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Although treatment with antiepileptic drugs can stop

CLINICAL FOCUS
seizures recurring, close monitoring of side effects is crucial

Epilepsy
pharmacological
treatment and
monitoring ❝ ANTIEPILEPTIC
MEDICATION
By Yogita Dawda, DipPsychPharm, MRPharmS, and
SHOULD BE
Niina Ezewuzie, MSc, MRPharmS
TAILORED
ACCORDING TO
he mainstay of treatment for epilepsy is with

Chagnon | SPL
INDIVIDUAL PATIENT
antiepileptic drugs (AEDs). The benefits of these
medicines in terms of preventing or reducing seizures REQUIREMENTS

❞
need to be weighed carefully against their possible adverse
effects. The aim of AED treatment is to control seizures as
quickly as possible — preferably using monotherapy —
with no or minimal adverse effects and without impact on
the patient’s quality of life. Effective pharmacological
treatment with AEDs requires a reasonable certainty of
the diagnosis of epilepsy or seizure type.
The therapeutic response to AEDs varies with seizure
type. Indeed, some AEDs can worsen certain types of
seizures. On the whole, about 50% of newly diagnosed
patients become seizure-free within one year of starting
treatment with an AED.1,2
This article will focus on the pharmacological
treatments used in managing epilepsy and the associated
drug monitoring.
Initiating treatment
The decision to start an AED should be made jointly by
the patient or his or her carers and a specialist following an
informed discussion of the risks and benefits of treatment.
Treatment with an AED is generally initiated after a
second epileptic seizure; however, consideration should be
given to starting treatment after a single unprovoked
seizure if:
SUMMARY
There is now a wide range of treatments available for patients with
epilepsy. The newer antiepileptic drugs (AEDs) are more acceptable in
terms of adverse effects and provide additional options for patients not
responding to first-line treatments. Treatment decisions should be made
jointly between the patient/carer and a specialist, and monitoring of
treatment response, side effects and drug interactions is essential.
Clinicians should discuss the possibility of discontinuing AED treatment
in adults who have been seizure-free for at least two years. A decision to
discontinue treatment should be based on the patient’s risk of seizures,
lifestyle, prognosis and seizure syndrome.
Status epilepticus is a medical emergency
● The patient has a neurological deficit
● An electroencephalogram shows unequivocal epileptic
activity
● The patient or carers consider the risk of having a
further seizure unacceptable
● Brain imaging shows a structural abnormality
Initial treatment should be with a single AED, started at
a low dose and increased gradually until seizures are
controlled or significant adverse effects occur. The
maintenance dose will be determined by the individual’s
response to therapy and the balance between control of
seizures and adverse effects.3–7
Choosing an AED
In general, AEDs exert their action by: mimicking or
increasing the effects of gamma-aminobutyric acid or other
inhibitory neurotransmitters; or limiting neuronal firing
by acting on voltage-gated sodium or calcium channels.
Antiepileptic medication should be tailored according
to individual patient requirements. When choosing an
AED, clinicians should consider:
● Seizure types and epilepsy syndrome
● Patient preference
● Age
● Childbearing potential
● Other comorbidities
● Likely interactions with concomitant medicines
● Formulations available
Guidance published by the National Institute for
Health and Clinical Excellence in 2004 recommends using
older AEDs as first-line monotherapy, with the newer
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90 Clinical Pharmacist March 2010 Vol 2
medicines used as adjuncts if seizures continue. The
CLINICAL FOCUS
newer drugs are recommended as options for first-line
treatment if the older drugs are contraindicated because
of adverse effects or interactions with existing medicines
and where applicable for women of childbearing age.
Once seizures are controlled, drug therapy should be
continued until the patient has been seizure-free for at
least two years.
Older AEDs
In the UK the most commonly prescribed AEDs are
carbamazepine and sodium valproate, although phenytoin
is still widely used.
Carbamazepine Carbamazepine is the drug of choice
for treating simple and complex seizures and for tonic-
clonic seizures secondary to a focal discharge. It is not
usually effective in absence and myoclonic seizures.
Baseline liver function tests (LFTs), full blood count
(including platelet count) and urea and electrolytes
should be obtained before starting treatment and repeated
six-monthly thereafter. LFTs are particularly important
for patients with a history of liver disease and for elderly
patients. Carbamazepine should be withdrawn immediately
if acute liver disease develops or if liver dysfunction
worsens.
It is essential to start at a low dose (100–200mg once or
twice a day orally for adults, lower for the elderly) and
increase slowly at increments of 100–200mg every two
weeks. The dose is titrated upwards until seizures are
controlled or the patient is not able to tolerate side effects.
Plasma drug monitoring may be used to guide dosing of
carbamazepine; however, the maintenance dose should be
determined by patient response not by drug levels.
The most common dose-related side effects include
fatigue, nausea, blurred vision and ataxia. These are usually
lessened by dose-reduction or changing to a modified-
release formulation. Rare but serious adverse effects
include agranulocytosis, Stevens-Johnson syndrome (SJS),
aplastic anaemia, thrombocytopenia and hepatic
impairment. In addition to carefully monitoring patients’
clinical state, clinicians should educate patients and carers
on early signs indicating haematological, dermatological or
hepatic toxicities (eg, fever, sore throat, rash, mouth ulcers,
easy bruising or bleeding) and advise them to report these
immediately so carbamazepine can be withdrawn promptly.
The allele HLA-B*1502 in patients of Han Chinese
and Thai origin has been shown to predict strongly the
risk of developing carbamazepine-associated SJS. Where
possible, patients of these ethnic groups should be
screened for this allele before initiating treatment with
“Older” antiepileptic drugs and effects on bone
Phenytoin, primidone, carbamazepine and sodium valproate have been
linked with reduced bone mineral density among patients, leading to an
increased risk of osteopenia, osteoporosis and fractures resulting from falls.
Healthcare professionals have been advised in the April 2009 Drug Safety
Update (published by the Medicines and Healthcare products Regulatory
Agency) to consider prescribing supplementary vitamin D — especially for
at-risk individuals who receive long-term treatment.8
carbamazepine. If tested positive, carbamazepine should
be avoided unless there is no other therapeutic option. It
should be noted that patients who test positive for
HLA-B*1502 may be at increased risk of hypersensitivity
from other AEDs. Cross-sensitivity occurs between the
AEDs in up to 70% of patients. It is probably advisable to
avoid other AEDs also known to cause SJS, namely
lamotrigine, phenytoin and phenobarbital.
Being an enzyme inducer, carbamazepine has a high
potential for interactions; possible drug-drug interactions
❝
should be monitored closely and patients counselled
appropriately.
ONCE SEIZURES ARE Sodium valproate Sodium valproate is effective in
CONTROLLED, DRUG controlling tonic-clonic seizures particularly in primary
THERAPY SHOULD generalised epilepsy. It is the drug of choice for primary
BE CONTINUED generalised seizures, generalised absences and myoclonic
UNTIL THE PATIENT seizures.
HAS BEEN SEIZURE- Liver function, platelet count, bleeding time/
FREE FOR AT LEAST coagulation and full blood count should be tested before
TWO YEARS starting treatment (and before surgery also) and then
❞
periodically during the first six months of treatment.
Severe liver damage, including hepatic failure, is a very
rarely reported adverse effect of sodium valproate. Those
most at risk are children under the age of three years and
those with severe seizure disorders, organic brain disease,
or congenital metabolic or degenerative disease associated
with mental retardation — especially when using multiple
AEDs. The likelihood of severe liver damage is
significantly reduced after the age of three years and
progressively decreases with age. Patients and carers
should be educated to report urgently any signs or
symptoms suggesting pancreatic, blood or hepatic
disorders (eg, jaundice, malaise, anorexia, lethargy,
drowsiness, vomiting and abdominal pain) so valproate
can be withdrawn and possible causes can be investigated
without delay.
For adults the oral starting dose is usually 600mg daily
in two divided doses, increasing by 200mg/day every
three days up to a maximum of 2,500mg/day, until
adequate control is achieved. A modified-release
formulation (Epilim Chrono) allows once-daily dosing,
which may improve treatment adherence. Valproate is
highly bound to plasma proteins — when used
concomitantly with other highly protein-bound drugs, eg,
aspirin, free valproic acid levels can increase (hence the
valproate dose may need to be reduced to prevent toxicity).
Side effects include gastrointestinal pain, tremor,
ataxia, sedation, hair loss, increased appetite and weight
gain (>10% body weight).
Phenytoin Phenytoin is effective for treating tonic-clonic
and partial seizures. The medicine shows non-linear
pharmacokinetics — ie, small increases in phenytoin dose
can produce large increases in plasma drug levels, which
increases the risk of toxicity. Plasma drug monitoring is
therefore highly valuable to guide dose adjustments.
Patients and carers should be educated on the
importance of reporting any fever, sore throat, rash,
mouth ulcers, bruising or bleeding immediately, since
these may indicate adverse effects associated with blood
or skin disorders.
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Vol 2 March 2010 Clinical Pharmacist 91

The phenytoin dose should be individualised because Summary of “newer” antiepileptic drugs

CLINICAL FOCUS
there can be wide inter-patient variability in phenytoin
serum levels with equivalent dosage. It should be initiated DRUG YEAR OF LICENSED INDICATIONS COMMENTS
UK LAUNCH MONO-/ADJUNCTIVE THERAPY
at a low dose, increased in gradual increments determined
by plasma drug levels. The dose should be increased until Vigabatrin 1989 Monotherapy: treatment of Selective inhibitor of GABA.
seizure control is achieved or until side effects limit West syndrome. Adjunctive Visual field defects
further increases. therapy: for other seizure experienced by
types when other drug approximately one third of
Side effects include hirsutism, gum hypertrophy and
combinations are ineffective patients. Defects may be
aggravation of acne. Phenytoin treatment is also associated or poorly tolerated. non-reversible.
with SJS and should be discontinued if rash appears.
Lamotrigine 1991 Monotherapy: from age 12 Blocks voltage-gated sodium
years for partial seizures channels. Risk of skin rash
Phenobarbital and primidone Phenobarbital is and primarily or secondarily when used with valproate or
effective against tonic-clonic and partial seizures. It is now generalised seizures. on rapid dose escalation.
generally considered as second-line therapy because of its Adjunctive therapy: from age May alter the efficacy of
side effects, which include sedation, agitation, depression, two years combined oral
behavioural changes and hyperkinesia (in children), as contraceptives.
well as the risk of withdrawal seizures. Primidone has Gabapentin 1993 Monotherapy or adjunctive GABA analogue. Can worsen
similar uses and side effect profile as phenobarbital (which therapy: partial seizures myoclonic or absence
with/without secondary seizures. Minimal drug-drug
is one of the active metabolites of primidone).
generalisation. Licensed interactions. Also licensed for
only as adjunctive therapy in peripheral neuropathic pain.
Newer AEDs children.
All “newer” antiepileptic drugs were initially licensed as Topiramate 1995 Monotherapy (from age six Blocks voltage-gated sodium
adjuncts to the established older agents in combination years) or adjunctive therapy channels, enhances effects of
therapy. Although still referred to as “new” most of these (from age two years): GABA at some receptors and
drugs have been marketed in the UK for a considerable treatment of partial seizures weakly antagonises excitatory
length of time (see Box, right). In general, the newer AEDs with/without secondary activity of some glutamate
generalisation and primarily receptors. Also licensed for
have simpler pharmacokinetics, are less likely to interact
or secondarily generalised migraine prophylaxis. Has
with other medicines, have more favourable side effect seizures. Adjunctive therapy: been associated with acute
profiles and require less laboratory monitoring than the in Lennox-Gastaut syndrome. myopia with secondary
older AEDs. angle-closure glaucoma.
A recent report looking at the uptake of the 2004 Tiagabine 1998 Adjunctive therapy: from age GABA reuptake inhibitor.
NICE guidelines states that in the year leading up to 12 years in partial seizures
March 2008 the rate of prescribing of newer antiepileptic with/without secondary
drugs overall, and as a proportion of all antiepileptic generalisation
drugs, increased and that these medicines accounted for Levetiracetam 2000 Monotherapy (from age 16 Mechanism of action not
39% of AEDs dispensed and 65% of the total cost. A years) or adjunctive therapy fully understood. Drowsiness
partial update of the clinical guideline is expected in (from age one month): is most common side effect
partial seizures with/without and patient should be
2011.
secondary generalisation. advised to be cautious when
Adjunctive therapy: from age driving or performing skilled
“Third-generation” AEDs 12 years for myoclonic tasks. Dose reduction may
Lacosamide is licensed for adjunctive therapy in partial seizures and primarily be required in renal or
seizures with or without secondary generalisation. generalised tonic-clonic hepatic impairment and in
Rufinamide is licensed for the adjunctive treatment of seizures. the elderly.
Lennox-Gastaut syndrome. There is a risk of severe Oxcarbazepine 2000 Monotherapy and adjunctive Carbamazepine analogue.
hypersensitivity syndrome when rufinamide is started, therapy: in partial seizures Can induce liver enzymes
with/without secondary but to a lesser extent than
especially in children. Zonisamide is licensed as
generalisation carbamazepine.
adjunctive treatment for refractory partial seizures with or
Pregabalin 2004 Adjunctive therapy: for Binds to voltage-gated calcium
without secondary generalisation.
partial seizures with/without channels. Also licensed for
secondary generalisation. neuropathic pain and
Other AEDs GABA = gamma-aminobutyric acid generalised anxiety disorder.
Benzodiazepines clonazepam and clobazam are licensed
for the treatment of tonic-clonic or partial seizures and
adjunctive therapy for epilepsy, respectively. However, This multicentre, non-blind, randomised, controlled
their usefulness is restricted by sedative side effects and a study in hospital-based outpatient clinics aimed to
decrease in efficacy when used continuously long term. On compared the longer-term clinical outcomes and cost-
the other hand, benzodiazepines are extremely valuable in effectiveness of newer and older AEDs.
the management of status epilepticus (see p94). The study consisted of two arms: arm A (1,721 subjects
recruited) assessed carbamazepine, as the standard
Comparison of treatment options treatment, against lamotrigine, oxcarbazepine, gabapentin
The “Standard and newer antiepileptic drugs” (SANAD) and topiramate in the treatment of partial epilepsy;9 arm
study was sponsored by the National Institute for Health B (716 subjects recruited) assessed the treatment of
Research’s Health Technology Assessment Programme. generalised and unclassifiable epilepsy with sodium
CP, Mar, p89-94, CF2.qxp 26/2/10 09:03 Page 92

92 Clinical Pharmacist March 2010 Vol 2

valproate, as the standard therapy, against lamotrigine and Therapeutic drug monitoring6,7
CLINICAL FOCUS

topiramate as newer agents.10 The two primary outcomes

assessed were time to treatment failure and time to 12-
month remission.
In arm A, lamotrigine outperformed the other agents
in time to treatment failure with the least favourable
outcomes for gabapentin and topiramate. Carbamazepine
was found to be better than the other agents in the time to
12-month remission measure. In arm B, for the time to
treatment failure measure, sodium valproate was found to
be better than topiramate, and no significant difference
was observed between sodium valproate and lamotrigine.
With regard to time to 12-month remission, sodium
valproate was found to be better than lamotrigine; no
significant difference was found between sodium
valproate and topiramate. Although the SANAD research
has some methodological weaknesses that have been
discussed in many commentaries, it is a large study of
substantial duration that has attempted to provide further
evidence to guide treatment choice in epilepsy.
Failed response and treatment resistance
When monotherapy with a first-line AED has failed,
because of adverse effects or continued seizures,
monotherapy with the second-line agent should be tried
under the guidance of an epilepsy specialist. Extreme
caution is required to limit the breakthrough of seizures
when changing from one AED to another. The second
drug should be started and an adequate dose established
before the first drug is slowly withdrawn.
When treatment for newly diagnosed epilepsy has failed,
clinicians should consider the following possibilities:
Routine monitoring of AED blood levels is not recommended and should
only be done if clinically indicated. There are clinically useful dose-
response and dose-toxicity relationships for carbamazepine and phenytoin
but not for sodium valproate or the newer AEDs. Plasma drug monitoring
may be useful for the following:
● Assessing medicines adherence
● Assessing drug toxicity
● Adjusting phenytoin doses — the drug’s pharmacokinetic profile often
makes accurate dose adjustment difficult without assessing levels
● Managing patients with specific clinical conditions, eg, during
pregnancy, organ failure or status epilepticus
● Managing pharmacokinetic interactions
Different preparations and formulations of AEDs are not necessarily
bioequivalent. It is advised to exercise caution when a change in
formulation is necessary and use plasma drug monitoring to guide dosing
where applicable.
Carbamazepine plasma concentration reaches steady state within about
one to two weeks, depending on auto-induction (where the drug induces an
increase in its own metabolism). Hence, plasma levels should not be
requested less than two weeks after starting treatment or changing the
dose, unless toxicity is suspected. Blood should be taken pre-dose and the
normal therapeutic range (trough) is 4–12mg/L.
Phenytoin is extensively metabolised by the liver and is highly protein
bound. Blood should be taken pre-dose and the normal therapeutic range
(trough) is 10–20mg/L.
into account medicines’ side effect profiles and their
potential for drug interactions.

● An incorrect diagnosis Women of childbearing potential

● An inappropriate choice of treatment for the Contraception Women of childbearing age should be
epilepsy syndrome advised of the need for contraception while taking AEDs
● Non-adherence to treatment (see “Pregnancy” section, below). They should also be
● Interaction with other medicines, which might be informed that enzyme-inducing AEDs such as
affecting plasma levels
● An underlying cerebral neoplasm
● Covert drug or alcohol misuse

If treatment has failed with monotherapy, combination

treatment with two or at most three AEDs may be
necessary. The choice of combinations should take into
account the possible increased risk of drug interactions
and adverse effects. The patient should be established on
the regimen that provides the best balance between
tolerability and control of seizures.
If seizure control is not attained with adequate dosing
of two AEDs and all other causes of treatment failure have
Irina Alyakina | Dreamstime.com

been ruled out, the individual may be suffering from

drug-resistant epilepsy. Once drug resistance is
determined, tertiary referral is recommended at an early
stage since neurosurgery could be an option.

Special populations
Older patients The rate and intensity of AED adverse
effects tend to be greater in older patients (>65 years).
This combined with the high likelihood of polypharmacy
can make treatment choice difficult. Decisions should take
CP, Mar, p89-94, CF2.qxp 26/2/10 11:21 Page 93
carbamazepine, oxcarbazepine, phenobarbital, topiramate
and phenytoin can lower the efficacy of both the
combined and progesterone-only oral contraceptive pills,
hence alternative contraceptive methods should be
discussed and advised where appropriate. NICE provides
detailed guidance on contraception in this setting.
Pregnancy The overall rate of minor and major birth
defects seen in offspring born to mothers with epilepsy
receiving a single AED is two to three times higher than
the rate reported in the general population
(approximately 2–3%). Data suggest that the risk may be
greater with valproate than with carbamazepine or
lamotrigine.
The most common major malformations associated
with AEDs include neural tube defects (spina bifida,
anencephaly), orofacial defects, congenital heart
abnormalities and hypospadias.
Summaries of product characteristics for valproate
products recommend that women of childbearing
potential should not be started on sodium valproate
without specialist advice. When a patient is planning to
become pregnant the risks and benefits of continuing
valproate treatment throughout pregnancy should be
borne in mind and discussed with her. Folate
supplementation (folic acid 5mg/day) before pregnancy
has been shown to reduce the incidence of neural tube
defects and should be offered to all women of
childbearing potential who are taking AEDs. It should be
continued until the end of the first trimester. If a woman
on maintenance valproate treatment becomes pregnant
(unplanned), NICE says consideration should be given to
stopping the valproate.
If valproate is to be continued during pregnancy:
● Monotherapy is preferred
● Folic acid 5mg/day supplementation should be
prescribed
Seizure type can be assessed with
the help of electroencephalography
Vol 2 March 2010 Clinical Pharmacist 93
● The lowest effective dose should be used (£1g/day
CLINICAL FOCUS
since the incidence of neural tube defects, notably
spina bifida, increases above this dose
● Peaks in valproate levels should be avoided by
reducing the dosing interval or using slow-release
formulations while reducing the dosing interval (eg,
use Epilim Chrono rather than Epilim enteric-
coated tablets; give as 400mg twice a day rather
than 800mg once a day)
There are limited data on the safety of the newer
AEDs in pregnancy.
Breastfeeding The benefits of breastfeeding should be
weighed against the possibility of adverse effects
occurring in the infant.
Valproate concentrations in breast milk are low with a
concentration of 1–10% of total maternal serum levels;
breastfeeding would therefore appear to be relatively safe
although haematological effects have been reported in a
small number of infants. Breastfed infants should be
monitored closely for liver and platelet changes.
Carbamazepine concentrations in breast milk have
been shown to be low. Breastfed infants should be
observed for possible adverse effects (eg, excessive
somnolence, allergic skin reaction).
Conversely, lamotrigine breast milk concentrations are
high. Lamotrigine should be avoided for women who are
breastfeeding because of the risk of SJS in the infant.
Children and adolescents Although treatment choices
for children and adolescents are guided by similar
principles as for adults, there are some important
differences: there are a greater number of causes of
epilepsy and epileptic syndromes in children; refractory
epilepsy in children is usually generalised epilepsy; the
syndrome may vary with the age of the child; and the
potential impact on social, behavioural and educational
outcomes may be profound in children.
Cognitive and behavioural side effects of AEDs appear
more common in children and occurrence of these should
prompt a review of therapy. The cognitive effects of AEDs
can be difficult to distinguish from the underlying illness.
Epilepsy itself may impact on cognition (especially
memory) in some children.
Up to 50% of children with epilepsy require additional
support in school. Furthermore, the prevalence of
epilepsy is high in children with learning difficulties and
cerebral palsy. When a child has epilepsy and learning
difficulties, he or she is three times more likely to be
diagnosed with autism by the age of 10 years.7
The interactions of AEDs with hormonal
contraceptives and teratogenic risks should be considered
when selecting medicines for adolescent girls.
Many AEDs are not licensed below a particular age and,
moreover, altering existing formulations for ease of
administration often constitutes unlicensed use. Unlicensed
and “off-label” use should be guided by informed choice as
detailed in a policy statement issued in 2000 by the
Standing Committee of Medicines (a joint committee of
the Royal College of Paediatrics and Child Health and the
Neonatal and Paediatric Pharmacists Group).
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94 Clinical Pharmacist March 2010 Vol 2
Discontinuing treatment
CLINICAL FOCUS
Clinicians should discuss the possibility of discontinuing
AED treatment in adults who have been seizure-free for at
least two years. The decision to discontinue treatment
must be made jointly between the patient/carer and a
specialist and be based on the patient’s risk of seizures,
lifestyle, prognosis and seizure syndrome.
Few studies have reported on AED discontinuation in
adults who were seizure-free for at least two years. One
prospective multicentre randomised study (1,013 patients)
looked at continued AED treatment versus slow
withdrawal of treatment over six months; seizure relapse
occurred for 22% of patients who continued treatment
compared with 41% of the withdrawal group.11 Similar
results were observed in another study of 330 patients.12
A specialist should manage the planned withdrawal of
AEDs. Only one drug should be withdrawn at a time. AED
treatment should normally be stopped gradually over at
least two to three months, preferably longer, and six
months or longer for barbiturates and benzodiazepines.
In the event of a medical emergency, eg, toxicity or
hypersensitivity reaction, abrupt discontinuation of the
AED might be necessary.
Management of status epilepticus
Status epilepticus may present as convulsive or non-
convulsive seizures, although non-convulsive status
epilepticus is uncommon and management is less urgent.
Generalised tonic-clonic status epilepticus is a medical
emergency associated with significant morbidity and
mortality, necessitating rapid diagnosis and emergency
treatment in secondary care. Local protocols for the
management of status epilepticus exist in many trusts.
Parenteral thiamine and pyridoxine are also used in the
management of status epilepticus where the underlying
cause is alcohol misuse or genetic pyridoxine deficiency.
For children, the Status Epilepticus Working Party of
the British Paediatric Neurology Association produced a
consensus guideline in 2000.13 An algorithm from this
guideline is reproduced in appendices to the NICE and
SIGN epilepsy guidelines.
Initial management Pre-hospital care includes securing
the airway, giving oxygen, assessing cardiac and
respiratory function and (where applicable) correcting
hypoglycaemia. If resuscitation facilities are not
immediately available initial treatment is with diazepam
or buccal midazolam (unlicensed use).
Diazepam solution is given rectally. The usual dose for
adults is 10–20mg (10mg for the elderly), and the dose can
be repeated once after 15 minutes. For children and
neonates, the dosing of rectal diazepam solution ranges
from 1.25mg to 10mg depending on the age of the child. A
second dose can be repeated after five minutes.
For children aged over 10 years and adults the dose of
buccal midazolam is 10mg, repeated if necessary after 10
minutes. Dosing varies with age for younger children and
neonates.
In hospital, convulsive status epilepticus is treated with
intravenous lorazepam or clonazepam repeated after 10
minutes if seizures recur. Formulations of diazepam other
than rectal solution are not recommended because of a high
risk of thrombophlebitis with intravenous use and the slow
absorption from suppositories or the intramuscular route.
Failed response If seizures fail to respond within 30
❝
minutes or recur, phenytoin sodium can be administered
by slow intravenous infusion. Fosphenytoin is a prodrug of
phenytoin that can be given more rapidly and is associated
A SPECIALIST with fewer injection site reactions than phenytoin. Both
SHOULD MANAGE agents require electrocardiogram monitoring due to the
THE PLANNED risk of severe cardiovascular reactions with intravenous
WITHDRAWAL OF administration. Intramuscular phenytoin administration is
ANTIEPILEPTICS. too slow and erratic to be appropriate.
ONLY ONE DRUG Phenobarbital sodium may also be used intravenously to
SHOULD BE treat status epilepticus. Rectally administered paraldehyde
WITHDRAWN AT A has a lower risk of causing respiratory depression and can be
TIME a useful alternative where facilities for resuscitation are poor.
❞
Refractory status epilepticus Refractory status
epilepticus in adults (seizures fail to respond within 60
minutes of treatment with phenytoin sodium,
fosphenytoin or phenobarbital sodium) requires initiation
of general anaesthesia using midazolam, thiopental or
propofol (unlicensed use). Full intensive care support
should be available.
References
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approach. Epilepsy & Behavior 2008;12:501–39.
2 Stein MA, Kanner AM. Management of newly diagnosed epilepsy: a
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3 National Institute for Health and Clinical Excellence. The epilepsies: the
diagnosis and management of the epilepsies in adults and children in
primary and secondary care. October 2004. www.nice.org.uk/cg20
(accessed 22 February 2010).
4 National Institute for Health and Clinical Excellence. Newer drugs for
epilepsy in adults. March 2004. www.nice.org.uk/ta76 (accessed 22
February 2010).
5 National Institute for Health and Clinical Excellence. Newer drugs for
epilepsy in children. April 2004. www.nice.org.uk/ta79 (accessed 22
February 2010).
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epilepsy in adults. April 2003 (updated October 2005). www.sign.ac.uk/
guidelines/fulltext/70/index.html (accessed 22 February 2010).
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guidelines/fulltext/81/index.html (accessed 22 February 2010).
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adverse effects on bone. Drug Safety Update 2009;2(9):2.
9 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine,
or topiramate for treatment of partial epilepsy: an unblinded randomised
controlled trial. Lancet 2007;369:1000–15.
10 Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
effectiveness of valproate, lamotrigine, or topiramate for generalised and
unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet
2007;369:1016–26.
11 Medical Research Council Antiepileptic Drug Withdrawal Group.
Randomised study of antiepileptic drug withdrawal in patients in
remission. Lancet 1991;337:1175–80.
12 Specchio LM, Tramacere L, Neve AL, et al. Discontinuing antiepileptic
drugs in patients who are seizure free on monotherapy. Journal of
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13 Appleton R, Choonara I, Martland T, et al. The treatment of convulsive
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Yogita Dawda is lead pharmacist for mental health services for Central and
North West London NHS Foundation Trust. Niina Ezewuzie is lead pharmacist
for mental health services for Central and North West London NHS Foundation
Trust (Chelsea and Westminster Hospital NHS Foundation Trust).
E: yogita.dawda@nhs.net