Formulary
Valproic acid: Indications, Dosing, Side Effects and Interactions
Valproic acid clinical drug profile including indications, dosing, side effects, cautions and interactions.
MedNext Academy | 9 min read
Valproic acid: Indications, Dosing, Side Effects and Interactions
Valproic acid clinical drug profile including indications, dosing, side effects, cautions and interactions.
Indications and dose
**Treatment of manic episodes associated with bipolar disorder**
- **Adult** (By Mouth): Initially 750 mg daily in 2-3 divided doses, then increased to 1-2 g daily, adjusted according to response, doses greater than 45 mg/kg daily require careful monitoring.
**Migraine prophylaxis**
- **Adult** (By Mouth): Initially 250 mg twice daily, then increased if necessary to 1 g daily in divided doses.
**Epilepsy**
- **Adult** (By Mouth): Initially 600 mg daily in 2-4 divided doses, increased in steps of 150-300 mg every 3 days; usual maintenance 1-2 g daily in 2-4 divided doses, max. 2.5 g daily in 2-4 divided doses.
**Epilepsy for Convulex**
- **Child 1 month-11 years** (By mouth): Initially 10-15 mg/kg daily in 2-4 divided doses, max. 600 mg daily; usual maintenance 25-30 mg/kg daily in 2-4 divided doses, doses up to 60 mg/kg daily in 2-4 divided doses in infantile spasms; monitor clinical chemistry and haematological parameters if dose exceeds 40 mg/kg daily.
- **Child 12-17 years** (By mouth): Initially 600 mg daily in 2-4 divided doses, increased in steps of 150-300 mg every 3 days; usual maintenance 1-2 g daily in 2-4 divided doses, max. 2.5 g daily in 2-4 divided doses.
Cautions
Systemic lupus erythematosus Cautions, further information 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 relevant abnormalities). M The MHRA advises consider vitamin D supplementation in patients who are immobilised for long periods or who have inadequate sun exposure or dietary intake of calcium.
Contraindications
Acute porphyrias ; known or suspected mitochondrial disorders (higher rate of acute liver failure and liver-related deaths); personal or family history of severe hepatic dysfunction; urea cycle disorders (risk of hyperammonaemia)
Side effects
Common or very common Abdominal pain; agitation; alopecia; anaemia; behaviour abnormal; concentration impaired; confusion; diarrhoea; drowsiness; haemorrhage; hallucination; headache; hearing loss; hepatic disorders; hypersensitivity; hyponatraemia; memory impairment; menstrual cycle irregularities; movement disorders; nail disorder; nausea; nystagmus; oral disorders; seizures; stupor; thrombocytopenia; tremor; urinary disorders; vomiting; weight increased Uncommon Angioedema; bone disorders; bone fracture; bone marrow disorders; coma; encephalopathy; eosinophilic pleural effusion; hair changes; hyperandrogenism; hypothermia; leucopenia; pancreatitis; paraesthesia; parkinsonism; peripheral oedema; renal failure; SIADH; skin reactions; vasculitis; virilism Rare or very rare Agranulocytosis; cerebral atrophy; cognitive disorder; dementia; diplopia; hyperammonaemia; hypothyroidism; infertility male; learning disability; myelodysplastic syndrome; nephritis tubulointerstitial; obesity; polycystic ovarian syndrome; red blood cell abnormalities; rhabdomyolysis; severe cutaneous adverse reactions (SCARs); systemic lupus erythematosus (SLE) Frequency not known Gynaecomastia; hypocarnitinaemia; suicidal behaviours Side-effects, further information Hepatic dysfunction Withdraw treatment immediately if persistent vomiting and abdominal pain, anorexia, jaundice, oedema, malaise, drowsiness, or loss of seizure control. Pancreatitis Discontinue treatment if symptoms of pancreatitis develop.
Interactions
**Severe interactions:**
- In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g.
- Methotrexate Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures.
- Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or...
**Other interactions (38):**
- Effects of Valproate on other drugs Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines Valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO...
- Lithium Valproate does not effect serum concentrations of lithium.
- Olanzapine Valproic acid may decrease the olanzapine plasma concentration.
- Phenobarbital Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children.
- Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital...
- Primidone Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment.
Pregnancy
Important safety information For valproic acid MHRA/CHM advice: Antiepileptics: risk of suicidal thoughts and behaviour (August 2008) See Epilepsy . MHRA/CHM advice: Antiepileptic drugs: updated advice on switching between different manufacturers' products (November 2017) See Epilepsy and see also Prescribing and dispensing information . Valproate and reproductive risks Valproate is highly teratogenic and evidence shows that use in pregnancy can lead to neurodevelopmental disorders (approx. 30-40% risk) and congenital malformations (approx. 11% risk). It can also potentially cause infertility in males and neurodevelopmental disorders in children born to males treated with valproate in the 3 months prior to conception. Valproate must not be initiated in any patients under 55 years of age unless 2 specialists independently review and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply. Male patients under 55 years of age who are already taking valproate can continue to have it prescribed in accordance with standard clinical practice by a single prescriber. In females of childbearing potential, the conditions of the Pregnancy Prevention Programme must be met and a valproate risk acknowledgement form completed annually. Male patients (of any age) who may father a child must be counselled on using effective contraception during treatment and for 3 months after stopping. Patients should be informed not to stop taking valproate without advice from a specialist because epilepsy or bipolar disorder may worsen without treatment. For further information and resources, see MHRA/CHM advice below, Conception and contraception , Pregnancy , Prescribing and dispensing information , and Patient and carer advice ; refer to the MHRA information page at: . MHRA/CHM advice: Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review (January 2021) See Epilepsy . MHRA/CHM advice: Full pack dispensing of valproate-containing medicines (October 2023) Valproate medicines have been dispensed to patients in alternative packaging because the prescribed amount was different to that of the manufacturer's original full pack. This resulted in patients not always receiving all the risk materials about the use of these medicines in pregnancy. Pharmacists are advised that all patients (male and female) must receive their valproate medicines in the manufacturer's original full pack (i.e. original pack dispensing) and the amount dispensed must be as close as possible to the amount stated on the prescription (NHS or private). Rarely, exceptions to this requirement can be made on an individual patient basis, provided a risk assessment is carried out on the need to dispense repackaged valproate medicines (e.g. in a monitored dosage system), whereby a patient information leaflet must be supplied. MHRA/CHM advice: Valproate ( Belvo , Convulex , Depakote , and Syonell ): new safety and educational materials to support regulatory measures in men and women under 55 years of age (January 2024) Healthcare professionals are advised to review, and integrate into their clinical practice, safety and educational materials that support new regulatory measures (see Prescribing and dispensing information ). General practice and pharmacy teams should continue to prescribe and dispense valproate according to current safety measures. If required, patients should be referred to a specialist to discuss treatment options. Patients on valproate medicines should be fully informed of the potential risks and counselled on treatment options at initial prescribing and at all subsequent reviews. Healthcare professionals should advise patients to: not stop taking valproate medicines without advice from a specialist as their epilepsy or bipolar disorder may worsen; attend any offered appointments to discuss their treatment plan and to talk to a healthcare professional if they have any concerns; consult the new Patient Guide and Patient Information Leaflet for information on the risks of valproate. MHRA/CHM advice: Valproate use in men: as a precaution, men and their partners should use effective contraception (September 2024) The MHRA has reviewed findings from a retrospective observational study that suggest a potential increased risk of neurodevelopmental disorders in children born to males taking valproate medicines in the 3 months before conception; however, causality is unconfirmed. In addition to current safety measures, healthcare professionals should advise male patients (of any age) who may father a child: about this risk at treatment initiation or at the next treatment review, irrespective of indication and also after intravenous valproate; to use effective contraception (i.e. condoms plus contraception used by their female partner) during and for 3 months after valproate treatment; to refrain from donating sperm during and for 3 months after valproate treatment. Healthcare professionals are also advised that: male patients who are planning a family in the next year should be referred to a specialist to discuss alternative treatment; female partners of male patients taking valproate medicines who are pregnant or planning a pregnancy (including those undergoing IVF) should be referred for prenatal counselling. MHRA/CHM advice: Valproate ( Belvo , Convulex , Depakote , and Syonell ): review by two specialists is required for initiating valproate but not for male patients already taking valproate (February 2025) Healthcare professionals are reminded that the current safety measure advising all patients under 55 years of age to be reviewed by two specialists before initiating valproate remains in place, however, the CHM has advised that this will not be required for male patients who are already taking valproate. Healthcare professionals are also reminded that all previously issued safety measures continue to apply. The CHM has produced infographics to clarify the situations where review by two specialists may be required. For female patients under 55 years of age, see: . For male patients under 55 years of age, see: . For male and female patients aged 55 years and older, see: . MHRA/CHM advice: Valproate ( Belvo , Convulex , Depakote and Syonell ): updated safety and educational materials to support patient discussion on reproductive risks (June 2025) The MHRA reminds healthcare professionals of the potential risk of neurodevelopmental disorders in children fathered by males taking valproate around the time of conception. Children exposed to valproate in utero also have a higher risk of being born with a low birth weight or being small for gestational age, compared to those unexposed to antiepileptic drugs or exposed to lamotrigine. Safety and educational materials have therefore been updated in line with regulatory requirements and are available at: . These should be reviewed and integrated into clinical practice for all patients being treated with valproate.
Breast feeding
Present in milk-risk of haematological disorders in breast-fed newborns and infants.
Hepatic impairment
Manufacturer advises avoid.
Renal impairment
Dose adjustments Consider dose reduction. M
Medicinal forms
Solution,Tablet,Capsule
Clinical governance
**Author:** MedNext Clinical Team. **Clinical reviewer:** Dr Shameer Deen, MBBS, MS, MRCS. **Sources:** BNF, Indian Pharmacopoeia, CIMS India. **Correction:** Report errors at support@mednext.academy.
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