SUMMARY OF PRODUCT CHARACTERISTICS

V This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1    NAME OF THE MEDICINAL PRODUCT

Sodium Valproate Teva 500 mg Gastro-resistant Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg of Sodium Valproate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Gastro-resistant Tablet

Lilac, biconvex Gastro-resistant tablet

4    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Sodium valproate Gastro-resistant tablets are indicated for the treatment of generalised, partial or other epilepsy.

Treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to valproate for acute mania.

4.2 Posology and method of administration

Posology

Epilepsy

Daily dosage requirements vary according to age and body weight.

Sodium valproate tablets may be given twice daily. The tablets should be swallowed whole and not crushed or chewed.

Monotherapy

The usual requirements are as follows:

Adults

Initially 600 mg daily, increasing by 200 mg at three day intervals until control is achieved. Usually maintenance is achieved within the dosage range 1000 mg to 2000 mg per day, (i.e. 20-30 mg/kg/day body weight). If acceptable control is not achieved, the dosage may be increased to 2500 mg per day.

Paediatric population

Children over 20 kg

Initially 400 mg daily, (irrespective of weight), with spaced increases until control is achieved. This is usually within the dosage range 20-30 mg/kg body weight per day. If this does not achieve acceptable control of seizures, the dose may be increased to 35 mg/kg body weight per day

Children under 20 kg

20 mg/kg body weight daily. This may be increased in severe cases but only if plasma valproic acid levels can be monitored. At doses higher than 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Older people

The pharmacokinetics of valproate are modified in the elderly, (a combination of an increased volume of distribution and a decrease in serum albumin binding sites results in an increase of free plasma valproic acid levels which will affect the clinical interpretation). Although this is likely to be of limited clinical significance, care should be exercised when determining the dosage regimen. Dosage should be determined by the degree of seizure control.

In patients with renal insufficiency

It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2, Pharmacokinetic Properties).

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with valproate since they employ the same metabolic pathway (see also sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 Contraindications and 4.4 Special Warnings and Precautions for Use).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome). In addition in conjunction with sodium valproate, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).

Combined therapy

When initiating sodium valproate therapy in patients already taking other anticonvulsants, the dosage of these should be tapered slowly and the initiation of sodium valproate therapy should be gradual, with the target dose being reached after about 2 weeks. When used in conjunction with anticonvulsants known to induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine, it may be necessary to raise the dose of sodium valproate by 5 to 10 mg/kg/day. Once therapy with such enzyme inducers has ceased, adequate control may be achieved on a lower dose of sodium valproate. The dosage of concomitantly administered barbiturates should be reduced if sedation is observed (especially in children).

As in monotherapy, for children requiring doses higher than 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Optimum dosage is mainly determined by seizure control. Routine measurement of plasma levels is unnecessary, although a method for measurement of plasma levels is available and may be of use in cases where there is poor control or side effects are suspected (see section 5.2, Pharmacokinetic Properties).

Manic episodes in bipolar disorder:

In adults

The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750mg. In addition, in clinical trials a starting dose of 20mg Valproate /kg body weight has also shown an acceptable safety profile. Prolonged-release formulation can be given once or twice daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1000 and 2000mg Valproate. Patients receiving daily dose higher than 45mg/kg/day body weight should be carefully monitored.

Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.

In children and adolescents:

The safety and efficacy of Valproate for the treatment of manic episodes in bipolar disorder have not been evaluated in patients aged less than 18 years.

Female children, female adolescents, women of childbearing potential and pregnant women

Sodium valproate should be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Treatment should only be initiated if other treatments are ineffective or not tolerated (see section 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably sodium valproate should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses.

Method of administration

For oral administration.

4.3 Contraindications

•    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

•    Active liver disease, porphyria, or a personal or family history of severe hepatic dysfunction, especially when drug related.

•    Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase y (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4)

4.4 Special warnings and precautions for use

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

Special warnings

Female children/Female adolescents/Women of childbearing potential/Pregnancy:

Sodium valproate should not be used in female children, in female adolescents, in women of childbearing potential and pregnant women unless alternative treatments are ineffective or not tolerated because of its high teratogenic potential and risk of developmental disorders in infants exposed in utero to valproate. The benefit and risk should be carefully reconsidered at regular treatment reviews, at puberty and urgently when a woman of childbearing potential treated with sodium valproate plans a pregnancy or if she becomes pregnant.

Women of childbearing potential must use effective contraception during treatment and be informed of the risks associated with the use of sodium valproate during pregnancy (see section 4.6).

The prescriber must ensure that the patient is provided with comprehensive information on the risks alongside relevant materials, such as a patient information booklet, to support her understanding of the risks.

In particular the prescriber must ensure the patient understands:

1)    The nature and the magnitude of the risks of exposure during pregnancy, in particular the teratogenic risks and the risks of developmental disorders.

2)    The need to use effective contraception.

3)    The need for regular review of treatment.

4)    The need to rapidly consult her physician if she is thinking of becoming pregnant or there is a possibility of pregnancy.

In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible (see section 4.6).

Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy or bipolar disorder.

Liver dysfunction:

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 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, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 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 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. Such patients should have closed clinical supervision (see the section 4.8)

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, valproate should be discontinued.

Patients should be advised to consult their doctor immediately if they develop symptoms suggestive of pancreatitis (e.g. abdominal pain, nausea and vomiting). Medical evaluation (including measurement of serum amylase) should be undertaken in patients presenting with symptoms suggestive of pancreatitis and sodium valproate should be discontinued if pancreatitis is diagnosed.

Patients with known or suspected mitochondrial disease

Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase y (POLG), e.g. Alpers-Huttenlocher Syndrome.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to 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. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).

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

Concomitant use of valproic acid/sodium Valproate and carbapenem agents is not recommended(see section 4.5)

4.4.2 Precautions

Haematological: Prior to initiation of therapy and also before surgery, clinicians should assure themselves, using the appropriate blood tests (blood cell count including platelet count, bleeding time and coagulation tests), that there is no undue potential for bleeding complications (see also 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: herefore, caution should be used when treating patients with features which may suggest systemic lupus erythematosus (see also section 4.8 Undesirable Effects). Rarely signs of an immune disorder have occurred following treatment with sodium valproate, t

Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate.

Weight gain: Sodium valproate very commonly causes weight gain which may be marked and progressive. All patients should be warned of this risk at the initiation of therapy and appropriate strategies adopted to minimise weight gain. (see section 4.8 Undesirable Effects). Monitor body weight during sodium valproate therapy.

Pregnancy

Women of childbearing potential should not be started on sodium valproate without specialist neurological advice. Adequate counselling should be made available to all 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: False positive results in urine testing for possible diabetics may occur as valproate is eliminated from the kidneys partly as ketone bodies.

Alcohol

Alcohol intake is not recommended during treatment with valproate

Paediatric population

See ‘Liver dysfunction’ and ‘Pancreatitis’ in subsection 4.4.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of Valproate on Other Drugs:

Antipsychotics, MAO Inhibitors, Antidepressants and Benzodiazepines: The effects of other psychotropics such as antipsychotics, monoamine oxidase inhibitors, benzodiazepines and other anti-depressants may be enhanced by sodium valproate. Therefore, clinical monitoring is advised and dosage 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.

Felbamate

Valproic acid may decrease the felbamate mean clearance by up to 16%. Lithium

Sodium valproate has no effect on serum lithium levels

Phenobarbital: Phenobarbital plasma levels may increase (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Clinical monitoring is recommended throughout the first 15 days of combined therapy with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

Primidone: 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.

Phenytoin:    Valproate decreases phenytoin total plasma concentration.

Moreover 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.

Carbamazepine: Clinical toxicity has been reported when 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.

Lamotrigine: Valproate may reduce the metabolism of lamotrigine and increase its mean half-life by nearly two fold, dosages should be adjusted (lamotrigine dosage decreased) when appropriate. Concomitant administration of sodium valproate and lamotrigine may increase the risk of rash.

Zidovudine: Zidovudine plasma concentration may be raised and may lead to increased zidovudine toxicity.

Vitamin K-dependent anticoagulants: The 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.

Temozolomide: Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

Effects of Other Drugs on Valproate:

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to blood levels in case of combined therapy.

On the other hand, combination of felbamate and valproate may increase valproic acid plasma concentration. Valproate dosage should be monitored.

Both mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. The dosage of sodium valproate may need adjustment accordingly.

In case of concomitant use of 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 and erythromycin.

Decrease in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60-100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4)

The absorption of valproate may be decreased in the presence of colestyramine.

Rifampicin may decrease the valproate blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.

Other interactions:

Caution is advised when using valproic acid in combination with new antiepileptics 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, sodium valproate does not reduce efficacy of oestroprogesterone agents in women receiving hormonal contraception, including the oral contraceptive pill.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Sodium valproate should not be used in female children, in female adolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

Women of childbearing potential should not be started on sodium valproate without specialist neurological advice.

Adequate counselling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (See also section 4.6.1). Women who are taking sodium valproate and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.

Sodium valproate is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, sodium valproate should be used only in patients resistant to other treatment.

When sodium valproate treatment is deemed necessary, precautions to minimise the potential teratogenic risk should be followed. (See also section 4.6.1 paragraph entitled “In view of the above”).

Pregnancy

If pregnancy is planned, consideration should be given to cessation of sodium valproate treatment, if appropriate.

From experience in treating mothers with epilepsy, the risk associated with the use of sodium valproate during pregnancy has been described as follows:

- Risk associated with epilepsy and antiepileptics

In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be 2 to 3 times higher than the rate (approximately 3%) reported in the general population. Although an increased number of children with malformations have been reported in cases of multiple drug therapy, the respective role of treatments and disease in causing the malformations has not been formally established. Malformations most frequently encountered are cleft lip and cardiovascular malformations.

Epidemiological studies have suggested an association between in-utero exposure to sodium valproate and a risk of developmental delay. Developmental delay has been reported in children born to mothers with epilepsy. It is not possible to differentiate what may be due to genetic, social, environmental factors, maternal epilepsy or antiepileptic treatment. Notwithstanding those potential risks, no sudden discontinuation in the antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both the mother and the foetus.

-Risk associated with valproate

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.

In 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.

Congenital malformations

Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16 -13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.

Available data show an increased incidence of minor and major malformations. The most common types of 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 involving various body systems.In humans: an increased incidence of minor or major malformations including neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations and multiple anomalies involving various body systems has been demonstrated in offspring born to mothers with epilepsy treated with valproate. Some data from studies of women with epilepsy, have suggested an association between in-utero sodium valproate exposure and the risk of developmental delay (frequently associated with craniofacial abnormalities), particularly of verbal IQ.

Developmental disorders

Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.

Studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.

Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.

Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.

There are limited data on the long term outcomes.

Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.

Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).

Valproate use is associated with neural tube defects such as myelomeningocele and spina bifida. The frequency of this effect is estimated to be 1 to 2%.

-In view of the above data

When a woman is planning pregnancy, this provides an opportunity to review the need for anti-epileptic treatment. Women of childbearing age should be informed of the risks and benefits of continuing anti-epileptic treatment throughout pregnancy.

Female children, female adolescents and women of child-bearing potential (see above and section 4.4)

If a woman wants to plan a pregnancy

•    During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.

•    In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed.

•    In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

Valproate therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy or bipolar disorder. If based on a careful evaluation of the risks and the benefits valproate treatment is continued during the pregnancy, it is recommended to:

•    Use the lowest effective dose and divide the daily dose valproate into several small doses to be taken throughout the day. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations.

•    Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure. women should be advised to start taking folic acid supplementation (5mg) as soon as contraception is discontinued If

•    To institute specialized prenatal monitoring 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 1000mg 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. During pregnancy, valproate anti-epileptic treatment should not be discontinued if it has been effective. 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 neonate

•    Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenaemia and/or to a decrease in other coagulation factors. Afibrinogenaemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. 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 their pregnancy.

•    Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.

•    Withdrawal syndrome (such as, in particular, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.

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). Women of child-bearing potential have to use effective contraception during treatment.

Breast-feeding

Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Sodium valproate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8). Valproate administration may also impair fertility in men (see section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

Excretion of valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels; up to now children breast fed that have been monitored during the neonatal period have not experienced clinical effects. There appears to be no contra-indication to breast-feeding by patients on valproate.

4.7 Effects on ability to drive and use machines

The use of sodium valproate may provide seizure control such that the patient may again be eligible to hold a driving licence. However, patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).

4.8 Undesirable effects

Frequencies are defined as: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very Rare (<1/10,000, including isolated reports), not known (cannot be estimated from the available data).

List of adverse reactions

Blood and lymphatic system disorders

Common: anaemia, thrombocytopenia (see section 4.4.2 Precautions). Uncommon: leucopenia or pancytopenia

Rare: Bone marrow failure, including pure red cell aplasia. Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6).

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).

Agranulocytosis, anaemia macrocytic, macrocytosis.

Immune system disorders

Rare: Angioedema, allergic reactions (hypersensitivity reactions)

Endocrine Disorders:

Uncommon: syndrome of Inappropriate Secretion of ADH (SIADH) Rare: hypothyroidism (see section 4.6 Fertility, pregnancy and lactation)

Metabolism and nutrition disorders

Common: hyponatraemia.

Rare: Obesity.

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, 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 treatment 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.

Psychiatric disorder:

Common: confusional state, aggression*, agitation*, disturbance in attention* has been reported

Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder* *These ADRs are principally observed in the paediatric population.

Nervous system disorders

Very common: tremor

Common: cases of reversible extrapyramidal symptoms including parkinsonism

Uncommon: reversible parkinsonism, ataxia

Rare: 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. Lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions. 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.

Rare: reversible dementia associated with reversible cerebral atrophy. Encephalopathy and coma.

Not known: an increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.

Ear and labyrinth disorders

Common: hearing loss, either reversible or irreversible; however a cause and effect relationship has not been established.

Vascular disorders

Not known: vasculitis

Respiratory, thoracic and mediastinal disorders:

Uncommon: pleural effusion

Gastrointestinal disorders

Very common: nausea Common: gastralgia, diarrhoea

The 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 administering the tablets with or after food.

Uncommon: pancreatitis sometimes lethal (see section 4.4). Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as haemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use (see section 4.4).

Hepatobiliary disorders

Common: liver dysfunction, Increased liver enzymes, particularly early in treatment, and may be transient (see section 4.4.1).

Not known: severe liver damage, including hepatic failure sometimes resulting in death has been reported (see also sections 4.2, 4.3 and 4.4.1).

Skin and subcutaneous tissue disorders:

Common: nail and nail bed disorders

Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become curlier than previously. Hirsutism and acne have been very rarely reported.

Uncommon: angioedema, rash

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia, Systemic Symptoms (DRESS) syndrome and allergic reactions (including rash).

Very Rare: Acne, hirsutism

Musculoskeletal and connective tissue disorders

Uncommon: There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with sodium valproate gastro-resistant tablets. The mechanism by which sodium valproate gastro-resistant tablets affects bone metabolism has not been identified.

Rare: systemic lupus erythematosus (see section 4.4.2 Precautions)

Renal and urinary disorders

Rare: enuresis. There have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria), but the mode of action is as yet unclear.

Reproductive system and breast disorders

Common: dysmenorrhea Uncommon: Amenorrhoea and irregular periods Rare: male infertility, polycystic ovaries Very Rare: gynaecomastia.

Congenital, familial and genetic disorders

Not known: Congenital malformations and developmental disorders (see section 4.4 and section 4.6).

General disorders and administration site conditions

Uncommon: non-severe peripheral oedema.

Investigations:

Common: increase in weight gain may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4).

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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professional are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Cases of accidental and suicidal overdose have been reported. 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.

In massive overdose, i.e. plasma concentrations of 10 to 20 times the maximum therapeutic levels there may be serious CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function and metabolic acidosis. The symptoms can however, be variable and seizures have been reported in the presence of very high plasma levels (see section 5.2). Cerebral oedema and intracranial hypertension have been reported. Deaths have occurred following large overdoses; nevertheless, a favourable outcome is usual.

Hospital management of overdosage should be symptomatic, including cardiorespiratory monitoring. Gastric lavage may be useful up to 10 to 12 hours following ingestion. Intravenous naloxone has also been used in a few isolated cases, sometimes in association with activated charcoal administered orally.

In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, ATC Code: N03AG01

Sodium valproate and valproic acid are anticonvulsants.

The most likely mode of action for valproate is potentiation of the inhibitory action of gamma amino-butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

In certain in-vitro studies it was reported that sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

5.2    Pharmacokinetic properties

The half life of sodium valproate ranges from 8 - 20 hours. It is usually shorter in children.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100 mg/litre (278-694 micromol/litre). This reported range may depend on time of sampling and the presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of sodium valproate may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of sodium valproate has been established after many years of clinical use. Please refer to section 4.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Povidone (E1201)

Talc

Calcium Silicate Magnesium Stearate (E572)

Hypromellose

Citric Acid Anhydrous

Macrogol 6000

Polyvinyl Acetate Phthalate

Diethyl Phthalate

Stearic Acid

Violet Lake Solids.

6.2    Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package.

6.5    Nature and contents of container

Blister packs consisting of polyamide/aluminium/heat seal lacquer blister laminate with aluminium/heat seal lacquer lidding foil, in cardboard cartons of 100 and 112 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0325

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/04/1998

10 DATE OF REVISION OF THE TEXT

27/04/2016