update on newer aeds - youngepilepsy.org.uk · antiepileptic drugs (aeds), which includes...
TRANSCRIPT
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