Drugs List

Therapeutic Indications

Uses

Treatment of manic episodes associated with bipolar disorder

Unlicensed Uses

Migraine (prophylaxis)

Contraindications

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
Pancreatitis
Porphyria
Pregnancy

Precautions and Warnings

During surgery
Females of childbearing potential
Breastfeeding
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

Pregnancy

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.

Lactation

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.

Side Effects

Acne
Aggression
Agitation
Agranulocytosis
Amenorrhoea
Anaemia
Angioedema
Ataxia
Attention disturbances
Behavioural disturbances
Bone marrow failure
Bruising
Changes in hair colour
Changes in hair texture
Cognitive impairment
Coma
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
Gingival hyperplasia
Gynaecomastia
Haemorrhage
Hair disorder
Hair growth abnormal
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
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
Psychomotor hyperactivity
Rash
Red cell aplasia
Reduction of fibrinogen
Renal failure
Reversible confusional states
Rhabdomyolysis
Sedation
Somnolence
Stevens-Johnson syndrome
Stomatitis
Stupor
Systemic lupus erythematosus
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urinary incontinence
Vasculitis
Virilism in females
Vomiting
Weight gain

Presentation

Oral formulations containing valproic acid (as valproate semisodium).

Drugs List

Therapeutic Indications

Uses

Treatment of manic episodes associated with bipolar disorder

Unlicensed Uses

Migraine (prophylaxis)

Dosage

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.

Adults

Additional Dosage Information

Contraindications

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
Pancreatitis
Porphyria
Pregnancy

Precautions and Warnings

During surgery
Females of childbearing potential
Breastfeeding
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

Pregnancy

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.

Lactation

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.

Counselling

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

Acne
Aggression
Agitation
Agranulocytosis
Amenorrhoea
Anaemia
Angioedema
Ataxia
Attention disturbances
Behavioural disturbances
Bone marrow failure
Bruising
Changes in hair colour
Changes in hair texture
Cognitive impairment
Coma
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
Gingival hyperplasia
Gynaecomastia
Haemorrhage
Hair disorder
Hair growth abnormal
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
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
Psychomotor hyperactivity
Rash
Red cell aplasia
Reduction of fibrinogen
Renal failure
Reversible confusional states
Rhabdomyolysis
Sedation
Somnolence
Stevens-Johnson syndrome
Stomatitis
Stupor
Systemic lupus erythematosus
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urinary incontinence
Vasculitis
Virilism in females
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: 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: 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: 10 January 2019

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 10 September 2019

The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last accessed: 10 September 2019

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Valproic acid Last revised: 03 June 2019
Last accessed: 10 September 2019