Contraindicated in female children and women of childbearing potential unless conditions of Pregnancy Prevention Programme (Prevent) are met. Only use Valproate in such individuals if other treatments are ineffective or not tolerated. Contraindicated in pregnancy unless no suitable alternative treatment. If patient becomes pregnant or is planning a pregnancy, immediately refer to specialist. Risk minimisation materials that form Prevent can be accessed here: https://www.gov.uk/guidance/valproate-use-by-women-and-girls
(Please refer to the full SmPC before prescribing)
Indications: Under 55: For all female and all male patients initiating valproate: Treatment of generalised, partial or other epilepsy only when there is no other effective or tolerated treatment. For all female patients aged over 55 years and male patients established on treatment with valproate or aged over 55 years: Treatment of generalised, partial or other epilepsy. Available strengths: 200, 300 and 500mg prolonged-release tablets x 14, 30, 48, 72, 90 or 100 tablets. Dosage: Adults: start 600mg daily, increase by 200mg at three-day intervals until controlled (usually 1000-2000mg/day). Children over 20kg: Initial dose 400mg/day with spaced increases until controlled (usually 20-30mg/kg bodyweight per day). If control not achieved, can increase to 35mg/kg bodyweight per day. In children requiring >40mg/kg/day, monitor clinical chemistry and haematology. Children under 20kg: Use alternative formulation of sodium valproate. Elderly: Determine dose by seizure control. Renal impairment: May need to decrease dose in patients with renal insufficiency or to increase the dose in patients on haemodialysis. Valproate is dialysable. Adjust dose according to clinical monitoring. Hepatic impairment: Do not use salicylates concomitantly as they use same metabolic pathway. Female children and women of childbearing potential aged under 55 years: Do not initiate new patients on valproate or prescribe unless two specialists independently consider and document there are no other effective/tolerated treatments. Must be supervised by a specialist. For existing patients, where possible, switch to another treatment unless 2 specialists independently consider and document there are no other effective/tolerated treatments. In patients continuing valproate, carefully reconsider benefits/risks regularly, at least annually. Must be prescribed and dispensed as per Valproate Pregnancy Prevention Programme. Preferably prescribe as monotherapy at lowest effective dose – divide daily dose into at least two single doses. Male children and men aged under 55 years: Do not initiate new patients on valproate unless 2 specialists independently consider and document there is no other effective/tolerated treatment, or the risk of infertility/potential risk of testicular toxicity are not applicable. Specialists should discuss and complete the risk acknowledgment form with the patient/carer at initiation to make them aware of the risk of infertility and data showing testicular toxicity in animals exposed to valproate. Combined therapy: Taper other anti-convulsants slowly then gradually initiate Dyzantil – target dose being reached after about 2 weeks. Might need to raise dose by 5-10mg/kg/day when used in combination with liver enzyme inducing anti-convulsants. Once known enzyme inducers withdrawn, a reduced Dyzantil dose may maintain seizure control. If barbiturates used concomitantly, reduce dose, especially if sedation observed (particularly in children). Administration: Oral administration, swallow whole; don’t crush/chew. Contraindications: Pregnancy unless 2 specialists independently consider and document there is no effective/tolerated alternative. Women of childbearing potential aged under 55 years, unless two specialists independently consider and document there is no other effective/tolerated treatment and conditions of pregnancy prevention programme fulfilled. These conditions apply to women who are not currently sexually active, unless there are compelling reasons to indicate there is no risk of pregnancy. Active liver disease. Personal/family history of severe hepatic dysfunction especially drug related. Patients with urea cycle disorders. Hypersensitivity to sodium valproate, valproic acid or excipients. Porphyria. Patients with mitochondrial disorders due to mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG) and in children under two suspected of having POLG-related disorder. Patients with uncorrected systemic primary carnitine deficiency. Special warnings and precautions for use: Blood cell count, bleeding time and coagulation tests recommended prior to initiation. Discontinue gradually under specialist supervision, monitor for sudden recurrence of symptoms. Liver dysfunction: Severe liver damage including hepatic failure, sometimes fatal, reported very rarely – risk factors: under 3 years old, severe seizure disorders, organic brain disease and/or congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations or degenerative disease associated with mental retardation. Avoid concomitant salicylates in those under 3 years due to liver toxicity risk; do not use salicylates in those under 16 years. Monotherapy advised in children under 3 years, weigh benefit against risk of liver damage or pancreatitis before initiation. Advise patients to monitor for clinical signs of liver damage, report immediately to a physician and withdraw drug. Measure liver function before therapy and periodically during first 6 months, especially in patients at risk and those with history of liver disease. On changes to concomitant medicinal products known to impact the liver, liver monitoring should be restarted. Terminate therapy (and concomitant salicylates) if abnormally low prothrombin rate with other abnormalities (decreased fibrinogen/coagulation factors; increased bilirubin/transaminases). Patients with known/suspected mitochondrial disease: May trigger/worsen clinical signs of mitochondrial disease caused by mutations of mitochondrial DNA as well as nuclear encoded POLG gene. May lead to acute liver failure and liver-related death. Consider POLG mutation testing if family history or suggestive symptoms. Pancreatitis: May be severe and fatal. Promptly evaluate (including serum amylase) patients with nausea, vomiting or acute abdominal pain. Risk factors: Young children, severe seizures, and neurological impairment with combination anti-convulsant therapy. Hepatic failure with pancreatitis increases risk of fatal outcome. In case of pancreatitis, discontinue valproate. Female children, females of childbearing potential under 55 and pregnant women: Inform patient that valproate has high teratogenic potential – children exposed in utero have a high risk of congenital malformations (11%) and neurodevelopment disorders (up to 30-40%) which may lead to permanent disability Females of childbearing potential must meet conditions of pregnancy prevention programme. Make every effort to switch female children to alternative treatment before adulthood. Annually reassess those who have experienced menarche and consider alternative treatment options. Pregnancy must be excluded before valproate therapy initiated. Must use effective contraception without interruption during valproate therapy. Concomitant use with oestrogen-containing products may result in decreased valproate efficacy – monitor clinical response upon initiation/discontinuation. Review valproate treatment annually. Ensure Patient Guide and Card provided. If planning pregnancy, reassess and consider alternative treatment options. Make every effort to switch to alternative treatment prior to conception and before stopping contraception. If switching not possible, counsel woman on risks of valproate for unborn child. If pregnancy occurs, she must immediately contact her GP to be referred to a specialist to re-evaluate treatment. Discuss and complete an annual risk acknowledgement form with the patient/carer at treatment initiation and during each annual review by the specialist. Male children and men: All male patients and/or carers should be made aware of the potential risk to children born to men treated with valproate in the 3 months before conception, of the risk of infertility in men and of the data available showing testicular toxicity in animals exposed to valproate and the uncertain clinical relevance. A retrospective observational study suggests an increased risk of neuro-developmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception compared to those born to men treated with lamotrigine or levetiracetam. As a precautionary measure, GPs and specialists should inform male patients about this potential risk and recommend the need for male patients and their female partner to use effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment or for at least 3 months after treatment discontinuation. Male patients treated with valproate should be regularly reviewed by their GP or specialist. For male patients planning to conceive a child, the specialist should consider and discuss other suitable treatment options with the male patients. Individual circumstances should be evaluated in each case. Educational materials are available for healthcare professionals and male patients. A patient guide should be provided to male patients using valproate. Males under 55 – at the initiation of treatment, the specialist should discuss and complete risk acknowledgement form to ensure all male children and men under 55 are aware of risk of the potential risk to offspring and of infertility in males and testicular toxicity in animals. Aggravated convulsions: May see reversible worsening of convulsion frequency and severity (including status epilepticus), or onset of new types of convulsions with valproate – consult physician immediately if aggravated convulsions. Suicidal ideation and behaviour: Monitor for signs and behaviour – consider appropriate treatment. Nervous System Disorders: Sedation occasionally occurs, usually when in combination with other anti-convulsants. Possible increase in alertness, occasionally aggression, hyperactivity, behavioural deterioration. Rarely lethargy occasionally progressing to stupor with hallucinations/convulsions. Encephalopathy and coma rarely reported – often with too high starting dose/too rapid dose escalation or concomitant use of other anti-convulsants. Usually reversible on treatment withdrawal/dose reduction. Carbapenem agents: Concomitant use not recommended. Tests: Blood tests recommended before initiation/before surgery/in case of spontaneous bruising/bleeding. Renal insufficiency: may be necessary to decrease dosage. Adjust according to clinical monitoring. Patients with systemic lupus erythematosus: Use on a benefit/risk basis. Urea cycle disorders and risk of hyperammonaemia: If urea cycle enzymatic deficiency suspected, perform metabolic investigations prior to treatment due to risk of hyperammonaemia which may occur without change in liver function tests and is usually transient. If vomiting, ataxia, clouding of consciousness occur, discontinue Dyzantil. Patients at risk of hypocarnitinaemia: valproate may trigger or worsen hypocarnitinaemia which can result in hyperammonaemia (that may lead to hyperammonaemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis and Fanconi syndrome have been observed, mainly in patients with risk factors for or pre-existing hypocarnitinaemia. Risk factors: metabolic disorders including mitochondrial disorders related to carnitine, impaired carnitine nutritional uptake, patients younger than 10 years, concomitant use of pivalate-conjugated medicines or of other antiepileptics. Advise patients to immediately report signs such as ataxia, impaired consciousness and vomiting. Consider carnitine supplementation when hypocarnitinaemia symptoms observed. Valproate should only be used in patients with systemic primary carnitine deficiency and corrected hypocarnitinaemia if benefits outweigh risks and there is no therapeutic alternative. Implement carnitine monitoring in these patients. Warn patients with carnitine palmitoyltransferase (CPT) type II deficiency of greater risk of rhabdomyolysis, consider carnitine supplementation. Weight gain: factor for polycystic ovary syndrome, monitor weight increases. Warn patients that valproate commonly causes weight gain. Diabetic patients: Valproate eliminated mainly through kidneys partly as ketone bodies which may give false positive in urine testing of possible diabetics. Alcohol: Intake not recommended during therapy. Effects of valproate on other drugs: Valproate may potentiate effect of: antipsychotics, MAO inhibitors, antidepressants, benzodiazepines, carbamazepine: monitor clinically and adjust doses as necessary – valproate may potentiate effect of other psychotropics. Valproate may decrease plasma concentrations of: olanzapine, total phenytoin. Valproate may increase plasma concentrations of: phenobarbital (reduce dose if sedation), primidone (monitor for adverse effects e.g. sedation and adjust dose as necessary), phenytoin free form (monitor for possible overdose symptoms), lamotrigine (monitor for lamotrigine toxicity and reduce lamotrigine dose as necessary), felbamate, rufinamide (caution in children), propofol (consider reducing propofol dose), zidovudine (monitor for toxicity), nimodipine (decrease nimodipine if hypotension) Effects of other drugs on valproate: Drugs leading to a decrease in valproate plasma concentrations: liver enzyme inducing antiepileptics (adjust dose according to clinical response and blood levels), mefloquine/chloroquine (may lower seizure threshold – adjust valproate dose), carbapenem antibiotics (avoid use – if cannot avoid, monitor valproic acid blood levels), rifampicin (adjust valproate dose), protease inhibitors e.g. lopinavir, ritonavir, cholestyramine, oestrogen-containing products, including contraceptives (monitor valproate serum levels), metamizole and methotrexate (monitor clinical response and valproate serum levels). Drugs leading to an increase in valproate plasma concentrations: felbamate (monitor valproate dose), cimetidine, erythromycin. Valproic acid metabolite levels may increase with concomitant phenytoin or phenobarbital – monitor for hyperammonaemia. Anticoagulant effects of warfarin/other coumarin anticoagulants may be increased-monitor prothrombin time. Caution using concomitantly with newer antiepileptics whose pharmacodynamics not well known. Concomitant administration with topiramate or acetazolamide associated with encephalopathy and/or hyperammonaemia – monitor, especially if at-risk e.g. pre-existing encephalopathy. Concomitant use of salicylates should be avoided in children under 3 due to risk of liver toxicity. Concomitant use with pivalate-conjugated medicines increases risk of carnitine depletion and should be avoided, monitor for hypocarnitinaemia. Co-administration with quetiapine may increase risk of neutropenia/leucopenia. Concomitant use with multiple anticonvulsant therapy increases risk of liver damage, especially in young children. Concomitant use with cannabidiol increases the incidence of elevated liver transaminases. Monitor liver enzymes when valproate used with other anti-convulsants with potential hepatotoxicity including cannabidiol and consider dose reduction/discontinuation if significant liver parameter anomalies. Fertility, pregnancy and lactation: Contraindicated in pregnancy unless 2 specialists independently consider and document that there is no alternative (risk/benefit decision). Contraindicated in women of child-bearing potential under 55 unless 2 specialists independently consider and document that there is no alternative and that conditions of Pregnancy Prevention Programme fulfilled. Valproate monotherapy and polytherapy including other anti-epileptics – increased risk of major congenital malformations and neurodevelopmental disorders– congenital malformations, developmental disorders, hearing impairment/deafness. If valproate-exposed pregnancy, refer by their GP to a specialist for evaluation and counselling. If valproate taken during pregnancy, haemorrhagic syndrome, hypoglycaemia, hypothyroidism, withdrawal syndrome has been reported in neonates. Valproate excreted in breast milk, may cause haematological disorders in infants. Decide whether to discontinue breast-feeding or discontinue valproate. Amenorrhea, polycystic ovaries and increased testosterone reported in women. May impair fertility in men. Fertility dysfunction is in some cases reversible at least 3 months after discontinuation. Dose reduction may improve fertility function. Males and potential risk of neuro-developmental disorders in children of fathers treated with valproate in the 3 months prior to conception. A retrospective observational study in 3 Nordic countries suggests an increased risk of neuro-developmental disorders (NDDs) in children (from 0 to 11 years old) born to men treated with valproate as monotherapy in the 3 months prior to conception compared to those born to men treated with lamotrigine or levetiracetam as monotherapy, with a pooled adjusted hazard ratio (HR) of 1.50 (95% CI: 1.09-2.07). The adjusted cumulative risk of NDDs ranged between 4.0% to 5.6% in the valproate group versus between 2.3% to 3.2% in the composite lamotrigine/levetiracetam group. The study was not large enough to investigate associations with specific NDD subtypes and study limitations included potential confounding by indication and differences in follow-up time between exposure groups. Overall, an increased risk of NDDs in children of fathers treated with valproate in the 3 months prior to conception is possible however the causal role of valproate is not confirmed. In addition, the study did not evaluate the risk of NDDs to children born to men stopping valproate for more than 3 months prior to conception (i.e., allowing a new spermatogenesis without valproate exposure). As a precautionary measure, GPs and specialists should inform male patients about this potential risk and recommend the need for male patients and their female partner to use effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment or for at least 3 months after treatment discontinuation. Male patients treated with valproate should be regularly reviewed by their GP or specialist. For male patients planning to conceive a child, the specialist should consider and discuss other suitable treatment options with the male patients. Individual circumstances should be evaluated in each case. Effects on ability to drive/use machines: May cause transient drowsiness especially in cases of polytherapy or association with benzodiazepines. Undesirable effects: For full list of side effects consult SmPC. ‘Very Common’ ‘Common’ and ‘Serious’ side effects included in this prescribing information. Very common (≥1/10) Tremor, nausea. Common (≥1/100 to <1/10) Anaemia, thrombocytopenia, hyponatraemia, weight increase, confusional state, hallucinations, aggression, agitation, disturbance in attention, extrapyramidal disorder, stupor, somnolence, convulsion, memory impairment, headache, nystagmus, deafness, haemorrhage, vomiting, gingival disorder, stomatitis, gastralgia, diarrhoea, liver injury, increased liver enzymes, hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders, urinary incontinence, dysmenorrhea. Uncommon (≥1/1,000 to <1/100) serious side effects: Pancytopenia, leucopenia, SIADH, coma, encephalopathy, reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions, vasculitis, pleural effusion, pancreatitis (sometimes fatal), angioedema, osteoporosis, fractures, renal failure, peripheral oedema. Rare serious (≥1/10,000 to <1/1,000) side effects: Myelodysplastic syndrome, bone marrow failure, hypothyroidism, hyperammonaemia, psychomotor hyperactivity, learning disorder, reversible dementia associated with reversible cerebral atrophy, cognitive disorder, diplopia, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, systemic lupus erythematosus, rhabdomyolysis, tubulointerstitial nephritis, reversible Fanconi syndrome, male infertility, polycystic ovaries, coagulation factors decreased, abnormal coagulation tests. Very rare (<1/10,000) serious side effects: Hepatic failure, sometimes fatal. Serious, frequency not known (cannot be estimated from the available data): hypocarnitinaemia MA Number: PL5533/0152-0154 Cost: £2.45 for 200mg; £3.67 for 300mg & £6.11 500mg (x30 tablets). MAH: Aspire Pharma Ltd, Unit 4, Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG. Legal category: POM. Date reviewed: August 2024 Version number: 1010506966 v 7.0
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