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SUMMARY OF PRODUCT CHARACTERISTICS

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 Ivax BP 200mg/5ml Oral Solution Valpal (for Ashbourne)

Kentlim (for Kent/OPD)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Sodium Valproate BP 200mg Excipient(s) with known effect:

Sodium Methyl P-Hydroxy Benzoate BP

Sodium Propyl P-Hydroxy Benzoate BP Sorbitol solution (non crystallising) BP For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Pink clear liquid with cherry odour

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of generalised, partial or other epilepsy. In women of childbearing age sodium valproate should be used only in severe cases or in those resistant or refractory to other treatment.

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. Monotherapy

Usual requirements are as follows:

Adults

Dosage should start at 600 mg in divided doses increasing by 200 mg at three day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day, i.e. 20-30 mg/kg body weight. Where adequate control is not achieved within this range the dose may be further increased to a total of 2500 mg per day.

Paediatric population

Children over 20 Kg

Initial dosage should be 400mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20-30 mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight.

Children under 20 Kg

20 mg/kg of body weight per day; in severe cases this may be increased up to 40mg/kg/day but increases above this should be undertaken only in patients in whom plasma valproic acid levels, clinical chemistry and haematological parameters can be monitored.

Older people

Although the pharmacokinetics of sodium valproate are modified in older people, these have limited clinical significance and dosage should be determined by the control of clinical symptoms. The volume of distribution is increased in older people and, because of the reduced binding to serum albumin, the proportion of free drug is increased. This complicates any interpretation of the significance of plasma concentrations.

Sodium Valproate may be given twice daily.

Combined therapy

It may be necessary to increase the dose by 5-10 mg per kg per day when used in combination with other anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital, carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain control of seizures with a reduced dose of sodium valproate. When barbiturates are being administered concomitantly the dosage of barbiturate should be reduced should sedation occur.

General Considerations

Optimum dosage is determined by the clinical control of seizures; routine measurement of plasma levels is unnecessary and may be misleading. Measurement of plasma levels has proved to be an advantage when there is poor control of symptoms or side-effects are suspected. The reported effective range of valproic acid plasma levels is usually between 40-100mg/litre.

Manic episodes in bipolar disorder:

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 formulations 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 Oral.

4.3 Contraindications

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

Active liver disease. Porphyria. Family history of severe hepatic dysfunction, particularly drug-related.

Sodium valproate is contraindicated in 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.

4.4.1 Special warnings

In particular the prescriber must ensure the patient understands:

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

•    The need to use effective contraception.

•    The need for regular review of treatment.

•    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.

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 caseof pancreatitis, Sodium valproate should be discontinued.

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

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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 Oral Solution. 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.

4.4.2 Precautions

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 Adminstration 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. All patients should be warned of this risk at the initiation of therapy and appropriate strategies adopted to minimise weight gain. Monitor body weight during sodium valproate therapy.

See ‘Liver dysfunction’ and ‘Pancreatitis’ in subsection special warnings.

Pregnancy: Women of child bearing potential should not be started on sodium valproate without specialist neurological advice. 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 those resistant to other treatment. Women who are likely to get pregnant, should receive specialist advice because of the potential teratogenic risk to the foetus (see also 4.6 Pregnancy and Lactation).

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: Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone metabolites; this may give false positives in the urine testing of possible diabetics.

Carbapenem agents:

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

4.5 Interaction with other medicinal products and other forms of interaction

-    Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Like many other drugs, sodium valproate may potentiate the effects of other psychotropics such as antipsychotics,benzodiazepines, monoamine oxidase inhibitors and other antidepressants; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.The enzyme inducing effect associated with sodium valproate is less than that of other anticonvulsant drugs and loss of efficacy of oral contraceptive agents does not appear to be a problem.

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.

-    Phenobarbital

Sodium 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.

-    Primidone

Sodium 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

Sodium 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.

-    Carbamazepine

Clinical toxicity has been reported when sodium valproate was administered with carbamazepine as sodium valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

-    Lamotrigine

The risk of rash associated with the use of sodium valproate , may be inceased if lamotrigine is also administered. Sodium valproate may reduce lamotrigine metabolism and increase its mean half-life, dosages should be adjusted (lamotrigine dosage decreased) when appropriate. Concurrent use of sodium valproate and lamotrigine may lead to elevated serum levels of both drugs.

-    Zidovudine

Sodium valproate may raise zidovudine plasma concentration leading 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 sodium valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

Effects of other drugs on Sodium 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 sodium valproate may increase valproic acid plasma concentration. Sodium valproate dosage should be monitored.

Antimalarial drugs such as mefloquine may antagonise the anticonvulsant effects of sodium valproate. 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.

Caution is recommended when administering anticoagulants and other products which have anticoagulant properties (e.g. warfarin and aspirin). Aspirin may displace valproate from binding sites resulting in higher free levels of valproate. Sodium valproate decreases protein binding of warfarin but this may not lead to clinically significant effects. Phenytoin levels may be affected and these should be monitored, particularly the free form.

Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or 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 stabilished on valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4)

Colestyramine may decrease the absorption of sodium valproate .

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.

Dosage of sodium valproate may require adjustment when used in combination with other anticonvulsants (as stated in the combined therapy dosage section).

Other Interactions

Caution 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, sodium valproate does not reduce efficacy of oestroprogestative 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 minimize 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.

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.

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

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.

Epidemiological studies have suggested an association between in-utero exposure to sodium valproate and a risk of developmental delay. Many factors including maternal epilepsy may also contribute to this risk but it is difficult to quantify the relative contributions of these or of maternal anti-epileptic 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.

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.

In humans: 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%. An increased incidence of congenital malformations (including cases of facial dysmorphia, hypospadias and multiple malformations, particularly of the limbs) 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 exposure to valproate 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).

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.

Folate supplementation, prior to pregnancy, has been demonstrated to reduce the incidence of neural tube defects in the offspring of women at high risk. Although no direct evidence exists of such effects in women receiving antiepileptic drugs, women should be advised to start taking folic acid supplementation (5mg) as soon as contraception is discontinued.

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.

Nevertheless, specialist prenatal monitoring should be instituted in order to detect the possible occurrence of a neural tube defect or any other malformation. Pregnancies should be carefully screened by ultrasound, and

other techniques, if appropriate (see Section 4.4 Special Warnings and Precautions for use).

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.

•    To institute specialized prenatal monitoring in order to detect the possible occurrence of neural tube defects or other malformations.

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, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbitol 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, hyper-excitability, 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 childbearing 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 valproic acid 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.

4.7    Effects on ability to drive and use machines

If given concomitantly with CNS depressants (including alcohol) may reduce ability to drive vehicles or operate machinery.

Use of sodium valproate may provide seizure control such that the patient may be eligible to hold a driving licence.

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

The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of sodium valproate in the treatment of manic episodes have been identified.

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).

Blood and lymphatic system disorders

Rare: anaemia, hypoplasia erythroid (red cell hypoplasia) leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.

Agranulocytosis.

Not known: Valproic acid inhibits the second stage of platelet aggregation. Reversible prolongation of bleeding time and frequent occurrence of thrombocytopenia have been reported, but these are usually associated with doses above those recommended. Prior to initiation of therapy and also before surgery, clinicians should assure themselves that there is no undue potential for bleeding complications. Isolated reduction of fibrinogen may also occur.

Bone marrow failure, including pure red cell aplasia.

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 Pregnancy and Lactation).

Immune system disorders

Rare: Angioedema, syndrome, and allergic reactions (ranging from rash to hypersensitivity reactions) signs of an immune disorder, therefore caution should be observed when using the drug in patients with features which may suggest systemic lupus erythematosus.

Metabolism and nutrition disorders

Very common: weight gain which may be marked and progressive (see Section 4.4). Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4).

Not known: Cases of isolated and moderate hyperammonaemia without hepatic damage can occur in patients during treatment with valproic acid or sodium valproate. This is usually transient, but may occasionally appear 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.

Rare: Obesity

Very rare: hyponatraemia

Nervous system disorders

Not known: Ataxia and fine postural tremor have been occasionally reported and appear to be dose related effects.

Rare: Sedation has been reported occasionally, usually when used in combination with other anticonvulsants. In sodium valproate monotherapy sedation has occurred early in treatment on rare occasions and is usually transient.

Lethargy and confusion, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported.

An increase in alertness may occur which is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.

Very Rare: Coma, reversible extrapyramidal disorder including parkinsonism, or reversible dementia associated with reversible cerebral atrophy.

These side-effects have more usually been in combination therapy with other anticonvulsants, notably phenobarbitol, where starting doses were too high or too rapid a dose escalation and have been reversible on withdrawal of treatment or on reduction of dosage.

Ear and labyrinth disorders

Rare: Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.

Vascular disorders Not known: vasculitis.

Gastrointestinal Disorder

Very common: Nausea, gastralgia, diarrhoea occur frequently 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 .

Very rare: pancreatitis, sometimes lethal, have been reported (see section 4.4). There have been reports of pancreatitis occurring in patients receiving valproic acid or sodium valproate, usually within the first six months of therapy although this has occurred after several years of treatment (see Section 4.4). Patients experiencing acute abdominal pain should have their serum amylase estimated, if these levels are elevated treatment should be discontinued.

Not known: Increase in appetite may occur. Minor gastric irritation and, less frequently, nausea have been observed in some patients at the start of treatment, but these problems can usually be overcome by administering sodium valproate with or after food.

Hepatobiliary disorders

Common: Increased liver enzymes, particularly early in treatment, and may be transient (see section 4.4.1) or respond to reduction in dosage of sodium valproate.

Rare: Liver dysfunction.

Not known: Severe liver damage including hepatic failure resulting in fatalities has occurred in patients whose treatment included valproic acid or sodium valproate.

Patients most at risk are children particularly under the age of three and those with congenital metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation. The incidents mainly occurred during the first six months of therapy, the period of maximum risk being 2-12 weeks, and usually involved multiple anticonvulsant therapy. Monotherapy is to be preferred in this group of patients. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function including prothrombin time should be monitored until they return to normal. However an abnormally prolonged prothrombin time particularly in association with other relevant abnormalities requires cessation of treatment. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway.

Clinical symptoms are more meaningful than laboratory investigations in the early stage of hepatic failure. The onset of an acute illness, especially within the first six months, which may include symptoms of vomiting, lethargy or weakness, drowsiness, anorexia, jaundice or loss of seizure control, is an indication for immediate withdrawal of the drug. Patients should be instructed to report any such signs to the clinician should they occur. Available evidence to date does not establish any investigation which would predict this possible adverse effect. However, the routine measurement of liver function should be undertaken in the first six months of therapy with particular close attention to those who seem most at risk, and those with a prior history of liver disease. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function including prothrombin time should be monitored until they return to normal. However an abnormally prolonged prothrombin time particularly in association with other relevant abnormalities requires cessation of treatment. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway.

Skin and subcutaneous tissue disorders

Common: Nail and nail bed disorders

Rare: Rash, Acne, hirsutism, Drug Rash with Eosinophilia and systemic symptoms (DRESS) syndrome.

Very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.

Not known: Transient hair loss has been noted in some patients. This effect does not appear to be dose-related and regrowth normally begins within six months, although their hair may become more curly than previously.

Musculoskeletal and connective tissue disorders

There have been reports of decreased bone mineral density, 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.

Not known: 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.

Very Rare: enuresis

Reproductive system and breast disorders

Very rare: Amenorrhoea or irregular periods have very rarely been reported.

Very rarely, gynaecomastia has occurred

Congenital, familial and genetic disorders

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

General disorders and administrative site conditions Rare: Oedema

Very rare: non-severe peripheral oedema have been reported.

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 deliberate sodium valproate overdosage 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.

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.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2).

Cases of intracranial hypertension related to cerebral oedema have been reported.

Hospital management of overdose should be symptomatic:, including cardiorespiratory monitoring.Gastric lavage may be useful up to 10 to 12 hours following ingestion.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given 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 is an anticonvulsant.

The most likely mode of action for sodium 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 mitogenlike 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 is usually reported to be within the range 820 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 levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100mg/litre (278- 694micromol/litre). This reported range may depend on time of sampling and 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.

Preclinical safety data

Not applicable

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Methyl P-Hydroxy Benzoate BP Sodium Propyl P-Hydroxy Benzoate BP Glycerol Ph. Eur.

Cherry Flavour Erythrosine E127

Sorbitol solution (non crystallising) BP

6.2    Incompatibilities

No major incompatibilities, other than those reported under 4.5 and 4.7 above.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store in a dry place below 25°C

6.5    Nature and contents of container

Azlon high density polyethylene bottle with tamper evident cap containing 300ml and 1000ml

6.6    Special precautions for disposal

No special instructions.

MARKETING AUTHORISATION HOLDER

Norton Healthcare Ltd.

T/A IVAX Pharmaceuticals UK Ridings Point,

Whistler Drive,

Castleford,

West Yorkshire,

WF10 5HX

8    MARKETING AUTHORISATION NUMBER(S)

PL 00530/0343

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of Grant: 05/07/91 Renewal: 05/07/96 , 19/05/03

10    DATE OF REVISION OF THE TEXT

08/04/2016