4–8 (12 )mg/day

• OD

• Fixed pricing irrespective of dose

• Fycompa

Caution

Carbamazepine, Phenytoin, Oxcarbazepine &

Topiramate reduce Perampanel levels

Reduced efficacy of progesterone containing

OCP

Not recommended in moderate or severe renal

failure

Caution in mild/moderate hepatic impairment

Zonisamide

2005

Rufinamide

2007

Lacosamide

2008

Eslicarb

azepine

2009

Retigabine

2011

Perampanel

2012

License >18yrs

>4 yrs >16yrs Adults 18yrs >12yrs

Spec

trum

broad broad focal focal focal focal

Mechan Na /GABA Na Na Na K AMPA

Dosing BD/OD BD BD OD TDS OD

Dosage 8mg/kg/day

100-300-

500mg/day

400 - 1200

mg bd

50-200mg bd 400-

800mg od

300 -

1200mg tds

2- 8(12) mg/

od

Side

effects

Sleep, dizzy,

Wt loss

Rash, renal

stones, blood,

acidosis, heat

stroke

Sleep, dizzy,

Headache

Sz increase,

Dizzy

Headache

Diplopia

AV block

Dizzy,

Sleepy

Rash,

diplopia

AV block

Fatigue

Bladder

retention, QT

Dizziness, sleep

Others Long half life

No effect on

OCP

LGS

Status

No

interactions

No effect on

OCP

IV

Avoid

oxcarb

Reduces

OCP

No significant

interactions

ECG

Interactions

Reduces OCP

Cost !

Phenobarb 60mg (28) - 71 p

Phenytoin 100mg(28) £30.00

Tegretol 200mg (84) £3.83

Epilim 200mg(100) £7.00

Leveteracetam 1gm (60)

£101.10

Pregabalin 300mg (56)

£64.60

Zonisamide 100mg (56)

£ 62.72

Rufinamide 400mg (60)

£102.96

Stiripentol 250mg(60) - £284,

500mg (60) - £493

Lacosamide 200mg (56)

£144.16

Retigabine 400mg (84)

£127.68

Perampanel 12mg(28) £140

Newer drugs are more

efficacious

They have novel modes of

action

Their side effects are less

Drug interactions are less

More cost effective

No

Some

Maybe

+ / -

Are they really superior to the older ones ?!

No

Newer AEDs

• Lack of efficacy of older drugs

• Contraindications to older drugs

• Interactions with other drugs (OCP)

• Older drugs poorly tolerated by the child

• The child is currently of childbearing potential or is likely to need treatment into her childbearing years

NICE

Any questions?

Summary

Many new drugs have novel mechanisms of

action

Side effect profile is better

They have a role in adjunctive therapy of drug

resistant epilepsy

Thank you!

Acknowledgments

BNF

NICE

EMA

Martin Brodie