Drug reference

Sodium valproate

BNF 80 (2020–2021)

Source: BNF 80 (2020–2021)
PDF pages: 366, 367, 368, 369

Review source pages for extracted sections and age labels. BNF dose snippets show only their first line.

Overview

Indications And Dose

All forms of epilepsy ▶BY MOUTH USING IMMEDIATE-RELEASE MEDICINES ▶Child 1 month–11 years: Initially 10–15 mg/kg daily in 1–2 divided doses (max. per dose 600 mg); Nervous system maintenance 25–30 mg/kg daily in 2 divided doses, doses up to 60 mg/kg daily in 2 divided doses may be used in infantile spasms; monitor clinical chemistry and haematological parameters if dose exceeds 40 mg/kg daily ▶Child 12–17 years: Initially 600 mg daily in 1–2 divided doses, increased in steps of 150–300 mg every 3 days; maintenance 1–2 g daily in 2 divided doses; maximum 2.5 g per day ▶Adult: Initially 600 mg daily in 1–2 divided doses, then increased in steps of 150–300 mg every 3 days; maintenance 1–2 g daily, alternatively maintenance 20–30 mg/kg daily; maximum 2.5 g per day Initiation of valproate treatment ▶INITIALLY BY INTRAVENOUS INJECTION ▶Adult: Initially 10 mg/kg, (usually 400–800 mg), followed by (by intravenous infusion or by intravenous injection) up to 2.5 g daily in 2–4 divided doses, alternatively (by continuous intravenous infusion) up to 2.5 g daily; (by intravenous injection or by intravenous infusion or by continuous intravenous infusion) usual dose 1–2 g daily, alternatively (by intravenous injection or by intravenous infusion or by continuous intravenous infusion) usual dose 20–30 mg/kg daily, intravenous injection to be administered over 3–5 minutes Continuation of valproate treatment ▶BY INTRAVENOUS INJECTION, OR BY INTRAVENOUS INFUSION, OR BY CONTINUOUS INTRAVENOUS INFUSION ▶Adult: If switching from oral therapy to intravenous therapy give the same dose as current oral daily dose, give over 3–5 minutes by intravenous injection or in 2–4 divided doses by intravenous infusion Migraine prophylaxis ▶BY MOUTH USING IMMEDIATE-RELEASE MEDICINES ▶Adult: Initially 200 mg twice daily, then increased if necessary to 1.2–1.5 g daily in divided doses EPILIM CHRONOSPHERE ® All forms of epilepsy ▶BY MOUTH ▶Adult: Total daily dose to be given in 1–2 divided doses (consult product literature) EPILIM CHRONO ® All forms of epilepsy ▶BY MOUTH ▶Adult: Total daily dose to be given in 1–2 divided doses (consult product literature) EPISENTA ® CAPSULES All forms of epilepsy ▶BY MOUTH ▶Adult: Total daily dose to be given in 1–2 divided doses (consult product literature) Mania ▶BY MOUTH ▶Adult: Initially 750 mg daily in 1–2 divided doses, adjusted according to response, usual dose 1–2 g daily in 1–2 divided doses, doses greater than 45 mg/kg daily require careful monitoring EPISENTA ® GRANULES All forms of epilepsy ▶BY MOUTH ▶Adult: Total daily dose to be given in 1–2 divided doses (consult product literature) Mania ▶BY MOUTH ▶Adult: Initially 750 mg daily in 1–2 divided doses, adjusted according to response, usual dose 1–2 g daily in 1–2 divided doses, doses greater than 45 mg/kg daily require careful monitoring EPIVAL ® All forms of epilepsy ▶BY MOUTH ▶Adult: Total daily dose to be given in 1–2 divided doses (consult product literature) l UNLICENSED USE Not licensed for migraine prophylaxis.

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Contra Indications

Acute porphyrias p. 1120. 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)

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Cautions

Systemic lupus erythematosus CAUTIONS, FURTHER INFORMATION Consider vitamin D supplementation in patients that are immobilised for long periods or who have inadequate sun exposure or dietary intake of calcium. ▶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).

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Prescribing And Dispensing Information

The Pregnancy Prevention Programme is supported by the following materials provided by the manufacturer: Patient Guide, Guide for Healthcare Professionals, Risk Acknowledgement Form, and for pharmacists, Patient Cards and Stickers with warning symbols; the MHRA has also produced a patient information sheet providing advice for women and girls taking valproate medicines. The Royal Pharmaceutical Society has also produced a safe supply algorithm, available at: www.rpharms.com/ safesupplyvalproate Switching between formulations Care should be taken when switching between oral formulations in the treatment of epilepsy. The need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with the patient or their carer, taking into account factors such as seizure frequency and treatment history. Patients being treated for epilepsy may need to be maintained on a speciﬁc manufacturer’s branded or generic oral sodium valproate product. EPILIM CHRONOSPHERE ® Prescribe dose to the nearest whole 50-mg sachet.

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Safety

Important Safety Information

MHRA/CHM ADVICE: VALPROATE MEDICINES: CONTRA-INDICATED IN WOMEN AND GIRLS OF CHILDBEARING POTENTIAL UNLESS CONDITIONS OF PREGNANCY PREVENTION PROGRAMME ARE MET (APRIL 2018) Valproate is highly teratogenic and evidence supports that use in pregnancy leads to neurodevelopmental disorders (approx. 30–40% risk) and congenital malformations (approx. 10% risk). Valproate must not be used in women and girls of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met (see Conception and contraception) and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist. Use of valproate in pregnancy is contra-indicated for migraine prophylaxis [unlicensed] and bipolar disorder; it must only be considered for epilepsy if there is no suitable alternative treatment (see Pregnancy). Women and girls (and their carers) must be fully informed of the risks and the need to avoid exposure to valproate medicines in pregnancy; supporting materials have been provided to use in the implementation of the Pregnancy Prevention Programme (see Prescribing and dispensing Information). The MHRA advises that: . GPs must recall all women and girls who may be of childbearing potential, provide the Patient Guide, check they have been reviewed by a specialist in the last year and are on highly effective contraception; . Specialists must book in review appointments at least annually with women and girls under the Pregnancy Prevention Programme, re-evaluate treatment as necessary, explain clearly the conditions as outlined in the supporting materials and complete and sign the Risk Acknowledgement Form—copies of the form must be given to the patient or carer and sent to their GP; . Pharmacists must ensure valproate medicines are dispensed in whole packs whenever possible—all packs dispensed to women and girls of childbearing potential should have a warning label either on the carton or via a sticker. They must also discuss risks in pregnancy with female patients each time valproate medicines are dispensed, ensure they have the Patient Guide and have seen their GP or specialist to discuss their treatment and the need for contraception. MHRA/CHM ADVICE: VALPROATE MEDICINES: ARE YOU ACTING IN COMPLIANCE WITH THE PREGNANCY PREVENTION MEASURES? (DECEMBER 2018) The MHRA advises that all healthcare professionals must continue to identify and review all female patients on valproate, including when used outside licensed indications (off-label use) and provide them with the patient information materials every time they attend appointments or receive their medicines. Guidance for psychiatrists on the withdrawal of, and alternatives to, valproate in women of childbearing potential who have a psychiatric illness is available from the Royal College of Psychiatrists. MHRA/CHM ADVICE: VALPROATE MEDICINES AND SERIOUS HARMS IN PREGNANCY: NEW ANNUAL RISK ACKNOWLEDGEMENT FORM AND CLINICAL GUIDANCE FROM PROFESSIONAL BODIES TO SUPPORT COMPLIANCE WITH THE PREGNANCY PREVENTION PROGRAMME (APRIL 2019) The Annual Risk Acknowledgement Form has been updated and should be used for all future reviews of female patients on valproate. Specialists should comply with guidance given on the form if they consider the patient is not at risk of pregnancy, including the need for review in case her risk status changes. Guidance has been published to support healthcare professionals with the use of valproate. These include a summary by NICE of their guidance and safety advice, pan-college guidance by national healthcare bodies, and paediatric guidance by the British Paediatric Neurology Association and the Royal College of Paediatrics and Child Health. MHRA/CHM ADVICE (UPDATED JANUARY 2020): VALPROATE

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Pregnancy

PREVENTION PROGRAMME The Guide for Healthcare Professionals has been updated and should be used for all future reviews of female patients on valproate medicines, in conjunction with other supporting materials (see Prescribing and dispensing Information). For migraine prophylaxis[unlicensed] and bipolar disorder, the MHRA advises that valproate must not be used. For epilepsy, the MHRA advises valproate must not be used unless there is no suitable alternative treatment; in such cases, access to counselling about the risks should be provided (see Healthcare Professional Guide for more information) and a Risk Acknowledgement Form signed by both specialist and patient. If valproate is to be used during pregnancy, the lowest effective dose should be prescribed in divided doses or as modiﬁed- release tablets to avoid peaks in plasma-valproate concentrations; doses greater than 1 g daily are associated with an increased risk of teratogenicity. Neonatal bleeding (related to hypoﬁbrinaemia) reported. Neonatal hepatotoxicity also reported. See also Pregnancy in Epilepsy p. 321. Monitoring Specialist prenatal monitoring should be instigated when valproate has been taken in pregnancy. The dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.

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Interactions

→Appendix 1: antiepileptics

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Side Effects

GENERAL SIDE-EFFECTS ▶Common or very common Abdominal pain. agitation. alopecia (regrowth may be curly). anaemia. behaviour abnormal. concentration impaired. confusion. deafness. diarrhoea. drowsiness. haemorrhage. hallucination. headache. hepatic disorders. hypersensitivity. hyponatraemia. memory loss. menstrual cycle irregularities. movement disorders. nail disorder. nausea. nystagmus. oral disorders. seizures. stupor. thrombocytopenia. tremor. urinary disorders. vomiting. weight increased ▶Uncommon Androgenetic alopecia. angioedema. bone disorders. bone fracture. bone marrow disorders. coma. encephalopathy. hair changes. hypothermia. leucopenia. pancreatitis. paraesthesia. parkinsonism. peripheral oedema. pleural effusion. renal failure. SIADH. skin reactions. vasculitis. virilism ▶Rare or very rare Agranulocytosis. cerebral atrophy. cognitive disorder. dementia. diplopia. gynaecomastia. hyperammonaemia. hypothyroidism. infertility male. learning disability. myelodysplastic syndrome. nephritis Nervous system tubulointerstitial. polycystic ovaries. red blood cell abnormalities. rhabdomyolysis. severe cutaneous adverse reactions (SCARs). systemic lupus erythematosus (SLE). urine abnormalities ▶Frequency not known Alertness increased SPECIFIC SIDE-EFFECTS ▶Common or very common ▶With intravenous use Dizziness 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.

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Conception And Contraception

The MHRA advises that all women and girls of childbearing potential being treated with valproate medicines must be supported on a Pregnancy Prevention Programme—pregnancy should be excluded before treatment initiation and highly effective contraception must be used during treatment.

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Breast Feeding

Present in milk—risk of haematological disorders in breast-fed newborns and infants.

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Hepatic Impairment

Manufacturer advises avoid.

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Renal Impairment

Dose adjustments Reduce dose.

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Monitoring Requirements

▶Plasma-valproate concentrations are not a useful index of efﬁcacy, therefore routine monitoring is unhelpful. ▶Monitor liver function before therapy and during ﬁrst 6 months especially in patients most at risk. ▶Measure full blood count and ensure no undue potential for bleeding before starting and before surgery. l EFFECT ON LABORATORY TESTS False-positive urine tests for ketones.

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Dose and formulations

Directions For Administration

▶With intravenous use Manufacturer advises for intravenous injection, give over 3–5 minutes. For intravenous infusion, dilute with Glucose 5% or Sodium Chloride 0.9%. Reconstitute Epilim ® with solvent provided then dilute with infusion ﬂuid if required. Displacement value may be signiﬁcant, consult local guidelines. EPIVAL ® Tablets may be halved but not crushed or chewed. EPISENTA ® CAPSULES Contents of capsule may be mixed with cold soft food or drink and swallowed immediately Nervous system without chewing. EPILIM ® SYRUP May be diluted, preferably in Syrup BP; use within 14 days. EPISENTA ® GRANULES Granules may be mixed with cold soft food or drink and swallowed immediately without chewing. EPILIM CHRONOSPHERE ® Granules may be mixed with soft food or drink that is cold or at room temperature, and swallowed immediately without chewing.

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Medicinal Forms

There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: oral suspension, oral solution, suppository Modified-release tablet CAUTIONARY AND ADVISORY LABELS 8, 10, 21, 25 ▶Epilim Chrono (Sanofi) A Sodium valproate 200 mg Epilim Chrono 200 tablets | 30 tablet P £3.50 | 100 tablet P £11.65 DT = £11.65 Sodium valproate 300 mg Epilim Chrono 300 tablets | 30 tablet P £5.24 | 100 tablet P £17.47 DT = £17.47 Sodium valproate 500 mg Epilim Chrono 500 tablets | 30 tablet P £8.73 | 100 tablet P £29.10 DT = £29.10 ▶Epival CR (Healthcare Pharma Ltd) A Sodium valproate 300 mg Epival CR 300mg tablets | 30 tablet P £5.24 | 100 tablet P £17.47 DT = £17.47 Sodium valproate 500 mg Epival CR 500mg tablets | 30 tablet P £8.73 | 100 tablet P £29.10 DT = £29.10 Gastro-resistant tablet CAUTIONARY AND ADVISORY LABELS 5, 8, 10, 25 A ▶Sodium valproate (non-proprietary) Sodium valproate 200 mg Sodium valproate 200mg gastro- resistant tablets | 30 tablet P £2.77 | 100 tablet P £9.45– £14.51 DT = £9.45 Sodium valproate 500 mg Sodium valproate 500mg gastro- resistant tablets | 30 tablet P £6.93 | 100 tablet P £22.76– £34.95 DT = £22.76 ▶Epilim (Sanofi) A Sodium valproate 200 mg Epilim 200 gastro-resistant tablets | 30 tablet P £2.31 | 100 tablet P £7.70 DT = £9.45 Sodium valproate 500 mg Epilim 500 gastro-resistant tablets | 30 tablet P £5.78 | 100 tablet P £19.25 DT = £22.76 Tablet CAUTIONARY AND ADVISORY LABELS 8, 10, 21 ▶Epilim (Sanofi) A Sodium valproate 100 mg Epilim 100mg crushable tablets | 30 tablet P £1.68 | 100 tablet P £5.60 DT = £5.60 Powder and solvent for solution for injection A ▶Sodium valproate (non-proprietary) Sodium valproate 400 mg Sodium valproate 400mg powder and solvent for solution for injection vials | 4 vial P £49.00 ▶Epilim (Sanofi) A Sodium valproate 400 mg Epilim Intravenous 400mg powder and solvent for solution for injection vials | 1 vial P £13.32 DT = £13.32 Solution for injection A ▶Sodium valproate (non-proprietary) Sodium valproate 100 mg per 1 ml Sodium valproate 400mg/4ml solution for injection ampoules | 5 ampoule P £57.90 DT = £57.90 ▶Episenta (Desitin Pharma Ltd) A Sodium valproate 100 mg per 1 ml Episenta 300mg/3ml solution for injection ampoules | 5 ampoule P £35.00 DT = £35.00 Modified-release capsule CAUTIONARY AND ADVISORY LABELS 8, 10, 21, 25 ▶Episenta (Desitin Pharma Ltd) A Sodium valproate 150 mg Episenta 150mg modified-release capsules | 100 capsule P £7.00 DT = £7.00 Sodium valproate 300 mg Episenta 300mg modified-release capsules | 100 capsule P £13.00 DT = £13.00 Oral solution CAUTIONARY AND ADVISORY LABELS 8, 10, 21 A ▶Sodium valproate (non-proprietary) Sodium valproate 40 mg per 1 ml Sodium valproate 200mg/5ml oral solution sugar free sugar-free | 300 ml P £14.66 DT = £9.52 Sodium valproate 200 mg per 1 ml Depakin 200mg/ml oral solution | 40 ml P s ▶Epilim (Sanofi) A Sodium valproate 40 mg per 1 ml Epilim 200mg/5ml liquid sugar- free | 300 ml P £7.78 DT = £9.52 Epilim 200mg/5ml syrup | 300 ml P £9.33 DT = £9.33 Modified-release granules CAUTIONARY AND ADVISORY LABELS 8, 10, 21, 25 ▶Epilim Chronosphere MR (Sanofi) A Sodium valproate 50 mg Epilim Chronosphere MR 50mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 Sodium valproate 100 mg Epilim Chronosphere MR 100mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 Sodium valproate 250 mg Epilim Chronosphere MR 250mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 Sodium valproate 500 mg Epilim Chronosphere MR 500mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 Sodium valproate 750 mg Epilim Chronosphere MR 750mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 Sodium valproate 1 gram Epilim Chronosphere MR 1000mg granules sachets sugar-free | 30 sachet P £30.00 DT = £30.00 ▶Episenta (Desitin Pharma Ltd) A Sodium valproate 500 mg Episenta 500mg modified-release granules sachets sugar-free | 100 sachet P £21.00 DT = £21.00 Sodium valproate 1 gram Episenta 1000mg modified-release granules sachets sugar-free | 100 sachet P £41.00 DT = £41.00

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Clinical care

Treatment Cessation

g Avoid abrupt withdrawal; if treatment with valproate is stopped, reduce the dose gradually over at least 4 weeks. h

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Patient And Carer Advice

Valproate use by women and girls The MHRA advises women and girls should not stop taking valproate without ﬁrst discussing it with their doctor. Blood or hepatic disorders Patients or their carers should be told how to recognise signs and symptoms of blood or liver disorders and advised to seek immediate medical attention if symptoms develop. Pancreatitis Patients or their carers should be told how to recognise signs and symptoms of pancreatitis and advised to seek immediate medical attention if symptoms such as abdominal pain, nausea, or vomiting develop. Pregnancy Prevention Programme Pharmacists must ensure that female patients have a patient card—see also Important safety information. Medicines for Children leaflet: Sodium valproate for preventing seizures www.medicinesforchildren.org.uk/sodium-valproate- preventing-seizures Medicines for Children leaflet: Sodium valproate and pregnancy - information for girls and young women www.medicinesforchildren.org.uk/sodium-valproate-and- pregnancy-information-girls-and-young-women Medicines for Children leaflet: Sodium valproate and pregnancy - information for parents and carers www.medicinesforchildren. org.uk/sodium-valproate-and-pregnancy-information-parents- and-carers EPISENTA ® CAPSULES Patients and carers should be counselled on the administration of capsules. EPISENTA ® GRANULES Patients and carers should be counselled on the administration of granules. EPILIM CHRONOSPHERE ® Patients and carers should be counselled on the administration of granules.

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Dose text by age group

Child 1 month–11 years

Initially 10–15 mg/kg daily in

First-line fragment. Read the complete Indications and Dose section above.

PDF page 366

Child 12–17 years

Initially 600 mg daily in 1–2 divided

First-line fragment. Read the complete Indications and Dose section above.

PDF page 366

Age labels are extracted for navigation. Check the complete source section and current local guidance before clinical use.

Drug reference

Sodium valproate

BNF 80 (2020–2021)

Source: BNF 80 (2020–2021)
PDF pages: 366, 367, 368, 369

Review source pages for extracted sections and age labels. BNF dose snippets show only their first line.

Overview

Indications And Dose

PDF page 366

Contra Indications

PDF page 367

Cautions

PDF page 367

Prescribing And Dispensing Information

PDF page 368

Safety

Important Safety Information

PDF pages 366, 367

Pregnancy

PDF page 367

Interactions

→Appendix 1: antiepileptics

PDF page 367

Side Effects

PDF page 367

Conception And Contraception

PDF page 367

Breast Feeding

Present in milk—risk of haematological disorders in breast-fed newborns and infants.

PDF page 367

Hepatic Impairment

Manufacturer advises avoid.

PDF page 367

Renal Impairment

Dose adjustments Reduce dose.

PDF page 367

Monitoring Requirements

PDF page 367

Dose and formulations

Directions For Administration

PDF pages 367, 368

Medicinal Forms

PDF pages 368, 369

Clinical care

Treatment Cessation

g Avoid abrupt withdrawal; if treatment with valproate is stopped, reduce the dose gradually over at least 4 weeks. h

PDF page 367

Patient And Carer Advice

PDF page 368

Dose text by age group

Child 1 month–11 years

Initially 10–15 mg/kg daily in

First-line fragment. Read the complete Indications and Dose section above.

PDF page 366

Child 12–17 years

Initially 600 mg daily in 1–2 divided

First-line fragment. Read the complete Indications and Dose section above.

PDF page 366

Age labels are extracted for navigation. Check the complete source section and current local guidance before clinical use.