Sodium valproate oral modified release
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Modified release oral formulations of sodium valproate.
Drugs List
Therapeutic Indications
Uses
Treatment of all forms of epilepsy
Treatment of manic episodes associated with bipolar disorder
Treatment of all forms of epilepsy.
Some brands are also licensed for the treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated.
The continuation of treatment after manic episode could be considered in patients who have responded to sodium valproate for acute mania.
Dosage
Daily dosage requirements vary according to age and weight and should be adjusted individually to achieve adequate seizure control.
Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary, although may be helpful where there is poor control or side effects are suspected.
Adults
Monotherapy treatment of epilepsy
Initial dose: 600mg daily in one or two divided doses gradually increasing as per specific brand recommendation 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.
Treatment of manic episodes associated with bipolar disorder
Initial dose 750mg or 20mg/kg body weight daily in one or two doses increased as rapidly as possible to the lowest therapeutic dose which gives the desired clinical effect.
The usual dose range is between 1g and 2g daily. Continuation of treatment should include adjustment to give the lowest dose for clinical response for the individual patient.
Patients receiving over 45mg/kg per day should be carefully monitored.
Children
In children requiring doses higher than 40mg/kg per day clinical chemistry and haematological parameters should be monitored.
Monotherapy treatment of epilepsy
Children over 20kg:
Initial dose: 300mg or 400mg per day (see specific brand for details). The dose is gradually increased until seizure control is achieved.
Usual maintenance dose is in the range of 20mg/kg to 30mg/kg body weight per day. Where adequate seizure control is not achieved, the dose can be increased to 35mg/kg body weight per day.
Children under 20kg:
20mg/kg of body weight per day; in severe cases this may be increased up to 40mg/kg/day.
An alternative formulation may be required due to dose and the need for dose titration.
Additional Dosage Information
Combined therapy with other anticonvulsants:
When starting sodium valproate in patients already on other anticonvulsants, these should be tapered slowly. Initiation of sodium valproate 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 sodium valproate. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.
Switching to different dosage forms:
In patients where adequate control has been achieved, sodium valproate formulations are interchangeable with other sodium valproate conventional or prolonged release formulations of the same brand on an equivalent daily dosage basis.
NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.
Therapeutic Drug Monitoring
Routine monitoring is no longer considered necessary unless the patient does not have satisfactory seizure control, adverse effects are a problem or a compliance check is required. The therapeutic range for valproate is quoted as between 40mg/L to 100mg/L (278 to 694 micromols per litre). Clinical interpretation of plasma valproic levels may be altered in elderly patients due to age related changes in pharmacokinetics.
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
Pancreatic insufficiency
Porphyria
Pregnancy
Precautions and Warnings
Children under 3 years
Elderly
Females of childbearing potential
Prepubertal females
Breastfeeding
Carnitine deficiency
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
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
Not all presentations are licensed for all indications
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
Monitor hepatic function before treatment and during first 6 months
Advise patients of risks/benefits & review need for treatment regularly
May cause an increase in seizure frequency or onset of new seizure types
Monitor for signs of suicide ideation or behaviour
Monitor patient's weight
Perform metabolic tests if urea cycle enzyme deficiency suspected
Refer women considering pregnancy for specialist advice and monitoring
Regular pregnancy tests required during therapy
Advise patient of the risk of weight gain
Advise patient to consult Doctor if spontaneous bruising occurs
Advise patient to report any aggravated convulsions immediately
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue treatment if abnormally low prothrombin time detected
May affect thyroid function tests
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
Not licensed for all indications in all age groups
Advise patient to avoid alcohol during treatment
Male & female: May cause infertility
Female: Ensure adequate contraception during treatment
Advise patient that empty granule shells may be observed in stools
Advise patient/carers to report signs of suicide ideation or behaviour
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.
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. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).
Sodium valproate 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 sodium valproate, confirming a current Annual Risk Acknowledgement Form is in place. Further details can be found in the manufacturers pregnancy prevention programme documentation.
As sodium valproate 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 sodium valproate 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.
Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme POLG, e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder. POLG-related disorders should be suspected in 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. Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations.
Advise patients with underlying carnitine palmitoyltransferase type II deficiency there is an increased risk of rhabdomyolysis when taking sodium valproate.
Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome.
Some adverse reactions are more severe or principally observed in the paediatric population. Young children are at particular risk of pancreatitis. Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are predominantly observed in the paediatric population.
Pregnancy and Lactation
Pregnancy
Sodium valproate is contraindicated during pregnancy.
The manufacturer does not recommend sodium valproate in the treatment of epilepsy during pregnancy unless there is no suitable alternative treatment.
Valproate 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 (Schaefer 2015). 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, valproate 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 must switch all patients treated for bipolar disorder to a suitable alternative. Specialists should aim to switch all patients treated for epilepsy but where alternatives are ineffective or not tolerated, valproate may be continued with extreme caution. Further details can be found in the manufacturers pregnancy prevention programme documentation.
Lactation
Use sodium valproate with caution during breastfeeding.
The manufacturer advises that the patient either discontinues sodium valproate or discontinues breastfeeding. Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Haematological disorders have been reported in newborns and infants of treated women.
LactMed (2020), 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.
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 (LactMed, 2020).
Counselling
For patients with swallowing difficulties, the contents of the capsules may be sprinkled or stirred into soft food or drinks and swallowed immediately without chewing or crushing the granules. The food or drink should be cold or at room temperature and the mixture should not be stored for future use. Some granules may stick to the glass after the drink has been finished, the glass should be rinsed with a small amount of water and this water swallowed as well. The granules should not be given in babies' bottles as they can block the teat.
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.
Advise patients to report any aggravated convulsions immediately.
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 advised not to use alcohol during treatment.
Advise patients of risks/benefits and review need for treatment regularly.
Advise patient that empty granule shells may be seen in the stools for those taking the prolonged release granules and prolonged release capsules.
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 start puberty.
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
Acne
Aggression
Agitation
Agranulocytosis
Amenorrhoea
Anaemia
Angioedema
Ataxia
Attention disturbances
Behavioural disturbances
Bleeding
Bone marrow failure
Bruising
Cognitive impairment
Coma
Confusion
Constipation
Convulsions
Decrease in bone mineral density
Dementia (reversible) associated with cerebral atrophy (reversible)
Depression
Diarrhoea
Diplopia
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysmenorrhoea
Elevated blood testosterone
Encephalopathy
Enuresis
Erythema multiforme
Extrapyramidal effects
Fanconi syndrome
Fractures
Gastralgia
Gingival disorder
Gynaecomastia
Hair disorder
Hair loss
Hallucinations
Headache
Hearing loss
Hepatic failure
Hepatic impairment
Hirsutism
Hyperactivity
Hyperammonaemia
Hypersalivation
Hypersensitivity reactions
Hyponatraemia
Hypothermia
Hypothyroidism
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
Leucopenia
Liver damage
Macrocytic anaemia
Macrocytosis
Male infertility
Male pattern baldness
Myelodysplastic syndrome
Nail disorders
Nausea
Nystagmus
Osteopenia
Osteoporosis
Pancreatitis
Pancytopenia
Paraesthesia
Parkinsonism
Peripheral oedema
Pleural effusion
Polycystic ovaries
Porphyria
Rash
Red cell aplasia
Reduction of fibrinogen
Renal failure
Rhabdomyolysis
Sedation
Stevens-Johnson syndrome
Stomatitis
Stupor
Systemic lupus erythematosus
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Tremor
Urinary incontinence
Vasculitis
Vertigo
Virilism in females
Vomiting
Weight gain
Weight loss
Effects on Laboratory Tests
Sodium valproate may displace thyroid hormones from plasma protein binding sites, increasing their metabolism which can lead to false presumption diagnosis of hypothyroidism.
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: November 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: Dyzantil 200mg, 300mg and 500mg prolonged release tablets. Aspire Pharma Ltd. Revised April 2020.
Summary of Product Characteristics: Episenta 150mg and 300mg prolonged release capsules. Desitin Pharma Ltd. Revised December 2020.
Summary of Product Characteristics: Episenta 500mg and 1000mg prolonged release granules. Desitin Pharma Ltd. Revised December 2020.
Summary of Product Characteristics: Epilim Chrono controlled release tablets. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epilim Chronosphere MR modified release granules. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epival CR Prolonged-release tablets. Healthcare Pharma. Revised June 2018.
Educational Risk Minimisation Materials
Available at: www.medicines.org.uk
Valproate PREVENT programme. Last revised March 2019.
Last accessed: 03 May 2019
MHRA Drug Safety Update November 2017
Available at: https://www.mhra.gov.uk
Last accessed: 28 November 2018
MHRA Drug Safety Update April 2018
Available at: https://www.mhra.gov.uk
Last accessed: 26 April 2018
MHRA Drug Safety Update September 2018
Available at: https://www.mhra.gov.uk
Last accessed: 25 September 2018
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 09 November 2020
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/
Valproic Acid. Last revised: 21 September 2020
Last accessed: 09 November 2020
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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