This information is intended for use by health professionals

 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

Convulex 500 mg - Retardtabletten (AT)

valproat biomo 500 mg Retardtabletten (DE)

Epival CR 500 mg Prolonged-release Tablets (UK)

Convulex ® retard 500 mg prolonged-release tablets (BE, LU)

2. Qualitative and quantitative composition

Each tablet contains 500 mg sodium valproate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged-release tablet

White, oval-shaped prolonged-release tablet with a score line and engraving “CC5” on one side.

The tablet can be divided into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

Treatment of primary generalised epileptic seizures, secondary generalised epileptic seizures, and partial epileptic seizures.

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 sodium valproate for acute mania.

4.2 Posology and method of administration

Posology

sodium valproate Prolonged-release Tablets are a prolonged-release formulation of sodium valproate which reduces peak concentration and ensures more even plasma concentrations throughout the day.

Daily dosage requirements vary according to age and body weight. Optimum dosage is mainly determined by seizure control, and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected. (See section 5.2.)

Female children and women of childbearing potential

Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews.

Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (sections 4.3 and 4.4).

Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).

Epilepsy:

Monotherapy

Usual requirements are as follows:

Adults

Dosage should start at 600 mg (5-10 mg/kg body weight) daily, followed by gradual increases of 5-10 mg/kg at 3-7 day intervals until control is achieved. This is generally within the dosage range 1000 mg to 2000 mg 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 up to 2500 mg per day.

Paediatric population

For children the starting dose for sodium valproate is 10-20 mg/kg and the maintenance dose between 20 and 30 mg/kg; doses higher than 40 mg/kg daily may be required in individual cases. (See dosage table for orientation.)

Children over 20 kg

The recommended starting dose for sodium valproate Prolonged-release Tablets is 300 mg/day with increases at 3-7 day intervals 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 per day.

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

Children under 20 kg

An alternative formulation of valproate should be used in this group of patients, due to the need for dose titration.

Elderly

The pharmacokinetics of valproate may be altered in the elderly. Dosage should be determined by seizure control. (See section 5.2.)

The following daily doses for sodium valproate are recommended (table for orientation purposes):

Age

Body weight (kg)

Average dose (mg/day)

3 - 6 months

≈ 5.5 - 7.5

150

6 - 12 months

≈ 7.5 - 10

150 - 300

1 - 3 years

≈ 10 - 15

300 - 450

3 - 6 years

≈ 15 - 20

450 - 600

7 - 11 years

≈ 20 - 40

600 - 1200

12 - 17 years

≈ 40 - 60

1000 - 1500

Adults and elderly

≥ 60

1200 - 2100

Patients with renal insufficiency and/or hepatic dysfunction

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.)

Combined therapy

When starting sodium valproate Prolonged-release Tablets in patients already on other anticonvulsants, these should be tapered slowly; initiation of therapy with sodium valproate Prolonged-release Tablets should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine.

Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of sodium valproate Prolonged-release Tablets. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

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 750 mg. In addition, in clinical trials a starting dose of 20 mg 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 2000 mg valproate. Patients receiving daily doses 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.

Paediatric population:

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

Method of administration

sodium valproate Prolonged-release Tablets are for oral use.

sodium valproate Prolonged-release Tablets should be given once or twice daily. The tablets should be swallowed whole with fluid and not crushed or chewed. If at the start or during treatment gastrointestinal irritation occurs, sodium valproate Prolonged-release Tablets should be taken with or after food (see section 4.8.).

4.3 Contraindications

sodium valproate is contraindicated in the following situations:

- Hypersensitivity to sodium valproate or to any of the excipients,

- Active liver disease,

- Family history of severe hepatic dysfunction, particularly drug related,

- Manifest severe pancreatic dysfunction,

- Hepatic porphyria.

- Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (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).

Treatment of epilepsy

- in pregnancy unless there is no suitable alternative treatment (see section 4.4 and 4.6).

- in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

Treatment of bipolar disorder

- in pregnancy (see section 4.4 and 4.6).

- in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

4.4 Special warnings and precautions for use

Pregnancy Prevention Programme

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).

sodium valproate is contraindicated in the following situations:

Treatment of epilepsy

- in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.6).

- in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).

Treatment of bipolar disorder

- in pregnancy (see sections 4.3 and 4.6).

- in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).

Conditions of Pregnancy Prevention Programme:

The prescriber must ensure that

- Individual circumstances should be evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.

- the potential for pregnancy is assessed for all female patients.

- the patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.

- the patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.

- the patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (for further details please refer to subsection contraception of this boxed warning), without interruption during the entire duration of treatment with valproate.

- the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy, or bipolar disorders.

- the patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued.

- the patient understands the need to urgently consult her physician in case of pregnancy.

- the patient has received the patient guide.

- the patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Female children

- The prescribers must ensure that parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.

- The prescriber must ensure that parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.

- In patients who experienced menarche, the prescribing specialist must reassess the need for valproate therapy annually and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.

Pregnancy test

Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of child bearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a health care provider, to rule out unintended use in pregnancy.

Contraception

Women of childbearing potential who are prescribed valproate must use effective contraception, without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea she must follow all the advice on effective contraception.

Annual treatment reviews by a specialist

The specialist should at least annually review whether valproate is the most suitable treatment for the patient. The specialist should discuss the annual risk acknowledgement form, at initiation and during each annual review and ensure that the patient has understood its content.

Pregnancy planning.

For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.6). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.

For the indication bipolar disorder if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.

In case of pregnancy

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative options. The patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy (see section 4.6).

Pharmacist must ensure that

- the patient card is provided with every valproate dispensing and that the patients understand its content.

- the patients are advised not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.

Educational materials

In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings and provide guidance regarding use of valproate in women of childbearing potential and the details of the pregnancy prevention programme. A patient guide and patient card should be provided to all women of childbearing potential using valproate.

An annual risk acknowledgement form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.

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.

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.

Hepatic: Routine measurement of liver function should be undertaken before therapy and periodically during the first 6 months especially in those who seem most at risk, and those with a prior history of liver disease; such patients should have close clinical supervision. (See also section 4.8.)

Liver function tests should include: the prothrombin time, transaminases and/or bilirubin and/or fibrinogen degeneration products. Initially an increase in transaminases may occur, and is usually transient and responds to reduction in dosage.

Patients with 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.

Liver dysfunction, 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 those 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 6 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.

Clinical symptoms are more helpful than laboratory investigations in the early stages of hepatic failure. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms, usually of sudden onset, such as loss of seizure control, malaise, weakness, lethargy, oedema, anorexia, vomiting, abdominal pain, drowsiness, jaundice. These are an indication for immediate withdrawal of the drug. Patients should be instructed to report any such signs to the clinician for investigation should they occur. Whilst it is difficult to establish which, if any, investigation is predictive, tests which reflect protein synthesis, e.g. prothrombin time, may be most relevant.

In patients with hepatic dysfunction any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway and thus increase the risk of hepatic failure.

Haematological: Prior to initiation of therapy and also before surgery, clinicians should assure themselves, using appropriate blood tests (blood cell count, bleeding time and coagulation tests), that there is no undue potential for bleeding complications. (See also section 4.8.) Patients with a history of bone marrow damage should be closely monitored.

Pancreatic: Severe pancreatitis, which may be fatal, has been rarely reported. The risk of fatal outcome is greatest in young children and decreases with increasing age. Severe seizures or severe neurological impairment with combination anticonvulsant therapy may be risk factors for severe pancreatitis. Hepatic failure with pancreatitis increases the risk of fatal outcome. 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 prior history of pancreatitis should have close clinical supervision (see section 4.8.).

Weight gain: 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.

Systemic lupus erythematosus: Valproate may, although rarely, induce a systemic lupus erythematosus or aggravate an existing lupus erythematosus.

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.

Thyroid hormone: Dependent on its plasma concentration valproate may displace thyroid hormones from plasma protein binding sites and increase their metabolism which may lead to the false presumption diagnosis of hypothyroidism.

Diabetic patients: Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positive results in the urine testing of possible diabetics.

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 γ (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, ophthalmoplegia, 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).

The 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

Effects of valproate on other drugs

- Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines

Valproate may potentiate the effect of other psychotropics such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and dosage should be adjusted when appropriate. The combination with clonazepam may induce absences.

- Alcohol

Valproate may potentiate the effects of alcohol.

- Phenobarbital

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

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 lamotrigine metabolism and increase its mean half-life, dosages should be adjusted (lamotrigine dosage decreased) when appropriate. The combination of lamotrigine and valproate may increase the risk of (severe) skin reactions, especially in children.

- Zidovudine

Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.

- Vitamin K-dependent anticoagulants and acetylsalicylic acid

The anticoagulant effect of warfarin, other coumarin anticoagulants and the anti-platelet effect of acetylsalicylic acid may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored during oral anticoagulation.

- 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.

- Felbamate

Valproic acid may increase the serum level of felbamate by approximately 50%.

- Diazepam

In healthy test persons valproate displaced diazepam from the plasma albumin bond and inhibited its metabolism. In combination treatment the concentration of unbound diazepam may be increased and the plasma clearance and distribution volume of the free diazepam fraction lowered (by 25%; 20%). However, the half life remains unchanged.

- Lorazepam

In healthy individuals, simultaneous treatment with valproate and lorazepam led to a reduction in the plasma clearance of lorazepam by up to 40%.

Effects of other drugs on valproate

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, primidone, 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 may lower the seizure threshold. In addition, mefloquine may decrease valproate levels. The dosage of sodium valproate may need adjustment accordingly.

In case of concomitant use of valproate and highly protein bound agents (e.g. acetylsalicylic acid), free valproic acid plasma levels may be increased. Simultaneous administration of pharmaceuticals containing valproic acid and acetylsalicylic acid should no be performed in children under the age of 12, and should be performed only after careful risk-benefit assessment in adolescents.

Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100 % decrease in valproic acid levels 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).

Cholestyramine may decrease the absorption of valproate.

The valproic acid serum concentration may be increased by simultaneous administration of fluoxetine. In some cases the valproic acid concentration in the serum was lowered by the simultaneous intake of fluoxetine.

Pharmaceuticals with a potential hepatotoxic effect as well as alcohol may increase the liver toxicity of valproic acid.

Other interactions

Caution is advised when using sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.

Sodium valproate does not significantly induce hepatic enzymes, the efficacy of oral contraceptive agents does not appear to be affected.

4.6 Fertility, pregnancy and lactation

Pregnancy

Valproate is contraindicated as treatment for bipolar disorder during pregnancy. Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy. Valproate is contraindicated for use in women of childbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.4).

Teratogenicity and Developmental Effects

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.

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 effects, facial dysmorphia, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius) and multiple anomalities involving various body systems.

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).

If a woman plans a pregnancy

For the indication epilepsy, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy, must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.

For the indication bipolar disorder if a woman is planning to become pregnant a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued and if needed switched to an alternative treatment prior to conception, and before contraception is discontinued.

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4).

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.

If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy, it is recommended to:

- Use the lowest effective dose and divide the daily dose of 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 (see section 4.2).

All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding the exposed pregnancy. Specialized prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

.

Risk in the neonate

- Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This hemorrhagic 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 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, 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.

Breastfeeding

Valproate is excreted in human milk with a concentration ranging from 1% and 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.

4.7 Effects on ability to drive and use machines

Use of sodium valproate Prolonged-release Tablets may provide seizure control such that the patient may be eligible to hold a driving license.

However, patients should be warned when driving a vehicle or using machines of the risk of transient drowsiness especially in cases of anticonvulsant polytherapy or association with benzodiazepines.

4.8 Undesirable effects

Blood and lymphatic system disorders:

Valproic acid inhibits the second stage of platelet aggregation leading to prolongation of bleeding time and frequently to thrombocytopenia. These are usually associated with doses above those recommended and are reversible. Thrombocytopathia due to a deficiency in factor VIII/von Willebrand factor may also lead to a prolongation of bleeding time. Isolated reduction of fibrinogen may also occur.

Frequently mild reversible bone marrow suppression may occur. Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations. Agranulocytosis, occasionally lymphocytosis may occur. Red cell hypoplasia and pancytopenia have been reported rarely, leucopenia has been reported commonly; the blood picture returned to normal when the drug was discontinued.

Immune system disorders:

The occurrence of vasculitis has occasionally been reported. Allergic reactions (ranging from rash to hypersensitivity reactions) have been reported. Rarely systemic lupus erythematosus has been reported.

Endocrine disorders:

Irregular periods or amenorrhoea have been reported rarely. Very rarely gynaecomastia has occurred.

Rarely, raised testosterone levels have been observed.

Metabolism and nutrition disorders:

Hyperammonaemia without changes in liver function tests may occur. Isolated and moderate hyperammonaemia may occur frequently, is usually transient and should not cause treatment discontinuation. However, it may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur sodium valproate should be discontinued. Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.). Uncommonly oedema has been reported. Rarely obesity has been noted.

Psychiatric disorders:

Depression.

Nervous system disorders:

Ataxia and vertigo have been occasionally reported, tremor has been commonly reported; they appear to be dose-related effects.

Sedation has commonly been reported, usually when in combination with other anticonvulsants. In monotherapy it has occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy and uncommon cases of confusion, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy has been rarely observed, and coma has been very rarely observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital. They have usually been reversible on withdrawal of treatment or reduction of dosage.

Very rare cases of reversible extrapyramidal symptoms including parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported.

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

Hearing loss, either reversible or irreversible, has been reported rarely, though a causal relationship has not been established.

Headache has been uncommonly reported. Rarely nystagmus has been reported.

Paraesthesia has been reported commonly.

Diplopia has been reported rarely.

Ear and labyrinth disorders:

Tinnitus has been reported.

Gastrointestinal disorders:

Rare cases of pancreatitis, sometimes fatal, have been reported. (See section 4.4.) Appetite may increase and valproate very commonly causes weight gain which may be marked and progressive. (See section 4.4) On the other hand, weight loss has been commonly reported. Frequently at the start of treatment minor gastrointestinal irritation and, less commonly, nausea may occur. These problems can usually be overcome by taking sodium valproate Prolonged-release Tablets with or after food or by using enteric-coated sodium valproate capsules. Vomiting, diarrhoea, anorexia and constipation may occur. Hypersalivation has been uncommonly reported.

Hepatobiliary disorders:

Initially transient increases of transaminases may occur. Uncommonly severe hepatic damage has been reported after the intake of sodium valproate, occasionally with fatal results. (See section 4.4) Rarely porphyria has been reported.

Skin and subcutaneous tissue disorders:

Transient hair loss has commonly been noted in some patients, but is dose dependent. Regrowth normally begins within six months, although the hair may become more curly than previously. Also nail and nail bed disorders have been reported commonly. Rarely porphyria has been reported. Hirsutism and acne have been very rarely reported.

Cutaneous reactions such as exanthematous rash have been reported rarely. In exceptional cases toxic epidermal necrolysis, Stevens-Johnson syndrome, and rarely erythema multiforme have been reported.

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.

Renal and urinary disorders:

A reversible Fanconi´s syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy has been rarely reported, but the mode of action is as yet unclear.

Enuresis in children has been reported.

Reproductive system and breast disorders:

Rarely, polycystic ovaries were observed.

Congenital, familial and genetic disorders:

Congenital malformations and developmental disorders (see section 4.4 and section 4.6).

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 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Cases of accidental and deliberate 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.

In massive overdose, i.e. with plasma concentrations 10 to 20 times maximum therapeutic levels, there may be serious CNS depression and respiration may be impaired. However, the symptoms may be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2.). Cerebral oedema and intracranial hypertension have been reported. A number of deaths have occurred following large overdoses. Hospital management of overdose including induced vomiting, gastric lavage, assisted ventilation, and other supportive measures is recommended.

Haemodialysis and haemoperfusion have been used successfully. Intravenous naloxone has also been used sometimes in association with activated charcoal given orally.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutical group: Antiepileptics, Fatty acid derivatives

ATC code: N03A G01

Sodium valproate is an anticonvulsant.

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.

5.2 Pharmacokinetic properties

Absorption

Valproate is well absorbed. The absolute bioavailability is almost 100%. Peak plasma levels are obtained at ca. 1-6 hours, depending on the pharmaceutical form. For sodium valproate Prolonged-release Tablets, mean peak plasma levels are obtained at ca. 6-14 hours. Steady state plasma levels are achieved within 3-4 days. Effective therapeutic plasma levels are in the range of 40-100 mg/l (278-694 µmol/l). A high inter- and intra-individual variability in plasma levels is observed.

Distribution

Valproic acid binding to serum proteins is approximately 80-95%. At plasma levels above 100 mg/l, the free fraction increases. Valproic acid is mainly distributed into blood. The concentration of valproic acid in the cerebrospinal fluid is comparable with the free valproic acid concentration in plasma. Valproic acid passes the placenta, and is excreted into breast milk (1-10% of the total serum concentration).

Biotransformation

Valproic acid is metabolised in the liver, mainly glucuronidated. Valproic acid inhibits the cytochrome P450 enzyme system.

Elimination

Valproic acid is mainly excreted into the urine as glucuronidates. The plasma elimination half-life is 10-15 hours and is significantly shorter in children, namely 6-10 hours.

sodium valproate Prolonged-release Tablets are a prolonged-release formulation which in pharmacokinetic studies demonstrates less fluctuation in plasma concentration compared to other established conventional formulations of valproic acid. For sodium valproate Prolonged-release Tablets, the pharmacological effects may not be clearly correlated with the total or free (unbound) plasma valproic acid levels. In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of sodium valproate Prolonged-release Tablets make the measurement of plasma levels less dependent upon time of sampling.

Special patient groups

Elderly: Pharmacokinetics of valproic acid may be altered in elderly patients due to an increased distribution volume and a decrease in protein binding, which may result in an increase in free drug concentration.

Patients with renal insufficiency: Pharmacokinetics of valproic acid may be altered in patients with renal insufficiency, due to a decrease in protein binding, resulting in an increase in free drug concentrations.

Patients with hepatic dysfunction: Elimination half-lives in patients with cirrhosis and in patients recovering from acute hepatitis were significantly prolonged compared with controls, indicating impaired clearance in patients with liver dysfunction.

sodium valproate Prolonged-release Tablets are bioequivalent to other prolonged release valproate formulations with respect to the mean areas under the plasma concentration time curves. Steady-state pharmacokinetic data indicate that the peak concentration (Cmax) and trough concentration (Cmin) of sodium valproate Prolonged-release Tablets lie within the effective therapeutic range of plasma levels as generally accepted for sodium valproate.

5.3 Preclinical safety data

Chronic toxicity studies with valproic acid demonstrated reduced spermatogenesis and testicular atrophy in rats and dogs. Genotoxicity testing revealed no mutagenic potential. In studies on the carcinogenic potential an increased incidence of subcutaneous fibrosarcomas was observed in male rats. The significance of these findings for humans is unknown. Valproic acid was shown to be a potent animal teratogen.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core:

Citric acid monohydrate

Ethylcellulose

Ammonio methacrylate copolymer (type B) (contains sorbic acid)

Purified talc

Colloidal hydrated silica

Magnesium stearate

Film-coating material:

Ammonio methacrylate copolymer (type A & B) (contains sorbic acid)

Purified talc

Carmellose sodium

Titanium dioxide (E 171)

Triethyl citrate

Vanillin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Keep the container tightly closed.

6.5 Nature and contents of container

a) Amber glass tablet container (hydrolytic resistance type III, Ph.Eur.) with HDPE tamper-resistant white screw-cap, and HDPE white tear-band lid further packed into a cardboard carton.

Or alternatively

b) HDPE cylindrical tablet container with LDPE tamper-resistant snap-on cap with LDPE tear-band lid and LDPE sealing ring further packed into a cardboard carton

Pack sizes: 50, 100 tablets (AT, BE, LU, UK)

Pack sizes: 50, 100, 200 (2x100) and 500 (5x100) tablets (DE)

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

G.L. Pharma GmbH, Schlossplatz 1, A-8502 Lannach, Austria (AT, BE, LU, UK)

biomo pharma GmbH, Josef-Dietzgen-Straße 3, D-53773 Hennef, Deutschland (DE)

8. Marketing authorisation number(s)

1-24547 (AT)

BE 238043, BE 238052 (BE)

54240.01.00 (DE)

0381/02/10/0045 (LU)

PL 21597 / 0006 (UK)

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation:

June 17th, 2002 (AT)

July 1st, 2002 (BE)

July 2nd, 2002 (DE)

October 30th, 2002 (LU)

June 13th, 2001 (UK)

Date of last renewal: April 17th, 2006

10. Date of revision of the text

06.2018