Epilim Chronosphere 750mg prolonged-release granules

Each sachet of prolonged-release granules contains:

Equivalent to 750mg sodium valproate

For excipients, see 6.1.

Prolonged-release granules.

Sachets containing small, off-white to slightly yellow, waxy microgranules.

In the treatment of generalised, partial or other epilepsy.

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

Epilim Chronosphere is a pharmaceutical form particularly suitable for children (when they are able to swallow soft food) and adults with swallowing difficulties.

Epilim Chronosphere is a controlled release formulation of Epilim, which reduces peak concentration and ensures more regular plasma concentration throughout the day.

Epilim Chronosphere may be given once or twice daily.

In patients where adequate control has been achieved, Epilim Chronosphere formulations are interchangeable with other conventional or prolonged-release formulations of Epilim on an equivalent daily dosage basis.

Daily dosage should be established according to age and body weight and should be given to the nearest whole 50mg sachet. Partial sachets should not be used. However, the wide individual sensitivity to valproate should also be considered.

A good correlation has not been established between daily dose, serum concentration and therapeutic effect, and optimum dosage should be determined primarily according to the clinical response. The determination of valproic acid plasma levels should be considered in addition to clinical monitoring when adequate seizure control is not achieved, or when adverse effects are suspected. The reported effective range is usually between 40-100 mg/L (300-700 μmol/L).

Initiation of Epilim Chronosphere therapy (oral administration)

- In patients who are not currently using other antiepileptic drugs, the dosage should preferably be increased by successive dose levels at 2-3 day intervals in order to reach the optimum dosage in about one week.

- In patients who are already receiving antiepileptic agents, substitution with Epilim Chronosphere should be progressive, the optimum dosage being reached in about 2 weeks and other treatments being tapered off and then stopped.

- Other antiepileptic agent should be added progressively where necessary (see 4.5. "Drug interactions").

Oral administration of Epilim Chronosphere: practical considerations

Dosage in Epilepsy

Initial daily dosage is usually 10-15 mg/kg, then doses are titrated up to the optimum dosage (see 4.2 "Initiation of Epilim Chronosphere therapy").

This is generally within the range 20-30 mg/kg. Nevertheless, where seizure control is not achieved within this range, the dose may be further increased as required; patients should be carefully monitored when receiving daily doses higher than 50 mg/kg (see 4.4 "Precautions")

- In children, the usual dosage is about 30 mg/kg per day.

- In adults, the usual dosage is within the range 20-30 mg/kg per day.

- In elderly, although the pharmacokinetics of Epilim Chronosphere are modified, they have limited clinical significance and dosage should be determined by seizure control.

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.

In children and adolescents:

The safety and efficacy of Epilim Chronosphere for the treatment of manic episodes in bipolar disorder have not been eva luated in patients aged less than 18 years.

Administration

Epilim Chronosphere prolonged-release granules should be sprinkled on a small amount of soft food or in drinks, which should be cold or at room temperature, for example yoghurt, mousse, jam, ice cream, milk shake, orange juice or something similar.

If the granules are taken in a drink, after the drink has been finished the glass should be rinsed with a small amount of water and this water should be taken as well, as some granules may stick to the glass.

The mixture of food or drink and granules should be swallowed immediately; the granules should not be crushed or chewed.

A mixture of the granules with liquid or soft food should not be stored for future use.

Epilim Chronosphere prolonged-release granules should not be sprinkled on warm or hot foods and drinks, for example soup, coffee, tea, or something similar.

If preferred the granules can be poured directly into the mouth and washed down with a cold drink.

Epilim Chronosphere prolonged-release granules should not be given in babies' bottles as they can block the nipple.

The chronosphere granules contain a non-absorbable matrix which is designed to slowly release the active substance. Occasionally the matrix may pass through the gastrointestinal tract without disintegrating and may be visible in the patient's stools but this does not indicate that the drug has a reduced effect.

- Active liver disease

- Personal or family history of severe hepatic dysfunction, especially drug related

- Hypersensitivity to sodium valproate or to any of the excipients

- Porphyria.

Stopping treatment may lead to an immediate relapse of the underlying symptoms; care should therefore be taken when consideration is being given to the withdrawal of treatment. The concomitant use of valproic acid/sodium valproate and carbapenem agents is not recommended (see section 4.5)

4.4.1 Special warnings

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been exceptionally 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.

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 Epilim 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.

Pancreatitis: Severe pancreatitis, which may result in fatalities, has been very rarely reported. Patients experiencing acute abdominal pain should have a prompt medical eva luation. Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Epilim should be discontinued.

Women of childbearing potential (see section 4.6):

A decision to use Epilim in women of childbearing potential should only be taken after very careful eva luation, if the benefits of its use outweigh the risks of congenital anomalies to the unborn child. This decision is to be taken; before Epilim is prescribed for the first time as well as before a woman already treated with valproic acid is planning a pregnancy.

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 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.

4.4.2 Precautions

Liver function tests should be carried out before therapy (see section 4.3 “Contraindications”), and periodically during the first 6 months, especially in patients at risk (see section 4.4.1 “Special warnings”).

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.

Children: Monotherapy is recommended in children under the age of 3 years when prescribing Epilim, but the potential benefit of Epilim should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see section 4.4.1 “Special warnings”).

The concomitant use of salicylates should be avoided in children under 3 due to the risk of liver toxicity.

Haematological: Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8 “Undesirable Effects”).

Renal insufficiency: In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 “Posology and Method of Administration” and 5.2 “Pharmacokinetic Properties”).

Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of Epilim, the potential benefit of Epilim should be weighed against its 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 Epilim.

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

Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimise it (see 4.8 “Undesirable Effects”).

4.5.1 Effects of Epilim on Other Drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Epilim may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.

In particular, a clinical study has suggested that adding olanzapine to valproate therapy may significantly increase the risk of certain adverse events associated with olanzapine.

- Phenobarbital

Epilim 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

Epilim 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

Epilim decreases phenytoin total plasma concentration. Moreover Epilim 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 eva luated.

- Carbamazepine

Clinical toxicity has been reported when Epilim was administered with carbamazepine as Epilim 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 may be increased by co-administration of lamotrigine with valproic acid, when Lamotrigine is added on to valproic acid. Epilim may reduce lamotrigine metabolism and increase its mean half-life, dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

- Zidovudine

Epilim 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.

4.5.2 Effects of Other Drugs on Epilim

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

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

Mefloquine and chloroquine increase valproic acid metabolism and have a convulsing effect. They may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. The dosage of Epilim may need to be adjusted accordingly.

In case of concomitant use of Epilim and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.

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

Carbapenem antibiotics such as panipenem, imipenem and meropenem: Decrease in valproic acid blood level, sometimes associated with convulsions, has been observed when panipenem, imipenem or meropenem were combined. If these antibiotics have to be administered, close monitoring of valproic acid blood levels is recommended.

Colestyramine may decrease the absorption of Epilim.

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.

4.5.3 Other Interactions

Caution is advised when using Epilim 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 hyperammonemia. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.

Epilim usually has no enzyme-inducing effect; as a consequence, Epilim does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

Concomitant food intake does not significantly influence the bioavailability of Epilim when administered as the Chronosphere formulation.

This medicine should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). Women of child-bearing potential have to use effective contraception during treatment.

4.6.1 Pregnancy

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

- Risk associated with seizures

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

- Risk associated with Epilim

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: Available data suggest an increased incidence of minor or major malformations including, in particular, neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations and multiple anomalies involving various body systems in offspring born to mothers with epilepsy treated with valproate when compared to the incidence for certain other antiepileptic drugs. Epilim 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%.

Data suggest that antiepileptic polytherapy including Epilim induces a higher teratogenic risk than monotherapy with valproate only.

Data suggest an association between in-utero Epilim exposure and a risk of developmental delay particularly of verbal IQ, in children born to mothers suffering from epilepsy and treated with valproate. Developmental delay is frequently associated with malformations and/or dysmorphic features. However, it is difficult to establish causal relationship in view of possible confounding factors such as low maternal or paternal IQ, genetic, social and environmental factors, and poor maternal seizure control during pregnancy.

Autism spectrum disorders have also been reported in children exposed to valproate in utero.

- In view of the above data

Women of childbearing potential should be informed in detail of the risks and benefits of the use of Epilim during pregnancy. Specialist advice is required and physicians are strongly encouraged to discuss reproductive issues with their patients before Epilim is prescribed for the first time or a woman already treated with Epilim is planning a pregnancy.

If a woman plans pregnancy, Epilim therapy should be reassessed whatever the indication. In bipolar disorders indication, cessation of Epilim prophylaxis should be considered. If, in any indication, further to a careful eva luation of the risks and benefits, Epilim treatment is continued during the pregnancy, it is recommended to use Epilim in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form.

In addition if appropriate, folate supplementation should be started before pregnancy and at relevant dosage (5 mg daily) as it may minimize the risk of neural tube defects.

During pregnancy, valproate therapy should not be discontinued without reassessment of the benefit/risk.

Specialized prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defect or other malformations. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Special Precautions for Use).

- Risk in the neonate

Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.

Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

4.6.2 Lactation

Excretion of Epilim in breast milk is low, with a concentration between 1 % to 10 % of total maternal serum levels. Based on literature and clinical experience, breastfeeding can be envisaged, taking into account the Epilim safety profile, especially haematological disorders (see section 4.8 Undesirable Effects).

Use of Epilim 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 Medicinal Products and Other Forms of Interaction”).

Congenital, familial and genetic disorders: (see section 4.6 “Pregnancy and Lactation”).

Hepatobiliary disorders: rare cases of liver injury (see section 4.4.1 “Special warnings”).

Gastrointestinal disorders: (nausea, upper abdominal pain, diarrhoea) frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Epilim with or after food or by using Enteric Coated Epilim.

Very rare cases of pancreatitis, sometimes lethal, have been reported (see section 4.4 “Special Warnings and Special Precautions for Use”).

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

Very rare cases of reversible parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Ataxia and transient and/or dose related fine postural tremor have occasionally been reported.

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

Cases of isolated and moderate hyperammonaemia without change in liver function may occur frequently and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur Epilim 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.

Metabolic and nutrition disorders:

Very rare cases of hyponatremia have been reported.

Syndrome of Inappropriate Secretion of ADH (SIADH)

Blood and lymphatic system disorders:

Frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopoenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.

Bone marrow failure, including pure red cell aplasia. Agranulocytosis. Isolated findings of a reduction in blood fibrinogen and/or increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Epilim 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”).

Skin and subcutaneous tissue disorders:

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

Transient and/or dose related alopecia, has often been reported. Regrowth normally begins within six months, although the hair may grow back curlier than before.

Reproductive system and breast disorders:

Amenorrhoea and dysmenorrhea have been reported. Very rarely gynaecomastia has occurred.

Vascular disorders:

The occurrence of vasculitis has occasionally been reported.

Ear and labyrinth disorders:

Deafness, either reversible or irreversible has been reported rarely.

Renal and urinary disorders:

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 cases of enuresis have been reported.

Immune system disorders:

Angioedema, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.

Psychiatric disorders:

Confusion

General disorders and administration site conditions:

Very rare cases of non-severe peripheral oedema have been reported.

Increase in weight may also occur. Since it is a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 “Special Warnings and Special Precautions for Use”).

Cases of accidental and deliberate Epilim 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.

Deaths have occurred following massive overdose; nevertheless, a favourable outcome is usual.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 “Pharmacokinetic Properties”). Cases of intracranial hypertension related to cerebral oedema have been reported.

Hospital management of overdose should be symptomatic: gastric lavage, cardio-respiratory monitoring. Haemodialysis and haemoperfusion have been used successfully. Naloxone has also been used in a few isolated cases. In cases of massive overdose, hemodialysis and hemoperfusion have been used successfully.

Valproic acid and sodium valproate are anticonvulsants.

The most likely mode of action for Epilim 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 has been reported that Epilim can stimulate HIV. However this effect is modest, variable, unrelated to the dose and not documented in man.

The half-life of sodium valproate is usually reported to be within the range of 8-20 hours. It is usually shorter in children.

The reported effective therapeutic range for plasma valproic acid levels is 40-100mg/litre (278-694 micromol/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 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 Epilim Chronosphere may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

Epilim Chronosphere is a prolonged (or modified) release formulation of Epilim which reduces peak concentration and ensures more even plasma concentrations throughout the day compared with other established conventional and modified release Epilim formulations. Following twice daily administration of a same dose, the range of plasma fluctuations is approximately reduced by half.

Compared with immediate release forms of Epilim it is characterized at an equivalent dose by:

- a similar bioavailability,

- a lower Cmax (decrease of approximately 25%),

- a relatively stable plateau between 4 and 14 hours after administration.

Steady-state pharmacokinetic data indicate that the peak concentration (Cmax) and trough concentration (Cmin) of Epilim Chronosphere lie within the effective therapeutic range of plasma levels found in pharmacokinetic studies with Epilim EC.

In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of Epilim Chronosphere make the measurement of plasma levels less dependent upon time of sampling.

The peak plasma level is achieved approximately 7 hours after administration, with an elimination half-life between 13 and 16 hours.

This pharmacokinetic profile is not affected by taking the drug with food.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Hard paraffin, glycerol dibehenate, colloidal hydrated silica.

This medicinal product must not be administered with hot meals or drinks.

2 years

Do not store above 25°C.

Epilim Chronosphere 750 mg prolonged-release granules are filled into sachets of:

• 3 layers complex: printed paper, aluminium, ionomer resin complex,

or

• 3 layers complex: printed paper with nitrocellulosic glaze, aluminium, ionomer resin complex.

Each sachet contains the equivalent of 750 mg sodium valproate.

Epilim Chronosphere sachets are available in pack sizes of 30 and 50 sachets.

Not all packs sizes may be marketed.

No special requirements.

sanofi-aventis Ireland Ltd.

Citywest Business Campus

Dublin 24

PA 540/150/8

Date of First Authorisation: 02March 2007

December 2010