Appendix B
Pharmacological treatment
1.1 Principles of AED prescribing
The following principles are based on best practice from the experience of the
GDG.
•
Tailor AED medication to seizure type, syndrome and individual
factors. (see Table 1 and Table 2)
•
Only start one drug at a time and only make one change at a time.
•
Prescribers may wish to establish base-line biochemistry prior to
commencing AED therapy.
•
AED therapy should be started in a dose no higher than recommended
by the manufacturer.
•
Start at a low dose and work up slowly.
•
Dosing will be determined by adverse effects and continuation of
seizures with the aim being to have seizure freedom and no adverse
effects. (See Table 4 and Table 5)
•
The dose can slowly be increased until seizure freedom is achieved but
do not increase the dose if there are adverse effects.
•
The rate of changes and the end dose will be determined by the
individual’s response to therapy. The balance of seizure control and
adverse effects should be discussed with the individual.
•
Individuals and carers should be given clear instructions to seek
medical attention urgently for symptoms including rash, bruising, or
drowsiness with vomiting especially in the first weeks of treatment.
•
If seizures continue despite maximum tolerated dose of an AED,
review the diagnosis and aetiology and ask about medication that the
individual is taking.
•
If AED has failed because of adverse effects or continued seizures,
start the second drug, build up to an adequate or maximum tolerated
dose and then taper the first drug slowly. If combination is successful,
some individuals may prefer to remain on the combination.
•
If the second drug is unhelpful, taper off either drug depending on the
side effects and how well the drug is tolerated, maintaining the
alternative drug, before starting a third drug.
1.2 AED choices by seizure type and by syndrome
Seizure Type
1st line drugs
Generalised tonic-clonic
Lamotrigine
Sodium valproate
Topiramate
Absence
Ethosuximide
Sodium valproate
Myoclonic
Sodium valproate
Topiramate
Tonic, Atonic
Lamotrigine
Sodium valproate
Partial
Simple, complex,
with/without secondary
generalisation
Carbamazepine
Lamotrigine
Oxcarbazepine
Sodium valproate
Topiramate
2nd line drugs
Carbamazepine
Clobazam
Clonazepam
Levetiracetam‡
Oxcarbazepine
Clobazam
Clonazepam
Lamotrigine
Topiramate
Clobazam
Clonazepam
Lamotrigine
Levetiracetam
Piracetam
Clobazam
Clonazepam
Levetiracetam
Topiramate
Clobazam
Gabapentin
‡
Levetiracetam
Phenytoin
Tiagabine
Other drugs
that may be
considered
Acetazolamide
Phenobarbitone
Phenytoin
Primidone*
Drugs to be avoided**
Carbamazepine
Gabapentin
Tiagabine
Vigabatrin
Carbamazepine
Gabapentin
Tiagabine
Vigabatrin
Acetazolamide
Phenobarbitone
Primidone*
Acetazolamide
Clonazepam
†
Felbamate
Phenobarbitone
Primidone*
Table 1 Drug options by seizure type
* Should rarely be initiated – if a barbiturate is required, phenobarbitone is preferred.
** Drugs to be avoided have been linked with making seizures worse rather than better.
†
‡
Felbamate is not marketed in the UK, but is available from the US.
Licensed only as adjunctive therapy for partial onset seizures
Epilepsy syndrome
1st line drugs
2nd line drugs
Childhood absence
epilepsy
Ethosuximide
Lamotrigine
Sodium valproate
Levetiracetam
Topiramate
Juvenile absence epilepsy
Lamotrigine
Sodium valproate
Levetiracetam
Topiramate
Juvenile myoclonic
epilepsy
Lamotrigine
Sodium valproate
Topiramate
Clobazam
Clonazepam
Levetiracetam
Acetazolamide
Generalized tonic clonic
seizures on waking
Lamotrigine
Sodium valproate
Topiramate
Levetiracetam
Focal epilepsies:
cryptogenic, symptomatic
Carbamazepine
Lamotrigine
Oxcarbazepine
Sodium valproate
Topiramate
Infantile spasms
Steroids
Vigabatrin
Benign epilepsy with
centrotemporal spikes
Carbamazepine
Lamotrigine
Oxcarbazepine
Carbamazepine
Lamotrigine
Oxcarbazepine
Clobazam
Clonazepam
Gabapentin
Levetiracetam
Phenytoin
Tiagabine
Clobazam
Clonazepam
Sodium valproate
Topiramate
Sodium valproate
Topiramate
Acetazolamide
Clobazam
Clonazepam
Oxcarbazepine
Phenobarbitone
Phenytoin
Primidone*
Acetazolamide
Phenobarbitone
Primidone*
Benign epilepsy with
occipital paroxysms
Severe myoclonic epilepsy
of infancy
Continuous spike wave of
slow sleep
Lennox Gastaut syndrome
Landau Kleffner syndrome
Myoclonic astatic epilepsy
‡
Clobazam
Clonazepam
Sodium valproate
Topiramate
Clobazam/Clonazepam
Ethosuximide
Lamotrigine
‡
Steroids
Lamotrigine
Sodium valproate
Topiramate
Lamotrigine
Sodium valproate
Steroids‡
Clobazam
Clonazepam
Sodium valproate
Topiramate
Drugs to be
avoided**
Other drugs
Carbamazepine
Phenytoin
Tiagabine
Vigabatrin
Carbamazepine
Phenytoin
Tiagabine
Vigabatrin
Carbamazepine
Phenytoin
Tiagabine
Vigabatrin
Vigabatrin
Nitrazepam
†
Sulthiame
Sodium valproate
Topiramate
Levetiracetam
Stiripentol†
Phenobarbitone
Levetiracetam
Sodium valproate
Topiramate
Clobazam
Clonazepam
Ethosuximide
Levetiracetam
Levetiracetam
Topiramate
Lamotrigine
Vigabatrin
Carbamazepine
Vigabatrin
Felbamate†
Sulthiame†
Lamotrigine
Levetiracetam
Table 2 Drug options by epilepsy syndrome
* Should rarely be initiated – if a barbiturate is required, phenobarbitone is preferred.
** Drugs to be avoided have been linked with making seizures worse rather than better.
†
‡
Not marketed in the UK, but is available from the US.
Steroids: prednisolone or ACTH
•
All drugs are listed in alphabetical order.
•
Second line drugs should be prescribed under the guidance of an
epilepsy specialist.
•
The Committee of Safety of Medicines (CSM) recommends that
‘women of child bearing potential should not be started on sodium
valproate without specialist advice’.1
•
Many drugs may not be in a suitable formulation for administration to
young children. Any manipulation of the formulation (for example,
preparation of a suspension), will mean the drug is being used outside
the product licence.
•
Choice of a benzodiazepine may be influenced by the availability of a
liquid preparation. This may be particularly important for children and
people who are unable to tolerate tablet forms of medication, for
example the very elderly.
•
Pyridoxine should be considered for children under the age of three
years with resistant seizures of unknown aetiology.
Drug
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Piracetam
Tiagabine
Topiramate
*partial seizures only
u=unlicensed
Age (yrs) below which use is unlicensed
Monotherapy
Adjunctive treatment
u
<6
<12
<2
u
<16*
<6
<6
u
<16
u
<12
<6
<2
Table 3 Unlicensed AEDs in children by age
1.3 Significant side effects of drug treatment in adults
•
Please refer to the British National Formulary and the Summary of
Product Characteristics for full details of side effects.
•
Prescribers should refer individuals who wish more information on side
effects to the National Society for Epilepsy website
(http://www.epilepsynse.org.uk/).
Drug
Acetazolamide
Carbamazepine*
Clobazam
Clonazepam
Ethosuximide
Gabapentin
Felbamate
Lamotrigine
Levetiracetam
Oxcarbazepine*
Phenobarbitone*
Phenytoin*
Piracetam
Primidone*
Sodium valproate
Tiagabine
Topiramate
Vigabatrin
Significant side effects include
Lack of appetite, loss of weight, drowsiness, depression, pins and needles in hands and feet, joint
pains, increased urine output, thirst, headache, dizziness, fatigue and irritability. Tolerance may
develop.
Skin rash, if allergic to carbamazepine. Blurred vision, double vision, unsteadiness and nausea
may occur initially or if the dose is too high.
Drowsiness may occur but this drug is less sedating than clonazepam or diazepam. Tolerance
may develop.
Drowsiness and sedation are quite common but these may wear off. Tolerance tends to develop.
Nausea, drowsiness and irritability may occur initially or if the dose is too high. Weight loss.
Drowsiness, dizziness, headache and fatigue.
Aplastic anaemia (monitoring required), leucopenia, acute hepatic failure (monitoring required),
anorexia, weight loss, nauseas, vomiting, insomnia, dizziness, somnolence, headache, skin rashes
Skin rash, if allergic to lamotrigine. Drowsiness, double vision, dizziness, headache, insomnia and
flu like symptoms. Behaviour change.
Dizziness, drowsiness, irritability, insomnia, some unsteadiness, tremor, headache, nausea and
loss of appetite may occur in high dosages or when doses are increased, but will usually disappear
after a few days.
Double vision, unsteadiness, headache, nausea, confusion. Skin rash if allergic to oxcarbazepine.
Drowsiness may occur initially. Sedation and slowing of mental performance may persist.
Skin rash if allergic to phenytoin. Drowsiness, unsteadiness and slurred speech may occur if the
dose is too high. Coarsening of facial features, overgrowth of gums, growth of excess hair and
acne may be problems with prolonged therapy, as can some anaemias (treated with folic acid).
Shaky movements, unsteady gait, rapid involuntary movement of the eye and sedation.
Very rare, but may include weight gain, diarrhoea, insomnia, drowsiness, nervousness, depression
and rash.
Nausea, unsteadiness and drowsiness may occur initially. Sedation and slowing of mental
performance may persist.
Drowsiness and tremor are infrequent side effects. Hair loss occurs in some people but this is not
usually severe and is usually reversible if the dose is reduced. Weight gain may occur. Liver
damage is very uncommon. Encephalopathy may occur. Also, hyperammonaemia, blood
dyscrasias, and rarely pancreatitis. Sodium valproate has been associated with increased
incidence of polycystic ovaries and menstrual irregularities. Any menstrual problems should be
reported to the GP and neurologist. Sodium valproate is associated with a higher risk of fetal
malformations if taken in pregnancy, than are other AEDs.
Dizziness, fatigue, anxiety, tremor, concentration difficulties, depression of mood, agitation and
jerkiness of limbs.
Headache, drowsiness, dizziness, pins and needles in hands and feet, loss of weight and kidney
stones. Slowing of mental performance and of language may occur when dose is increased but will
usually disappear after a few days. Rarely, reported cases of secondary angle-closure glaucoma
usually occurring within a month of starting treatment
Drowsiness, nausea, behaviour and mood changes. Psychotic reactions have been reported.
Visual field defects have been reported in one in three people taking vigabatrin in the long term.
Any person who has concerns about this should talk to their GP and neurologist. Visual field tests
should be done every six months while taking vigabatrin.
Table 4 Significant side effects of drug treatment in adults
* Hepatic enzyme inducing drugs
1.4 Significant side effects of drug treatment in children
•
Please refer to the British National Formulary and the Summary of
Product Characteristics for full details of side effects.
•
Prescribers should refer individuals and their families who wish more
information on side effects to the National Society for Epilepsy website
(http://www.epilepsynse.org.uk/).
Drug
Acetazolamide
Significant side effects include
Lack of appetite, loss of weight, drowsiness, depression, pins and needles in hands and feet,
joint pains, increased urine output, thirst, headache, dizziness, fatigue, irritability.
Carbamazepine* Skin rash, if allergic to carbamazepine. Blurred vision, double vision, unsteadiness and nausea
may occur initially or if the dose is too high. Dizziness and headaches.
Clobazam
Drowsiness may occur but this drug is less sedating than clonazepam or diazepam. Fatigue,
irritability and depression. Behaviour change.
Clonazepam
Drowsiness and sedation are quite common but these may wear off, and tolerance (decline in
effectiveness with time) tends to develop. Increased respiratory tract secretions. Fatigue,
aggression and overactive restlessness.
Ethosuximide
Nausea, headache and drowsiness.
Aplastic anaemia (monitoring required), leucopenia, acute hepatic failure (monitoring required),
Felbamate
anorexia, weight loss, nauseas, vomiting, insomnia, dizziness, somnolence, headache, skin
rashes
Gabapentin
Drowsiness, dizziness, headache, fatigue. double vision, unsteadiness and shaky movements.
Behaviour change.
Lamotrigine
Skin rash, particularly if rapid dose increase, if allergic to lamotrigine. Drowsiness, double
vision, dizziness, headache and flu like symptoms, if the dose is too high. Possibly insomnia.
Levetiracetam
Dizziness, nausea, sedation and behaviour change.
Oxcarbazepine* Double vision, unsteadiness, headache, nausea, and confusion. Skin rash if allergic to
oxcarbazepine.
Phenobarbitone* Drowsiness may occur initially, sedation and slowing of mental performance may persist.
Fatigue, listlessness, tiredness, depression, rash, insomnia and irritability. Hyperactivity,
aggression and subtle impairment of memory, mood and learning capacity.
Phenytoin*
Skin rash if allergic to phenytoin. Drowsiness, unsteadiness and slurred speech may occur if
the dose is too high. Coarsening of facial features, overgrowth of gums, growth of excess hair
and acne may be problems with prolonged therapy, as can some anaemias (treated with folic
acid). Shaky movements, unsteady gait, rapid involuntary movement of the eye and sedation.
Primidone*
Fatigue, listlessness, tiredness, depression, psychosis, overactive restlessness and irritability.
Sodium valproate Hair loss occurs in some people but this is not usually severe and is usually reversible if the
dose is reduced. Weight gain may occur with increased appetite. Gastric problems,
hyperactivity and behaviour problems. Drowsiness and shaky movements are infrequent side
effects. Liver damage has been reported but is uncommon. Most at risk are <2 years but most
likely related to undiagnosed metabolic disease so care should be demonstrated in this age
group where the diagnosis is unclear and where they are on polytherapy. Slightly abnormal
liver function tests are common and not indicative of damage. Encephalopathy may occur, and
may be associated with cognitive regression. Also, hyperammonaemia, blood dyscrasias, and
rarely pancreatitis. The use of sodium valproate has been associated with increased incidence
of polycystic ovaries and menstrual irregularities in young women but needs to be evaluated
further. Sodium valproate is associated with a higher risk of fetal malformations if taken in
pregnancy, than are other AEDs.
Stiripentol
Nausea, vomiting, gastro-intestinal disturbance, insomnia, occasional behaviour changes
Acute porphyria, nausea, vomiting
Sulthiame
Tiagabine
Dizziness, fatigue, anxiety, tremor, concentration difficulties, depression of mood, agitation and
jerkiness of limbs.
Topiramate
Headache, drowsiness, dizziness, pins and needles in hands and feet and loss of weight.
Increased risk of kidney stones. Slowing of mental performance and of language may occur but
minimised if dose started low and increased slowly. Cases of eye reactions (glaucoma
presenting as painful red eye) have rarely been associated with topiramate occurring within 1
month of starting treatment.
Vigabatrin
Drowsiness, nausea, behaviour and mood changes. Psychotic reactions have been reported.
Visual field defects have been reported in one in three adults taking vigabatrin in the long term.
Visual fields should be measured every six months while taking vigabatrin where possible
according to the developmental age of the child (>9 years).
Table 5 Significant side effects of drug treatment in children
* Hepatic enzyme inducing drugs
1.5 Drug interactions
•
Please refer to the British National Formulary and the Summary of
Product Characteristics for full details of possible drug interactions.
•
The issue of interaction with oral contraceptives is addressed in section
14.4 of the full guideline.
References
1.
Sodium valproate and prescribing in pregnancy. Current Problems in
Pharmacovigilance 2003;29:6.