sodium valproate (Epilim)

introduction

sodium valproate is an anticonvulsant which is also used to Rx bipolar disorder, and is sometimes used to reduce incidence of migraine attacks
it's actions are attributed to:
- the blockade of voltage dependent Na+ channels
- increased brain levels of gamma-aminobutyric acid (GABA)
it does not have any significant hypnotic effect and has less sedative effects than some older anticonvulsants
has been shown to be effective in the treatment of absence seizures (petit mal), tonic-clonic seizures (grand mal) and myoclonic seizures.
it has similar efficacy to lithium carbonate in the Rx of mania
serum levels are of limited utility but may be useful in assessing compliance

rapidly absorbed after oral dose in fasting patients with peak blood levels at 1-4hrs
absorption is delayed if taken with food with peak blood levels at 3-7hrs but abdorption is still almost complete
gastric irritation is less likely to occur with the enteric coated tablets
correlation between the daily dose per bodyweight and plasma levels of drug has been poor
correlation between plasma levels of drug and CNS actions has been poor
correlation between saliva levels and plasma levels of drug is poor
CSF levels are 5-15% of plasma levels
protein binding sites become saturated at plasma levels > 120 microgram/mL, or in patients with hypoalbuminaemia, causing free drug levels to rise dramatically with further dosage increase
40-60% metabolised by glucuronidation, most of remainder metabolised by oxidation
1-3% excreted unchanged in urine
plasma half-life is variable but appears to be 8-12 hours

pregnancy (category D) - if taken in 1st TM, 1-2% risk of neural tube defects, and may be associated with other fetal changes
hepatitis
PH HS to valproate
urea cycle disorders
hepatic porphyria

prenatal use in women who may become pregnant is not advised unless necessary or contraception is used
lactation
children - increased risk of pancreatitis, hepatitis; avoid concurrent salicylates or barbiturates
liver or renal dysfunction
pancreatitis
systemic lupus erythematosus (SLE)
ornithine transcarbamylase (OTC) deficiency
surgery - prolonged bleeding time and/or thrombocytopenia may occur
thrombocytopenia
suicidality - may increase risk of suicidal thoughts or behaviour
avoid abrupt withdrawal as risk of seizure
weight gain may occur
carbapenem antibiotics
diabetes mellitus or dental caries as Epilim syrup contains sucrose 3.6 g/5 mL
operating machinery or driving, particularly if high dose, rapid cessation, or other anticonvulsants or sedatives used

fetal malformations
dose-related cognitive deficits in children if taken during pregnancy
may increase risk of autism spectrum disorder when taken prenatally (adjusted hazard ratio 2.9)
fatigue
nausea
may cause some sedation, impaired memory, confusion, nystagmus
very uncommonly may cause other CNS effects such as ataxia
gastric irritation
sleeping disorders
flu-like illness
suicidality risk
alopecia
HS reactions
osteopenia / osteoporosis
prolonged bleeding time
thrombocytopenia
pancreatitis
hepatitis
deafness - reversible and irreversible
other more rare adverse effects

dose is usually bd
adults:
- start at 600mg/day and increase by 200mg/d every 3 days until control achieved or max. 2,500mg/day
- most require 1,000 to 2,000 mg/day (i.e. 20 to 30 mg/kg/day)
- it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbitone and carbamazepine.
iv dose for severe acute migraine:
- requires further study but 900-1200mg iv valproate appeared to substantially reduce migraine headache pain within 60 minutes in ~75% of patients ¹⁾

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