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Valproate semisodium oral

Updated 2 Feb 2023 | Valproate (in mania)


Oral formulations containing valproic acid (as valproate semisodium).

Drugs List

  • BELVO 250mg gastro-resistant tablets
  • BELVO 500mg gastro-resistant tablets
  • DEPAKOTE 250mg tablets
  • DEPAKOTE 500mg tablets
  • SYONELL 250mg gastro-resistant tablets
  • SYONELL 500mg gastro-resistant tablets
  • valproic acid 250mg gastro-resistant tablets
  • valproic acid 500mg gastro-resistant tablets
  • Therapeutic Indications


    Treatment of manic episodes associated with bipolar disorder

    Unlicensed Uses

    Migraine (prophylaxis)


    Dosage should be determined by clinical response as there is no clear correlation between daily dose, plasma concentration and therapeutic effect. There is wide variability in individual sensitivity to valproate semisodium.


    Initial dose: 750mg daily in two or three divided doses.
    Increased as rapidly as possible until the desired clinical effect is achieved.

    Average daily doses usually range between 1000mg and 2000mg given in two or three divided doses.

    Patients receiving doses higher than 45mg/kg body weight daily should be carefully monitored. Ongoing treatment should be individually adjusted to the minimum effective dose.

    Unlicensed use
    Migraine prophylaxis
    Initial dose: 250mg twice daily. Increased, if necessary, to 1000mg daily in divided doses.

    Additional Dosage Information

    Patients switching between brands
    When starting a different brand, initiate therapy with the same daily dose and regimen. Once patient is established with the new product, a daily scheme of 2 to 3 doses may be resumed.

    Combined therapy with other anticonvulsants:
    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. carbamazepine. Once known liver enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of valproic acid.


    Children under 18 years
    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
    Pancreatic insufficiency

    Precautions and Warnings

    During surgery
    Females of childbearing potential
    Carnitine deficiency
    Haematological disorder
    History of pancreatitis
    Renal impairment
    Systemic lupus erythematosus

    Children under 18 years: Increased risk of rare and severe adverse effects
    Confirm POLG mutation status if suspected in patient before initiating
    Consider increasing dosage in patients on haemodialysis
    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
    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
    Some brands contain Carmoisine (E122) - can trigger allergic reactions
    Some brands contain Sunset Yellow (E110) - can trigger allergic reactions
    Some formulations contain Ponceau 4R (E124)-may cause allergic reactions
    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 cause convulsions
    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 convulsions 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
    Maintain treatment at the lowest effective dose
    Advise patient to avoid alcohol during treatment
    Male & female: 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. 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.

    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.

    Advise patients with underlying carnitine palmitoyltransferase type II deficiency there is an increased risk of rhabdomyolysis when taking valproic acid.

    Some adverse reactions are more severe or principally observed in the paediatric population. Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are predominantly observed in the paediatric population.

    Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate. Treatment with valproate may also impair fertility in men. Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. A strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility is unknow.

    Pregnancy and Lactation


    Valproic acid is contraindicated during pregnancy.

    The manufacturer recommends valproic acid is not used 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 children exposed in utero. 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 in neonates. 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. The manufacturer states that all patients must be switched to an alternative. Further details can be found in the manufacturers Pregnancy Prevention Programme documentation.


    Valproic acid should be used with caution during breastfeeding.

    Manufacturers advise either abstaining from breastfeeding or discontinuing valproate. 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. Haematological disorders have been shown in breastfed infants of treated women.


    Patients should be advised not to use alcohol during treatment.

    Patients should be advised to consult their doctor immediately if they develop symptoms suggestive of pancreatitis (e.g. abdominal pain, nausea and vomiting).

    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.

    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.

    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.

    Patients should be warned of the risk of transient drowsiness, which may affect ability to drive or operate machinery, especially in cases of anticonvulsant polytherapy or association with benzodiazepines.

    Side Effects

    Attention disturbances
    Behavioural disturbances
    Bone marrow failure
    Changes in hair colour
    Changes in hair texture
    Cognitive impairment
    Decrease in bone mineral density
    Dementia (reversible) associated with cerebral atrophy (reversible)
    Drug rash with eosinophilia and systemic symptoms (DRESS)
    Erythema multiforme
    Extrapyramidal effects
    Fanconi syndrome
    Gingival disorder
    Gingival hyperplasia
    Hair disorder
    Hair growth abnormal
    Hair loss
    Hearing loss
    Hepatic failure
    Hepatic impairment
    Hypersensitivity reactions
    Impaired consciousness
    Impaired memory
    Inappropriate secretion of antidiuretic hormone
    Increased alertness
    Increased coagulation time
    Increased serum androgens
    Increases in hepatic enzymes
    Interstitial nephritis
    Learning disorder
    Liver damage
    Macrocytic anaemia
    Male infertility
    Male pattern baldness
    Myelodysplastic syndrome
    Nail disorders
    Peripheral oedema
    Pleural effusion
    Polycystic ovaries
    Psychomotor hyperactivity
    Red cell aplasia
    Reduction of fibrinogen
    Renal failure
    Reversible confusional states
    Stevens-Johnson syndrome
    Systemic lupus erythematosus
    Toxic epidermal necrolysis
    Urinary incontinence
    Virilism in females
    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.


    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 ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: February 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: Belvo 250mg gastro-resistant tablets. Consilient Health Ltd. Revised May 2019.

    Summary of Product Characteristics: Belvo 500mg gastro-resistant tablets. Consilient Health Ltd. Revised May 2019.

    Summary of Product Characteristics: Depakote 250mg Tablets. Sanofi-Aventis Pharmaceuticals Ltd. Revised December 2020.

    Summary of Product Characteristics: Depakote 500mg Tablets. Sanofi-Aventis Pharmaceuticals Ltd. Revised December 2020.

    Summary of Product Characteristics: Syonell 250mg gastro-resistant tablets. Lupin Healthcare (UK) Ltd. Revised May 2022.

    Summary of Product Characteristics: Syonell 500mg gastro-resistant tablets. Lupin Healthcare (UK) Ltd. Revised May 2022.

    Educational Risk Minimisation Materials
    Available at:
    Valproate PREVENT programme. Last revised March 2019.
    Last accessed: 03 May 2019

    MHRA Drug Safety Update April 2018
    Available at:
    Last accessed: 10 January 2019

    NICE Evidence Services Available at: Last accessed: 10 September 2019

    The Norwegian Porphyria Centre (NAPOS).
    Available at:
    Last accessed: 10 September 2019

    US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
    Available at:
    Valproic acid Last revised: 03 June 2019
    Last accessed: 10 September 2019

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