treatments are ineffective or not tolerated, as judged by
an experienced specialist.
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 (seePregnancy).
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 (seePrescribing 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.lCONTRA-INDICATIONSAcute porphyrias p. 603 .known or
suspected mitochondrial disorders (higher rate of acute
liver failure and liver-related deaths).personal or family
history of severe hepatic dysfunction
lCAUTIONSSystemic lupus erythematosus
CAUTIONS, FURTHER INFORMATIONConsider vitamin D
supplementation in patients that are immobilised for long
periods or who have inadequate sun exposure or dietary
intake of calcium.
▶Liver toxicityLiver 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 infirst 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
relevant abnormalities).
lINTERACTIONS→Appendix 1 : antiepileptics
lSIDE-EFFECTS
▶Common or very commonAbdominal pain.agitation.
alopecia (regrowth may be curly).anaemia.behaviour
abnormal.concentration impaired.confusion.deafness.
diarrhoea.dizziness.drowsiness.haemorrhage.headache
.hepatic disorders.hypersensitivity.hyponatraemia.
memory loss.menstrual cycle irregularities.movement
disorders.nausea.nystagmus.seizures.stupor.
thrombocytopenia.tremor.weight increased
▶UncommonAngioedema.bone disorders.bone fracture.
bone marrow disorders.coma.encephalopathy.
leucopenia.pancreatitis.paraesthesia.parkinsonism.
peripheral oedema.pleural effusion.SIADH.skin
reactions.vasculitis
▶Rare or very rareAgranulocytosis.cerebral atrophy.
cognitive disorder.dementia.enuresis.gynaecomastia.
hirsutism.hyperammonaemia.hypothyroidism.
infertility male.learning disability.myelodysplastic
syndrome.polycystic ovaries.red blood cell abnormalities
.severe cutaneous adverse reactions (SCARs).systemic
lupus erythematosus (SLE).urine abnormalities
▶Frequency not knownAlertness increased.hallucination
SIDE-EFFECTS, FURTHER INFORMATION
Hepatic dysfunctionWithdraw treatment immediately if
persistent vomiting and abdominal pain, anorexia,
jaundice, oedema, malaise, drowsiness, or loss of seizure
control.
PancreatitisDiscontinue treatment if symptoms of
pancreatitis develop.
lCONCEPTION AND CONTRACEPTIONThe 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.
lPREGNANCYFormigraine prophylaxis[unlicensed] and
bipolar disorder, the MHRA advises that valproate must not
be used. Forepilepsy, 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
should be prescribed in divided doses or as modified-
release tablets to avoid peaks in plasma-valproate
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.
MonitoringSpecialist 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
clinical basis.
lBREAST FEEDINGPresent in milk—risk of haematological
disorders in breast-fed newborns and infants.
lHEPATIC IMPAIRMENTAvoid if possible—hepatotoxicity
and hepatic failure may occasionally occur (usually infirst
6 months). Avoid in active liver disease.
lRENAL IMPAIRMENT
Dose adjustmentsReduce dose.
lMONITORING REQUIREMENTS
▶Plasma-valproate concentrations are not a useful index of
efficacy, therefore routine monitoring is unhelpful.
▶Monitor liver function before therapy and duringfirst
6 months especially in patients most at risk.
▶Measure full blood count and ensure no undue potential
for bleeding before starting and before surgery.
lEFFECT ON LABORATORY TESTSFalse-positive urine tests
for ketones.
lTREATMENT CESSATIONgAvoid abrupt withdrawal; if
treatment with valproate is stopped, reduce the dose
gradually over at least 4 weeks.h
lDIRECTIONS FOR ADMINISTRATION
▶With intravenous useForintravenous injection, may be
diluted in Glucose 5 %orSodium Chloride 0. 9 % and given
over 3 – 5 minutes. Forintravenous infusion, dilute injection
solution with Glucose 5 %orSodium Chloride 0. 9 %.
▶With rectal useForrectal administration, sodium valproate
oral solution may be given rectally and retained for
15 minutes (may require dilution with water to prevent
rapid expulsion).
EPIVAL®Tablets may be halved but not crushed or
chewed.BNFC 2018 – 2019 Epilepsy and other seizure disorders 209
Nervous system4