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

Epival CR 300 mg Prolonged-release Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 300 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 “CC3” 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 Epival CR for acute mania.

4.2 Posology and method of administration

Posology

Epival CR 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. Pharmacokinetic properties.)

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

Epival CR 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 Epival CR 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.

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. 2030 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.

Paediatic 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 Epival CR 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 5.2. Pharmacokinetic properties.)

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	o ll	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 5.2. Pharmacokinetic properties.)

Combined therapy

When starting Epival CR Prolonged-release Tablets in patients already on other anticonvulsants, these should be tapered slowly; initiation of therapy with Epival CR 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 Epival CR 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 Epival CR for the treatment of manic episodes in bipolar disorder have not been evaluated in patients aged less than 18 years.

Method of administration

Epival CR Prolonged-release Tablets are for oral use.

Epival CR 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, Epival CR Prolonged-release Tablets should be taken with or after food (see section 4.8. Undesirable effects).

4.3 Contraindications

-    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 y (POLG), e.g. Alpers-Huttenlocher

with a prior history of liver disease; such patients should have close clinical supervision. (See also section 4.8. Undesirable effects.)

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. Undesirable effects.) 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 4.8. Undesirable effects).

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

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

Epival CR should not be used in female children, in female adolescents, in women of child-bearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of child-bearing 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.

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.

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 fromcongenital 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 malformations 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 3040% 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).

Female children, female adolescents and woman of childbearing 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 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, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.

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 Epival CR 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 Epival CR 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. Special warnings and special precautions for use). 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.

Ear and labyrinth disorders: Tinnitus has been reported.

Gastrointestinal disorders: Rare cases of pancreatitis, sometimes fatal, have been reported. (See section 4.4. Special warnings and special precautions for use.) Appetite may increase and valproate very commonly causes weight gain which may be marked and progressive. (See section 4.4 Special warnings and special precautions for use.) 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 Epival CR Prolonged-release Tablets with or after food or by using enteric-coated Convulex capsules. Vomiting, diarrhoea, anorexia and constipation may occur. Hypersalivation has been uncommonly reported.

Hepato-biliary 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 Special warnings and special precautions for use.) 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:

Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

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. Pharmacokinetic properties). 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 Epival CR 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 (278694 pmol/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).

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

EliminationValproic 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.

Epival CR 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 Epival CR 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 Epival CR 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.

Epival CR 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 Epival CR 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

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

G.L. Pharma GmbH,

Schlossplatz 1,

A-8502 Lannach,

Austria

8    MARKETING AUTHORISATION NUMBER(S)

PL 21597 / 0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/06/2001 / 14/04/2006

10 DATE OF REVISION OF THE TEXT

19/02/2016