Drugs List

Therapeutic Indications

Uses

Treatment of all forms of epilepsy

Unlicensed Uses

Migraine (prophylaxis)

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
Porphyria
Pregnancy

Precautions and Warnings

Children under 3 years
Females of childbearing potential
Prepubertal females
Breastfeeding
Carnitine deficiency
Glucose-galactose malabsorption syndrome
Hereditary fructose intolerance
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
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
Staff & patients: Must comply with Pregnancy Prevention Programme
Treatment to be initiated and supervised by a specialist
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain hydroxybenzoate
Some formulations contain sucrose
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 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/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 those 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.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of 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 that 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 as treatment for 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. 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 migraine 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) indicates that valproic acid levels in breast milk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development. If valproic acid is needed to treat the mother, it is not necessarily a reason to discontinue breastfeeding. As such, sodium valproate may be used with caution when breastfeeding.

In theory, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy (LactMed, 2020).

Side Effects

Acne
Aggression
Agitation
Agranulocytosis
Amenorrhoea
Anaemia
Angioedema
Ataxia
Attention disturbances
Behavioural disturbances
Bleeding
Bone marrow failure
Bruising
Cognitive impairment
Coma
Confusion
Convulsions
Decrease in bone mineral density
Dementia (reversible) associated with cerebral atrophy (reversible)
Diarrhoea
Diplopia
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysmenorrhoea
Encephalopathy
Enuresis
Erythema multiforme
Extrapyramidal effects
Fanconi syndrome
Fractures
Gastralgia
Gingival disorder
Gynaecomastia
Haemorrhage
Hair disorder
Hair loss
Hallucinations
Headache
Hearing loss
Hepatic failure
Hepatic impairment
Hirsutism
Hyperactivity
Hyperammonaemia
Hypersensitivity reactions
Hyponatraemia
Hypothermia
Hypothyroidism
Impaired consciousness
Impaired memory
Inappropriate secretion of antidiuretic hormone
Increased alertness
Increased coagulation time
Increased serum androgens
Increased testosterone levels in females
Increases in hepatic enzymes
Interstitial nephritis
Learning disorder
Lethargy
Leucopenia
Liver damage
Macrocytic anaemia
Macrocytosis
Male infertility
Male pattern baldness
Myelodysplastic syndrome
Nail disorders
Nausea
Nystagmus
Obesity
Osteopenia
Osteoporosis
Pancreatitis
Pancytopenia
Paraesthesia
Parkinsonism
Peripheral oedema
Pleural effusion
Polycystic ovaries
Rash
Red cell aplasia
Reduction of fibrinogen
Renal failure
Rhabdomyolysis
Sedation
Somnolence
Stevens-Johnson syndrome
Stomatitis
Stupor
Suicidal tendencies
Systemic lupus erythematosus
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urinary incontinence
Vasculitis
Virilism in females
Vomiting
Weight gain

Presentation

Standard release oral formulations of sodium valproate.

Drugs List

Therapeutic Indications

Uses

Treatment of all forms of epilepsy

Unlicensed Uses

Migraine (prophylaxis)

Dosage

Daily dosage requirements vary according to age and weight.

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

Children

Neonates

Additional Dosage Information

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 plasma valproate levels 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
Porphyria
Pregnancy

Precautions and Warnings

Children under 3 years
Females of childbearing potential
Prepubertal females
Breastfeeding
Carnitine deficiency
Glucose-galactose malabsorption syndrome
Hereditary fructose intolerance
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
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
Staff & patients: Must comply with Pregnancy Prevention Programme
Treatment to be initiated and supervised by a specialist
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain hydroxybenzoate
Some formulations contain sucrose
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 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/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 those 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.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of 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 that 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 as treatment for 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. 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 migraine 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) indicates that valproic acid levels in breast milk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development. If valproic acid is needed to treat the mother, it is not necessarily a reason to discontinue breastfeeding. As such, sodium valproate may be used with caution when breastfeeding.

In theory, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy (LactMed, 2020).

Side Effects

Acne
Aggression
Agitation
Agranulocytosis
Amenorrhoea
Anaemia
Angioedema
Ataxia
Attention disturbances
Behavioural disturbances
Bleeding
Bone marrow failure
Bruising
Cognitive impairment
Coma
Confusion
Convulsions
Decrease in bone mineral density
Dementia (reversible) associated with cerebral atrophy (reversible)
Diarrhoea
Diplopia
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysmenorrhoea
Encephalopathy
Enuresis
Erythema multiforme
Extrapyramidal effects
Fanconi syndrome
Fractures
Gastralgia
Gingival disorder
Gynaecomastia
Haemorrhage
Hair disorder
Hair loss
Hallucinations
Headache
Hearing loss
Hepatic failure
Hepatic impairment
Hirsutism
Hyperactivity
Hyperammonaemia
Hypersensitivity reactions
Hyponatraemia
Hypothermia
Hypothyroidism
Impaired consciousness
Impaired memory
Inappropriate secretion of antidiuretic hormone
Increased alertness
Increased coagulation time
Increased serum androgens
Increased testosterone levels in females
Increases in hepatic enzymes
Interstitial nephritis
Learning disorder
Lethargy
Leucopenia
Liver damage
Macrocytic anaemia
Macrocytosis
Male infertility
Male pattern baldness
Myelodysplastic syndrome
Nail disorders
Nausea
Nystagmus
Obesity
Osteopenia
Osteoporosis
Pancreatitis
Pancytopenia
Paraesthesia
Parkinsonism
Peripheral oedema
Pleural effusion
Polycystic ovaries
Rash
Red cell aplasia
Reduction of fibrinogen
Renal failure
Rhabdomyolysis
Sedation
Somnolence
Stevens-Johnson syndrome
Stomatitis
Stupor
Suicidal tendencies
Systemic lupus erythematosus
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urinary incontinence
Vasculitis
Virilism in females
Vomiting
Weight gain

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: October 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: Epilim 100mg Crushable Tablets. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epilim 200 Gastro-resistant tablets. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epilim 500 Gastro-resistant tablets. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epilim Liquid. Sanofi. Revised December 2020.
Summary of Product Characteristics: Epilim Syrup. Sanofi. Revised December 2020.

Summary of Product Characteristics: Sodium Valproate 200mg Gastro-Resistant Tablets. Wockhardt UK Ltd. Revised September 2020.
Summary of Product Characteristics: Sodium Valproate 500mg Gastro-Resistant Tablets. Wockhardt UK Ltd. Revised September 2020.
Summary of Product Characteristics: Sodium Valproate 40mg/ml Oral Solution (sugar free) . Wockhardt UK Ltd. Revised September 2020.

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 April 2018
Available at: https://www.mhra.gov.uk
Last accessed: 25 April 2018

MHRA Drug Safety Update November 2017
Available at: https://www.mhra.gov.uk
Last accessed: 28 November 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: 07 October 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: 07 October 2020