twice daily, then increased in steps of 200 mg twice
daily (max. per dose 1.2 g twice daily), adjusted
according to response, dose to be increased at intervals
▶ Child 4–17 years (body-weight 70.1 kg and above): Initially
200 mg twice daily, then increased in steps of 200 mg
twice daily (max. per dose 1.6 g twice daily), adjusted
according to response, dose to be increased at intervals
▶ Adult (body-weight 30–50 kg): Initially 200 mg twice
daily, then increased in steps of 200 mg twice daily
(max. per dose 900 mg twice daily), adjusted according
to response, dose to be increased at intervals of not less
▶ Adult (body-weight 50.1–70 kg): Initially 200 mg twice
daily, then increased in steps of 200 mg twice daily
(max. per dose 1.2 g twice daily), adjusted according to
response, dose to be increased at intervals of not less
▶ Adult (body-weight 70.1 kg and above): Initially 200 mg
twice daily, then increased in steps of 200 mg twice
daily (max. per dose 1.6 g twice daily), adjusted
according to response, dose to be increased at intervals
Adjunctive treatment of seizures in Lennox-Gastaut
syndrome with valproate (initiated by a specialist)
▶ Child 1–3 years: Initially 5 mg/kg twice daily, then
increased in steps of up to 5 mg/kg twice daily (max.
per dose 15 mg/kg twice daily), adjusted according to
response, dose to be increased at intervals of not less
than 3 days to the target dose (maximum dose), each
dose should be given to the nearest 0.5 mL
▶ Child 4–17 years (body-weight up to 30 kg): Initially
100 mg twice daily, then increased in steps of 100 mg
twice daily (max. per dose 300 mg twice daily), adjusted
according to response, dose to be increased at intervals
▶ Child 4–17 years (body-weight 30–50 kg): Initially 200 mg
twice daily, then increased in steps of 200 mg twice
daily (max. per dose 600 mg twice daily), adjusted
according to response, dose to be increased at intervals
▶ Child 4–17 years (body-weight 50.1–70 kg): Initially 200 mg
twice daily, then increased in steps of 200 mg twice
daily (max. per dose 800 mg twice daily), adjusted
according to response, dose to be increased at intervals
▶ Child 4–17 years (body-weight 70.1 kg and above): Initially
200 mg twice daily, then increased in steps of 200 mg
twice daily (max. per dose 1.1 g twice daily), adjusted
according to response, dose to be increased at intervals
▶ Adult (body-weight 30–50 kg): Initially 200 mg twice
daily, then increased in steps of 200 mg twice daily
(max. per dose 600 mg twice daily), adjusted according
to response, dose to be increased at intervals of not less
▶ Adult (body-weight 50.1–70 kg): Initially 200 mg twice
daily, then increased in steps of 200 mg twice daily
(max. per dose 800 mg twice daily), adjusted according
to response, dose to be increased at intervals of not less
▶ Adult (body-weight 70.1 kg and above): Initially 200 mg
twice daily, then increased in steps of 200 mg twice
daily (max. per dose 1.1 g twice daily), adjusted
according to response, dose to be increased at intervals
326 Epilepsy and other seizure disorders BNF 78
l CAUTIONS Patients at risk of further shortening of QTc
l INTERACTIONS → Appendix 1: antiepileptics
l ALLERGY AND CROSS-SENSITIVITY Antiepileptic
hypersensitivity syndrome associated with rufinamide. See
under Epilepsy p. 305 for more information.
l PREGNANCY Manufacturer advises avoid unless
essential—toxicity in animal studies. See also Pregnancy in
l BREAST FEEDING Manufacturer advises avoid—no
l HEPATIC IMPAIRMENT Manufacturer advises caution in
mild to moderate impairment; avoid in severe impairment
Dose adjustments Manufacturer advises cautious dose
titration in mild to moderate impairment.
l DIRECTIONS FOR ADMINISTRATION Manufacturer advises
tablets may be crushed and given in half a glass of water.
l PRESCRIBING AND DISPENSING INFORMATION
Switching between formulations Care should be taken when
switching between oral formulations. The need for
continued supply of a particular manufacturer’s product
should be based on clinical judgement and consultation
with the patient or their carer, taking into account factors
such as seizure frequency and treatment history.
Patients may need to be maintained on a specific
manufacturer’s branded or generic rufinamide product.
l PATIENT AND CARER ADVICE Counselling on antiepileptic
hypersensitivity syndrome is advised.
Medicines for Children leaflet: Rufinamide for preventing seizures
www.medicinesforchildren.org.uk/rufinamide-preventingseizures
Driving and skilled tasks Manufacturer advises patients and
carers should be cautioned on the effects on driving and
performance of skilled tasks—increased risk of dizziness,
somnolence and blurred vision.
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (November
2008) that rufinamide (Inovelon ®) is accepted for restricted
use within NHS Scotland as adjunctive therapy in the
treatment of seizures associated with Lennox-Gastaut
syndrome in patients 4 years and above. It is restricted for
use when alternative traditional antiepileptic drugs are
The Scottish Medicines Consortium has advised (July
2012) that rufinamide 40 mg/mL oral suspension
(Inovelon ®) is accepted for restricted use within NHS
Scotland as adjunctive therapy in the treatment of seizures
associated with Lennox-Gastaut syndrome in patients
4 years and above. It is restricted for use when alternative
traditional antiepileptic drugs are unsatisfactory.
▶ In children The Scottish Medicines Consortium has advised
(April 2019) that rufinamide (Inovelon ®) is accepted for
restricted use within NHS Scotland as adjunctive therapy
is restricted for use when alternative traditional
antiepileptic drugs are unsatisfactory.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 8, 21
EXCIPIENTS: May contain Propylene glycol
Rufinamide 40 mg per 1 ml Inovelon 40mg/ml oral suspension
sugar-free | 460 ml P £94.71 DT = £94.71
CAUTIONARY AND ADVISORY LABELS 8, 21
Rufinamide 100 mg Inovelon 100mg tablets | 10 tablet P £5.15
Rufinamide 200 mg Inovelon 200mg tablets | 60 tablet P £61.77 DT = £61.77
Rufinamide 400 mg Inovelon 400mg tablets | 60 tablet P £102.96 DT = £102.96
▶ BY MOUTH USING IMMEDIATE-RELEASE MEDICINES
▶ Child 1 month–11 years: Initially 10–15 mg/kg daily in
1–2 divided doses (max. per dose 600 mg);
maintenance 25–30 mg/kg daily in 2 divided doses,
doses up to 60 mg/kg daily in 2 divided doses may be
used in infantile spasms; monitor clinical chemistry
and haematological parameters if dose exceeds
▶ Child 12–17 years: Initially 600 mg daily in 1–2 divided
doses, increased in steps of 150–300 mg every 3 days;
maintenance 1–2 g daily in 2 divided doses; maximum
▶ Adult: Initially 600 mg daily in 1–2 divided doses, then
increased in steps of 150–300 mg every 3 days;
maintenance 1–2 g daily, alternatively maintenance
20–30 mg/kg daily; maximum 2.5 g per day
Initiation of valproate treatment
▶ INITIALLY BY INTRAVENOUS INJECTION
▶ Adult: Initially 10 mg/kg, (usually 400–800 mg),
followed by (by intravenous infusion or by intravenous
injection) up to 2.5 g daily in 2–4 divided doses,
alternatively (by continuous intravenous infusion) up
to 2.5 g daily; (by intravenous injection or by
intravenous infusion or by continuous intravenous
infusion) usual dose 1–2 g daily, alternatively (by
intravenous injection or by intravenous infusion or by
continuous intravenous infusion) usual dose
20–30 mg/kg daily, intravenous injection to be
Continuation of valproate treatment
▶ BY INTRAVENOUS INJECTION, OR BY INTRAVENOUS INFUSION,
OR BY CONTINUOUS INTRAVENOUS INFUSION
▶ Adult: If switching from oral therapy to intravenous
therapy give the same dose as current oral daily dose,
give over 3–5 minutes by intravenous injection or in
2–4 divided doses by intravenous infusion
▶ BY MOUTH USING IMMEDIATE-RELEASE MEDICINES
▶ Adult: Initially 200 mg twice daily, then increased if
necessary to 1.2–1.5 g daily in divided doses
▶ Adult: Total daily dose to be given in 1–2 divided doses
(consult product literature) continued→
BNF 78 Epilepsy and other seizure disorders 327
▶ Adult: Total daily dose to be given in 1–2 divided doses
▶ Adult: Total daily dose to be given in 1–2 divided doses
▶ Adult: Initially 750 mg daily in 1–2 divided doses,
adjusted according to response, usual dose 1–2 g daily
in 1–2 divided doses, doses greater than 45 mg/kg daily
▶ Adult: Total daily dose to be given in 1–2 divided doses
▶ Adult: Initially 750 mg daily in 1–2 divided doses,
adjusted according to response, usual dose 1–2 g daily
in 1–2 divided doses, doses greater than 45 mg/kg daily
▶ Adult: Total daily dose to be given in 1–2 divided doses
Not licensed for migraine prophylaxis.
MHRA/CHM ADVICE: VALPROATE MEDICINES: CONTRA-INDICATED
IN WOMEN AND GIRLS OF CHILDBEARING POTENTIAL UNLESS
CONDITIONS OF PREGNANCY PREVENTION PROGRAMME ARE MET
Valproate is highly teratogenic and evidence supports
that use in pregnancy leads to neurodevelopmental
disorders (approx. 30–40% risk) and congenital
malformations (approx. 10% risk).
Valproate must not be used in women and girls of
childbearing potential unless the conditions of the
Pregnancy Prevention Programme are met (see
Conception and contraception) and only if other
treatments are ineffective or not tolerated, as judged by
Use of valproate in pregnancy is contra-indicated for
migraine prophylaxis [unlicensed] and bipolar disorder;
it must only be considered for epilepsy if there is no
suitable alternative treatment (see Pregnancy).
Women and girls (and their carers) must be fully
informed of the risks and the need to avoid exposure to
valproate medicines in pregnancy; supporting materials
have been provided to use in the implementation of the
Pregnancy Prevention Programme (see Prescribing and
dispensing Information). The MHRA advises that:
. GPs must recall all women and girls who may be of
childbearing potential, provide the Patient Guide,
check they have been reviewed by a specialist in the
last year and are on highly effective contraception;
. Specialists must book in review appointments at least
annually with women and girls under the Pregnancy
Prevention Programme, re-evaluate treatment as
necessary, explain clearly the conditions as outlined in
the supporting materials and complete and sign the
Risk Acknowledgement Form—copies of the form must
be given to the patient or carer and sent to their GP;
. Pharmacists must ensure valproate medicines are
dispensed in whole packs whenever possible—all packs
dispensed to women and girls of childbearing potential
should have a warning label either on the carton or via
a sticker. They must also discuss risks in pregnancy
with female patients each time valproate medicines
are dispensed, ensure they have the Patient Guide and
have seen their GP or specialist to discuss their
treatment and the need for contraception.
MHRA/CHM ADVICE: VALPROATE MEDICINES: ARE YOU ACTING IN
COMPLIANCE WITH THE PREGNANCY PREVENTION MEASURES?
The MHRA advises that all healthcare professionals must
continue to identify and review all female patients on
valproate, including when used outside licensed
indications (off-label use) and provide them with the
patient information materials every time they attend
appointments or receive their medicines.
Guidance for psychiatrists on the withdrawal of, and
alternatives to, valproate in women of child-bearing
potential who have a psychiatric illness is available from
the Royal College of Psychiatrists.
MHRA/CHM ADVICE: VALPROATE MEDICINES AND SERIOUS
HARMS IN PREGNANCY: NEW ANNUAL RISK ACKNOWLEDGEMENT
FORM AND CLINICAL GUIDANCE FROM PROFESSIONAL BODIES TO
SUPPORT COMPLIANCE WITH THE PREGNANCY PREVENTION
The Annual Risk Acknowledgement Form has been
updated and should be used for all future reviews of
female patients on valproate. Specialists should comply
with guidance given on the form if they consider the
patient is not at risk of pregnancy, including the need for
review in case her risk status changes.
Guidance has been published to support healthcare
professionals with the use of valproate. These include a
summary by NICE of their guidance and safety advice,
pan-college guidance by national healthcare bodies, and
paediatric guidance by the British Paediatric Neurology
Association and the Royal College of Paediatrics and
l CONTRA-INDICATIONS Acute porphyrias p. 1058 . known
or suspected mitochondrial disorders (higher rate of acute
liver failure and liver-related deaths). personal or family
history of severe hepatic dysfunction
l CAUTIONS Systemic lupus erythematosus
CAUTIONS, FURTHER INFORMATION Consider vitamin D
supplementation in patients that are immobilised for long
periods or who have inadequate sun exposure or dietary
▶ Liver toxicity Liver dysfunction (including fatal hepatic
failure) has occurred in association with valproate
(especially in children under 3 years and in those with
metabolic or degenerative disorders, organic brain disease
or severe seizure disorders associated with mental
retardation) usually in first 6 months and usually involving
multiple antiepileptic therapy. Raised liver enzymes
during valproate treatment are usually transient but
patients should be reassessed clinically and liver function
(including prothrombin time) monitored until return to
normal—discontinue if abnormally prolonged
prothrombin time (particularly in association with other
l INTERACTIONS → Appendix 1: antiepileptics
328 Epilepsy and other seizure disorders BNF 78
headache . hepatic disorders . hypersensitivity . hyponatraemia . memory loss . menstrual cycle
▶ Uncommon Androgenetic alopecia . angioedema . bone
oedema . pleural effusion .renal failure . SIADH . skin
reactions . vasculitis . virilism
tubulointerstitial . polycystic ovaries .red blood cell
abnormalities .rhabdomyolysis . severe cutaneous adverse
reactions (SCARs). systemic lupus erythematosus (SLE). urine abnormalities
▶ Frequency not known Alertness increased
▶ With intravenous use Dizziness
SIDE-EFFECTS, FURTHER INFORMATION Hepatic
dysfunction Withdraw treatment immediately if
persistent vomiting and abdominal pain, anorexia,
jaundice, oedema, malaise, drowsiness, or loss of seizure
Pancreatitis Discontinue treatment if symptoms of
l CONCEPTION AND CONTRACEPTION The MHRA advises
that all women and girls of childbearing potential being
treated with valproate medicines must be supported on a
Pregnancy Prevention Programme—pregnancy should be
excluded before treatment initiation and highly effective
contraception must be used during treatment.
l PREGNANCY For migraine prophylaxis[unlicensed] and
bipolar disorder, the MHRA advises that valproate must not
be used. For epilepsy, the MHRA advises valproate must
not be used unless there is no suitable alternative
treatment; in such cases, access to counselling about the
risks should be provided (see Healthcare Professional
Guide for more information) and a Risk Acknowledgement
Form signed by both specialist and patient. If valproate is
to be used during pregnancy, the lowest effective dose
concentrations; doses greater than 1 g daily are associated
with an increased risk of teratogenicity. Neonatal bleeding
(related to hypofibrinaemia) reported. Neonatal
hepatotoxicity also reported. See also Pregnancy in
Monitoring Specialist prenatal monitoring should be
instigated when valproate has been taken in pregnancy.
The dose should be monitored carefully during
pregnancy and after birth, and adjustments made on a
l BREAST FEEDING Present in milk—risk of haematological
disorders in breast-fed newborns and infants.
l HEPATIC IMPAIRMENT Manufacturer advises avoid.
▶ Plasma-valproate concentrations are not a useful index of
efficacy, therefore routine monitoring is unhelpful.
▶ Monitor liver function before therapy and during first
6 months especially in patients most at risk.
▶ Measure full blood count and ensure no undue potential
for bleeding before starting and before surgery.
l EFFECT ON LABORATORY TESTS False-positive urine tests
l TREATMENT CESSATION g Avoid abrupt withdrawal; if
treatment with valproate is stopped, reduce the dose
gradually over at least 4 weeks. h
l DIRECTIONS FOR ADMINISTRATION
▶ With intravenous use Manufacturer advises for intravenous
injection, give over 3–5 minutes. For intravenous infusion,
dilute with Glucose 5% or Sodium Chloride 0.9%.
Reconstitute Epilim® with solvent provided then dilute
with infusion fluid if required. Displacement value may be
significant, consult local guidelines.
▶ With rectal use in children For rectal administration, sodium
valproate oral solution may be given rectally and retained
for 15 minutes (may require dilution with water to prevent
EPIVAL ® Tablets may be halved but not crushed or
EPISENTA ® CAPSULES Contents of capsule may be mixed
with cold soft food or drink and swallowed immediately
EPILIM ® SYRUP May be diluted, preferably in Syrup BP;
EPISENTA ® GRANULES Granules may be mixed with cold
soft food or drink and swallowed immediately without
EPILIM CHRONOSPHERE ® Granules may be mixed with
soft food or drink that is cold or at room temperature, and
swallowed immediately without chewing.
l PRESCRIBING AND DISPENSING INFORMATION The
Pregnancy Prevention Programme is supported by the
following materials provided by the manufacturer: Patient
Guide, Guide for Healthcare Professionals, Risk
Acknowledgement Form, and for pharmacists, Patient Cards
and Stickers with warning symbols; the MHRA has also
produced a patient information sheet providing advice for
women and girls taking valproate medicines.
Switching between formulations Care should be taken when
switching between oral formulations in the treatment of
epilepsy. The need for continued supply of a particular
manufacturer’s product should be based on clinical
judgement and consultation with the patient or their
carer, taking into account factors such as seizure
frequency and treatment history.
Patients being treated for epilepsy may need to be
maintained on a specific manufacturer’s branded or
generic oral sodium valproate product.
EPILIM CHRONOSPHERE ® Prescribe dose to the nearest
Valproate use by women and girls The MHRA advises women
and girls should not stop taking valproate without first
discussing it with their doctor.
Blood or hepatic disorders Patients or their carers should be
told how to recognise signs and symptoms of blood or liver
disorders and advised to seek immediate medical attention
Pancreatitis Patients or their carers should be told how to
recognise signs and symptoms of pancreatitis and advised
to seek immediate medical attention if symptoms such as
abdominal pain, nausea, or vomiting develop.
Pregnancy Prevention Programme Pharmacists must ensure
that female patients have a patient card—see also
Medicines for Children leaflet: Sodium valproate for preventing
seizures www.medicinesforchildren.org.uk/sodium-valproatepreventing-seizures
Medicines for Children leaflet: Sodium valproate and pregnancy -
information for girls and young women
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