- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Use in renal impairment:
|Mild to moderate||- Reduce dose|
|Severe||- Alter dose according to free serum valproic acid concentration|
Conditions of occurrence:Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation.After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome).Monotherapy is recommended in children under the age of 3 years when prescribing sodium valproate, but the potential benefit of sodium valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy. In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks.
Suggestive signs:Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'):• non specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.• in patients with epilepsy, recurrence of seizures.These are an indication for immediate withdrawal of the drug.Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Detection:Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of sodium valproate therapy.As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Pancreatitis:Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors.Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, sodium valproate should be discontinued.
Women of childbearing potential (see section 4.6):This medicine should not be used in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before sodium valproate is prescribed for the first time, or when a woman of child bearing potential treated with sodium valproate plans a pregnancy.Women of child-bearing potential must use effective contraception during treatment.
Suicidal ideation and behaviour:Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate.Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.Carbapenem agents:The concomitant use of valproate and carbapenem agents is not recommended.
Haematological:Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8 Undesirable Effects).
Renal insufficiency:In patients with renal insufficiency, it may be necessary to decrease dosage.As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 Posology and Method of Administration and 5.2. Pharmacokinetic Properties).
Systemic lupus erythematosus:Although immune disorders have only rarely been noted during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus (see also section 4.8 Undesirable Effects).Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with sodium valproate.
Weight gain:Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects).
Pregnancy:Women of childbearing potential should not be started on sodium valproate without specialist neurological advice.Adequate counselling should be made available to all pregnant women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation).
Diabetic patients:Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.
Alcohol:Alcohol intake is not recommended during treatment with valproate
4.5.1 Effects of sodium valproate on other drugs• Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines Sodium valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.• Lithium Sodium valproate has no effect on serum lithium levels• PhenobarbitalSodium valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.• PrimidoneSodium valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.• PhenytoinSodium valproate decreases phenytoin total plasma concentration. Moreover sodium valproate increases phenytoin free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism).Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.• CarbamazepineClinical toxicity has been reported when sodium valproate was administered with carbamazepine as valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.• LamotrigineSodium valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.• FelbamateValproic acid may decrease the felbamate mean clearance by up to 16%.• Zidovudine Sodium valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.• Vitamin K-dependent anticoagulantsThe anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid.The prothrombin time should be closely monitored.• TemozolomideCo-administration of temozolomide and sodium valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
4.5.2 Effects of other drugs on sodium valproateAntiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.On the other hand, combination of felbamate and sodium valproate decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Sodium valproate dosage should be monitored.Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of sodium valproate may need adjustment.In case of concomitant use of sodium valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.Carbapenem antibiotics such as imipenem, panipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%-100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.Colestyramine may decrease the absorption of sodium valproate.Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
4.5.3 Other InteractionsCaution is advised when using sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.Sodium valproate usually has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.
4.6.1 Pregnancy• Risk associated with epilepsy and antiepilepticsIn offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3%) reported in the general population. An increased number of children with malformations has been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardiovascular malformations.No sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both the mother and the foetus.Antiepileptic drugs should be withdrawn under specialist supervision.• Risk associated with seizuresDuring pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.• Risk associated with valproateIn animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit. There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.In humans: available data suggest an increased incidence of minor or major malformations including neural tube defects, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems in offspring born to mothers treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other anti-epileptic drugs.Data from a meta-analysis (including registries and cohort studies) has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy at 10.73% (95% CI: 8.16 13.29). Available data indicate dose dependency of this effect.Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ. However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including valproate is associated with a higher risk of abnormal pregnancy outcome than valproate monotherapy.Autism spectrum disorders have also been reported in children exposed to valproate in utero.• In view of the above dataThe following recommendations should be taken into consideration: This medicine should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before sodium valproate is prescribed for the first time, or when a woman of child bearing potential treated with sodium valproate plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment.Women of childbearing potential should be informed of the risks and benefits of the use of sodium valproate during pregnancy.If a woman plans a pregnancy or becomes pregnant, sodium valproate therapy should be reassessed whatever the indication:• In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit/risk. If further to a careful evaluation of the risks and benefits, sodium valproate treatment is to be continued during pregnancy, it is recommended to use sodium valproate in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form.• In addition, if appropriate, folate supplementation should be started before pregnancy at relevant dosage (5mg daily) as it may minimise the risk of neural tube defects.• Specialised prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000 mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Precautions for use).- Risk in the neonateVery rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenaemia and/or to decreases in other coagulation factors; afibrinogenaemia has also been reported and may be fatal. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.Cases of hypoglycaemia have been reported in neonates, whose mothers have taken valproate during the third trimester of the pregnancy.Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
4.6.2 LactationExcretion of valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels. Although there appears to be no contraindication to breast feeding, physicians are advised that in any individual case, consideration should be given to the safety profile of sodium valproate, specifically haematological disorders (see section 4.8 Undesirable Effects).
Congenital and familial/genetic disorders:(see section 4.6 Fertility, pregnancy and lactation)Hepato-biliary disorders:Common: liver injury (see section 4.4.1 Warnings)Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).
Gastrointestinal disorders:Very common: nausea,Common: gastralgia, diarrhoeaThe above three adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking sodium valproate with or after food or by using Enteric Coated Sodium Valproate (Sodium Valproate Gastro-resistant Tablets).Uncommon: pancreatitis, sometimes lethal (see section 4.4 Special Warnings and Special Precautions for Use).
Nervous system disorders:Very common: tremorCommon: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmusUncommon: coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paresthesia.Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder.Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient.*Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Psychiatric disorder:Common: confusional state, aggression*, agitation*, disturbance in attention*Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder**These ADRs are principally observed in the paediatric population.
Metabolic disorders:Common: hyponatraemia.Rare: hyperammonaemia* (see section 4.4.2 Precautions)*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation.However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur sodium valproate should be discontinued.Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.
Endocrine Disorders:Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH)Rare: hypothyroidism (see section 4.6 Fertility, pregnancy and lactation)
Blood and lymphatic system disorders:Common: anaemia, thrombocytopenia (see section 4.4.2 Precautions).Uncommon: pancytopenia, leucopeniaThe blood picture returned to normal when the drug was discontinued.Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis.Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6 Fertility, pregnancy and lactation).
Skin and subcutaneous tissue disorders:Common: hypersensitivity, transient and/or dose related alopecia (hair loss). Regrowth normally begins within six months, although the hair may become more curly than previously.Uncommon: angioedema, rashHirsutism and acne have been very rarely reported.Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Reproductive system and breast disorders:Common: dysmenorrheaUncommon: amenorrheaRare: male infertility, polycystic ovariesVery rarely gynaecomastia has occurred.
Vascular disorders:Common: haemorrhage (see section 4.4.2 Precautions and 4.6 Fertility, pregnancy and lactation).Uncommon: vasculitis
Ear and labyrinth disorders:Common: Deafness, a cause and effect relationship has not been established.
Renal and urinary disorders:Rare: enuresis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with sodium valproate therapy, but the mode of action is as yet unclear.
General disorders and administration site conditions:Uncommon: non-severe oedema peripheral
Musculoskeletal and connective tissue disorders:Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with sodium valproate. The mechanism by which sodium valproate affects bone metabolism has not been identified.Rare: systemic lupus erythematosus (see section 4.4.2 Precautions)
Respiratory, thoracic and mediastinal disorders:Uncommon: pleural effusion
Investigations:Common: Weight increased*Rare: Coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged).*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4.2 Precautions)Neoplasms benign, malignant and unspecified (including cysts and polyps):Rare: myelodysplastic syndrome
Symptoms of overdose:At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.Signs of massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favourable outcome is usual, however some deaths have occurred following massive overdose.Seizures have been reported in the presence of very high plasma levels.Cases of intracranial hypertension related to cerebral oedema have been reported. Also, hyperammonaemia, hypotension, somnolence/drowsiness.
Treatment of overdose:Treatment of overdose consists primarily of supportive and symptomatic measures, including cardio-respiratory monitoring. The value of gastric decontamination following overdose is uncertain since valproic acid and its salts are rapidly absorbed. Activated charcoal may be tried if the patient presents within 1 hour of a potentially life-threatening overdose. Haemodialysis or tandem haemodialysis and hemoperfusion, may result in significant reductions in valproate serum concentrations. Maintenance of adequate urinary output must be ensured. Naloxone has been administered to counteract severe CNS depression, but is also theoretically reverses the anticonvulsant effect and should be used with caution.
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