Valproic acid oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of valproic acid.
Drugs List
Therapeutic Indications
Uses
Treatment of all forms of epilepsy
Treatment of generalised, partial or other epilepsy.
Dosage
Daily dosage requirements vary according to age and body weight.
Adults
Initial dose: 600mg daily in two or four divided doses increasing by 300mg at three day intervals until control is achieved.
The usual dose range is 1g to 2g per day, i.e. 20mg/kg to 30mg/kg body weight per day.
Where adequate control is not achieved within this range, the dose may be further increased to 2.5g per day.
Children
Children over 20kg
Initial dosage: Not more than 400mg daily (irrespective of weight) with spaced increases until control is achieved.
The usual dose range is 20mg/kg to 30mg/kg per day.
Where adequate control is not achieved within this range, the dose may be further increased to 35mg/kg per day.
Children under 20kg
20mg/kg daily.
In severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. With doses above 40mg/kg daily, clinical chemistry and haematological parameters should be monitored.
The following alternative dosing schedule may be suitable:
Children aged 12 to 18 years
Initial dose: 600mg daily, given in two to four divided doses. Increase in steps of 150mg to 300mg at three day intervals.
Maintenance dose: 1g to 2g daily, given in two to four divided doses.
Maximum dose: 2.5g daily, given in two to four divided doses.
Children aged 1 month to 12 years
Initial dose: 10mg/kg to 15mg/kg daily, given in two to four divided doses. Maximum dose: 600mg daily.
Maintenance dose: 25mg/kg to 30mg/kg daily, given in two to four divided doses. Give up to 60mg/kg daily in two to four divided doses in infantile spasms.
Monitor clinical chemistry and haematological parameters if dose exceeds 40mg/kg daily.
Additional Dosage Information
Switching from another anticonvulsant:
When starting valproic acid in patients already on other anticonvulsants, these should be tapered slowly. Initiation of valproic acid therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5mg/kg to 10mg/kg per day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known liver enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of valproic acid. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.
Contraindications
Family history of severe hepatic impairment
Patients not compliant with the Pregnancy Prevention Programme
Urea cycle enzyme deficiency
Hepatic disorder
History of severe hepatic disorder
Known or suspected mitochondrial disorder
Pancreatitis
Porphyria
Pregnancy
Precautions and Warnings
Children under 3 years
During surgery
Females of childbearing potential
Prepubertal females
Breastfeeding
Haematological disorder
Renal impairment
Systemic lupus erythematosus
Confirm POLG mutation status if suspected in patient before initiating
May exacerbate or activate systemic lupus erythematosus
Mitochondrial disorder: May trigger or exacerbate condition/symptoms
Advise patient drowsiness may affect ability to drive or operate machinery
Consider prescribing by manufacturer to ensure seizure control maintenance
Female: Specialist and patient to complete Annual Risk Acknowledgement Form
Female:Ensure information including a Patient Guide is received& understood
Increased risk of osteomalacia; consider vitamin D supplement
Staff & patients: Must comply with Pregnancy Prevention Programme
Treatment to be initiated and supervised by a specialist
Exclude pregnancy prior to initiation of treatment
Monitor haematological parameters before and during treatment
Perform liver function tests before commencing therapy
Advise patients of risks/benefits & review need for treatment regularly
Monitor hepatic function regularly during first 6 months, then as indicated
Monitor patient for signs and symptoms of depression
Perform metabolic tests if urea cycle enzyme deficiency suspected
Refer women considering pregnancy for specialist advice and monitoring
Advise patient of the risk of weight gain
Advise patient to report unexplained fever, sore throat, bruising, bleeding
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Advise patients to report symptoms of acute pancreatitis immediately
Advise patients/carers to seek medical advice if suicidal intent develops
Discontinue treatment if abnormally low prothrombin time detected
May give false positive in urine testing for ketones
Changeover to or from other anti-epileptic drugs should be gradual
Withdraw treatment gradually under supervision of a specialist
Advise patient to seek advice at first indications of pregnancy
Discontinue drug if bleeding abnormalities occur
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if pancreatitis occurs
Discontinue treatment if clinical symptoms of hyperammonaemia develop
Consider dose reduction in renal impairment
Male: May cause infertility
Female: Ensure adequate contraception during treatment
Severe liver damage, including fatal hepatic impairment has been reported. Most cases occur during the first 6 months of treatment (the period of maximum risk being 2 to 12 weeks) and are usually associated with patients taking multiple anticonvulsants. Risks are increased in children under the age of 3 and in patients with congenital metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation. Consider monotherapy in children under the age of 3. At the first signs of hepatic injury, treatment should be discontinued.
Monitor liver function prior to initiation and periodically during the first 6 months of treatment. Increased liver enzymes commonly occur and are usually transient. If detected, further biological investigations are required. Investigations which reflect protein synthesis (particularly prothrombin rate) are most relevant. Consider dose reduction and repeat investigations but in those with abnormally low prothrombin rate (particularly in association with a significant decrease in fibrinogen and coagulation factors or increases in bilirubin and transaminases) treatment should be withdrawn.
Pancreatitis has been reported with an increased risk in young children, patients with severe seizures and patients with severe neurological impairment using combination anticonvulsant therapy.
Valproic acid is a known human teratogen. Use in female patients of child bearing potential is restricted to cases where alternatives are ineffective or not tolerated and requires compliance with the valproate pregnancy prevention programme. Specialists must inform patients of potential risks, reviewing treatment on an annual basis including completion of an Annual Risk Acknowledgement Form. All patients must use highly effective contraception, regardless of current sexual activity. Patients wanting to plan a pregnancy (or patients with an unplanned pregnancy) must be referred to their specialist for an urgent review. GPs are responsible for ensuring continued use of contraception, checking patients have an annual review and where the GP is responsible for prescribing valproic acid, confirming a current Annual Risk Acknowledgement Form is in place. Further details can be found in the manufacturers pregnancy prevention programme documentation.
As valproic acid is generally used long term, use in prepubertal female children is also restricted to cases where alternatives are ineffective or not tolerated. Compliance with the valproate pregnancy prevention programme is not required however the patient and/or parent/caregiver/responsible person must be informed of risks should treatment continue once the child reaches puberty. Patients still prescribed valproic acid following their first period require specialist review. If treatment is to continue, compliance with a pregnancy prevention programme is then required, regardless of whether the patient is sexually active.
Prior to initiation, undertake POLG mutation testing in patients where mitochondrial disorders are suspected. This includes patients with a family history or suggestive symptoms of a POLG-related disorder, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura.
Blood tests (full blood count, platelet count, bleeding time and coagulation tests) are recommended prior to treatment initiation, prior to surgery and following cases of spontaneous bruising or bleeding.
Pregnancy and Lactation
Pregnancy
Valproic acid is contraindicated during pregnancy.
Valproic acid is a known human teratogen. Studies have shown congenital malformations in 10% of exposed neonates and neurodevelopment disorders in 30 to 40% of exposed children. Reported malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius) and multiple anomalies of various body systems. Following birth, cases of withdrawal syndrome, hypoglycaemia, hypothyroidism and haemorrhagic syndrome have also been reported. Use of high doses (above 1g daily) appear to carry an increased risk as does combination with other antiepileptic drugs. Evidence suggests that supplementation with folic acid has no effect on valproate-induced birth defects.
Patients planning a pregnancy or those with an unplanned pregnancy require urgent referral to their specialist. In the interim, valproic acid must be continued (even if the patient is already pregnant) as abrupt cessation carries a risk of relapse and subsequent maternal and/or foetal harm. Specialists should aim to switch all patients but where alternatives are ineffective or not tolerated, valproic acid may be continued with extreme caution. Further details can be found in the manufacturers pregnancy prevention programme documentation.
Lactation
Valproic acid should be used with caution during breastfeeding.
Manufacturers advise either abstaining from breastfeeding or discontinuing valproic acid. LactMed, Schaefer (2015) and Briggs (2015) suggest breastfeeding does not need to be discontinued where treatment is required although prescribing restrictions are in place for all women of child bearing potential (see Precautions and Warnings).
Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Due to the low levels in infant serum, no definitive adverse reactions have been reported. Studies have shown no adverse effects on infant growth or development. Theoretically, breastfed infants are at risk of valproate-induced hepatotoxicity and so infants should be closely observed for jaundice or other signs of liver damage. A questionable case of thrombocytopenia has been reported and as such monitoring for spontaneous bruising or bleeding is also advised.
Counselling
Patients should be advised to consult their doctor immediately if they develop symptoms suggestive of pancreatitis (e.g. abdominal pain, nausea and vomiting).
Patients should be warned of the risk of weight gain at the initiation of therapy, which may be marked and progressive, and the appropriate strategies should be adopted to minimise weight gain.
Patients should be warned of the risk of transient drowsiness, which may affect the ability to drive or operate machinery, especially in cases of anticonvulsant polytherapy or association with benzodiazepines.
Patients or their carers should be told how to recognise signs of blood or liver disorders and advised to seek immediate medical attention if symptoms develop.
Patients and caregivers should be aware of the need to monitor for the emergence of suicidal thoughts and behaviour, and the need to seek medical advice immediately if they present.
Advise female patients of child bearing potential of the terms of the valproate pregnancy prevention programme including potential risks should they become pregnant, the need for contraception and what action to take should they become pregnant or wish to plan a pregnancy.
Advise prepubertal female patients (or their parent/carer/responsible person) of potential risks should valproate be continued once they reach puberty.
Side Effects
Acne
Aggression
Allergic reaction
Amenorrhoea
Anaemia
Ataxia
Behavioural disturbances
Bruising
Coma
Confusion
Convulsions
Decrease in bone mineral density
Dementia (reversible) associated with cerebral atrophy (reversible)
Depression
Diarrhoea
Diplopia
Encephalopathy
Erythema multiforme
Exanthematous rash
Extrapyramidal effects
Fanconi's syndrome (reversible)
Fractures
Gastralgia
Gynaecomastia
Hair disorder
Hair loss
Hallucinations
Hearing loss
Hepatic failure
Hepatic impairment
Hirsutism
Hyperactivity
Hyperammonaemia
Hypersensitivity reactions
Impaired consciousness
Increased alertness
Increased coagulation time
Increases in hepatic enzymes
Irregular menstruation
Lethargy
Leucopenia
Liver damage
Nail disorders
Nausea
Obesity
Osteopenia
Osteoporosis
Pancreatitis
Pancytopenia
Parkinsonism
Peripheral oedema
Prolonged bleeding
Rash
Reduction of fibrinogen
Sedation
Stevens-Johnson syndrome
Stupor
Suicidal tendencies
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Vasculitis
Vomiting
Weight gain
Effects on Laboratory Tests
Valproic acid is eliminated, via the kidneys, partly in the form of ketone bodies which may result in false positives in the urine testing of possible diabetics.
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: May 2020
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Convulex capsules 150mg, 300mg & 500mg. G.L. Pharma UK Ltd. Revised January 2019.
MHRA Drug Safety Update April 2018
Available at: https://www.mhra.gov.uk
Last accessed: 11 January 2019
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://www.ncbi.nlm.nih.gov/books/NBK501274/
Valproic acid Last revised: 16 March 2020
Last accessed: 05 May 2020
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