Episenta^® solution for injection

Sodium valproate 100mg/ml

Solution for injection

Episenta^® solution for injection may be used for epileptic patients who would normally be maintained on oral sodium valproate but for whom oral therapy is temporarily not possible.

Dosage requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control. Patients already satisfactorily treated with oral sodium valproate may be continued at their current dosage. Episenta^® solution for injection is ready to use by intravenous infusion.

The total daily dose should be divided in three to four single slow intravenous injections or should be given by continuous or repeated infusion.

Monotherapy:

Adults: Dosage should start at 400 – 800mg daily increasing by 150 – 300mg at three day intervals until control is achieved. This is generally within the dosage range of 1000mg to 2000mg per day i.e. 20 – 30mg/kg body weight per daily. Where adequate control is not achieved within this range the dose may be further increased to a maximum of 2500mg per day.

Children: Initial dosage should be 300mg/day increasing until control is achieved. This is usually within the range 20 – 30mg/kg body weight per day. Where adequate control is not achieved within this range, the dose may be increased to 40 mg/kg bodyweight per day but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg body weight per day clinical chemistry and haematological parameters should be monitored.

Use in elderly: Care should be taken when adjusting dosage in the elderly since the pharmacokinetics of sodium valproate are modified. The volume of distribution is increased in the elderly and because of decreasing binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels. Dosage should be determined by seizure control.

In patients with renal insufficiency: It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring of plasma concentration may be misleading.

In patients with renal insufficiency: It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.

In patients with hepatic insufficiency: Salicylates should not be used concomitantly with sodium valproate since they employ the same metabolic pathway (see section 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

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

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome). In addition in conjunction with sodium valproate, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4 Special Warnings).

Combined Therapy: When starting Episenta^® in patients already on other anticonvulsants these should be tapered slowly. Initiation of Episenta^® therapy should then be gradual, with target dose reached after about two weeks. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with liver enzymes inducing drugs such as phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Episenta^®.

When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturates should be reduced.

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

Optimum dosage is mainly determined by seizure control 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).

Method of administration

Episenta^® solution for injection may be given by slow intravenous injection over 3 – 5 minutes or by infusion in 0.9% saline or 5% dextrose.

Episenta^® solution for injection should not be administered via the same intravenous line with other drugs.

The intravenous administration of Episenta^® solution for injection should be replaced by oral therapy as soon as practicable.

Close monitoring of plasma levels and – if necessary – dosage adjustments have to be performed during the change-over to a parenteral therapy, during parenteral therapy and during the switch back to oral therapy, in particular in such patients receiving higher doses of valproate or in patients receiving drugs potentially influencing the metabolism of valproate.

For instructions on preparation and dilution of Episenta^® solution for injection before administration see section 6.6 Special Precautions for Disposal.

Active liver disease.

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

Porphyria.

Hypersensitivity to valproate or any of the excipients.

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 antiepileptic 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.

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms.

The concomitant use of sodium valproate and carbapenem is not recommended (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Hepatic dysfunction :

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsants therapy, are infants and in particular young children under the age of 3 and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age. The concomitant use of salicylates should be avoided in children under 3 due to the risk liver toxicity. Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing Episenta^®, but the potential benefit of Episenta^® should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy.

In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 – 12 weeks.

Suggestive signs:

Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: Conditions of occurrence):

- non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.

- in patients with epilepsy, recurrence of seizures

These are an indication for immediate withdrawal of the drug.

Patients (or their carers), 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 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 decreases in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) require cessation of Episenta^® therapy.

As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.

As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.

Pancreatitis:

Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase). Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Episenta^® should be discontinued.

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 sodium valproate, the potential benefit of Episenta^® should be weighed against its potential risk in patients with systemic lupus erythematosus (see section 4.8 Undesirable effects).

Hyperammonaemia:

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

Weight gain:

Sodium valproate very commonly causes weight gain, which may be marked and progressive. 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 section 4.8 Undesirable effects)

Women of childbearing potential (see section 4.6 Pregnancy and lactation):

A decision to use Episenta^® in women of childbearing potential should not be taken without specialist neurological advice, and only if the benefits of its use outweigh the potential risks of congenital anomalies to the unborn child This decision is to be taken before Episenta^® is prescribed for the first time as well as before a woman already treated with valproic acid is planning pregnancy Adequate counselling should be made available to all women of childbearing potential regarding the risks associated with pregnancy (see section 4.6 Pregnancy and lactation).

Diabetic Patients:

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

4.5.1 Effects of Episenta^® on other drugs

Like many other drugs, Episenta^® may potentiate the effect of other psychotropics, such as antipsychotics, monoamine oxidase inhibitors, antidepressants and benzodiazepines. Therefore, clinical monitoring and the dosage of other psychotropics should be adjusted when appropriate. In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

Sodium valproate increases phenobarbital plasma concentrations and sedation may occur, particularly in children. Clinical monitoring is recommended throughout the first 15 days of combined treatment with an immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital levels when appropriate.

Sodium valproate increases primidone plasma levels causing an exacerbation of side effects, e.g. sedation; these signs cease with long term treatment.. Clinical monitoring is recommended especially when initiating combined therapy with dosage adjustment as necessary.

Phenytoin total plasma levels are decreased by sodium valproate acid; the free form of phenytoin is increased leading to possible overdosage symptoms. Therefore, clinical monitoring is recommended with the free form of phenytoin being measured.

The toxic effects of carbamazepine may be potentiated by sodium valproate requiring clinical monitoring and dosage adjustment particularly at initiation of combined therapy.

Sodium valproate may reduce lamotrigine metabolism and increase its mean half-life. The dosage of lamotrigine should be decreased as necessary. The risk of rash is increased in combined therapy with lamotrigine.

Sodium valproate may raise zidovudine plasma concentrations leading to increased zidovudine toxicity.

The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from the plasma protein binding site by valproate. The prothombin time should be closely monitored.

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

4.5.2 Effects of other drugs on Episenta^®

Antiepileptics with enzyme inducing effects e.g. phenytoin, phenobarbital, carbamazepine, decrease valproate plasma levels. Plasma levels should be monitored and dosage adjusted accordingly. On the other hand, combination of felbamate and sodium valproate may increase valproic acid plasma concentration. Episenta^® dosage should be monitored.

Mefloquine and chloroquine increases valproate metabolism and therefore epileptic seizures may occur in combined therapy. The dosage of sodium valproate may need adjustment.

Free valproate levels may be increased in the case of concomitant use with highly protein bound agents e.g. acetylsalicylic acid. Valproate plasma levels may also be increased when used concomitantly with cimetidine or erythromycin as a result of reduced hepatic metabolism.

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 rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stablised on valproic acid is not considered to be manageable and therefore should be avoided (see section 4.4 Special warnings and precautions for use).

Colestyramine may decrease the absorption of valproate.

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

4.5.3 Other interaction

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

Caution is advised when using Episenta^® in combination with newer antiepileptics whose pharmacodynamics may not be well established

Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.

Women of childbearing potential should not be started on Episenta^® without specialist neurological advice.

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

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

If pregnancy is planned, consideration should be given to cessation of Episenta^® treatment, if appropriate.

When Episenta^® treatment is deemed necessary, precautions to minimize the potential teratogenic risks should be followed (see section 4.6.1 paragraph entitled 'In view of the above data').

4.6.1 Pregnancy

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

Risk associated with epilepsy and antiepileptics

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

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

Risks associated with seizures

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

Risks associated with valproate

In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit. There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.

In humans: valproate is associated with neural tube defects such as myelomeningocele and spina bifida. The frequency of this effect is estimated to be 1 to 2%. An increased incidence of minor or major malformations including neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems has been reported in offspring born to mothers with epilepsy treated with valproate. The data suggests that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other antiepileptic drugs.

Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggests that antiepileptic polytherapy including sodium valproate is associated with a higher risk of abnormal pregnancy outcome than sodium valproate monotherapy.

Data have suggested an association between in-utero exposure to valproate and the risk of developmental; delay (frequently associated with dysmorphic features), particularly of verbal IQ. However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, 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

When a woman is planning pregnancy, this provides an opportunity to review the need for antiepileptic treatment. Women of childbearing age should be informed of the risks and benefits of continuing antiepileptic treatment throughout pregnancy. Specialist advice is required and physicians are strongly encouraged to discuss reproductive issues with their patients before Episenta^® is prescribed for the first time or a woman already treated with Episenta^® is planning a pregnancy

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

The available evidence suggests that anticonvulsants monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000 mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels.

During pregnancy, Episenta^® antiepileptic treatment should not be discontinued if it has been effective. Nevertheless, specialist prenatal monitoring should be instituted in order to detect the possible occurrence of a neural tube defect or any other malformation. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special warnings and 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 hypofibrinogenaemia; afibrinogenaemia 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 antiepileptic 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 valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels; up to now children breast fed that have been monitored during the neonatal period have not experienced clinical effects. Although there appears to be no contraindications to breast feeding by patients on Episenta^® physicians are advised that in any individual case, consideration should be given to the safety profile of Episenta^®, specifically haematological disorders (see section 4.8 Undesirable effects).

Use of Episenta^® may provide seizure control such that the patient may be eligible to hold a driving licence.

At the start of treatment with sodium valproate, at higher dosages or with a combination of other centrally acting drugs, reaction time may be altered to an extent that affects the ability to drive or to operate machinery, irrespective of the effect on the primary disease being treated. Patients should be warned of the risk of transient drowsiness. This is especially the case when taken during anticonvulsant polytherapy, concomitant use of benzodiazepines or in combination with alcohol.

Congenital and familial/genetic disorders: (see section 4.6 Pregnancy and lactation)

Hepato-biliary disorders:

Rare cases of hepatic dysfunction (see section 4.4 Special warnings and precautions for use). Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been reported (see sections 4.2 (Posology and method of administration, 4.3 Contraindications and 4.4 Special warnings and precautions for use). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4 Special warnings and precautions for use ).

Gastro-intestinal disorders: (nausea, gastralgia, diarrhoea)

Frequently occur at the start of the treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Episenta^® with or after food.

Very rare cases of pancreatitis, sometimes fatal, have been reported (see section 4.4 Special warnings and 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 a too high starting dose or a too rapid 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.

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

Metabolic disorders:

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur Episenta^® should be discontinued. Very rare cases of hyponatraemia have been reported. Hyperammonaemia associated with neurological symptoms have also been reported (see section 4.4 Special warnings and precautions for use). In such cases further investigation should be considered.

Blood and lymphatic system disorders:

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

Bone marrow failure, including red cell aplasia.

Agranulocytosis.

Isolated reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication of withdrawal of medication pending investigations (see section 4.6 Pregnancy and lactation).

Skin and subcutaneous disorders:

Rash rarely occurs with sodium valproate. In very rare cases, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported. Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within 6 months, although the hair may become more curly than previously. Hirsutism and acne have been very rarely reported.

Reproductive system and breast disorders:

Amenorrhoea and irregular periods have been reported. Very rarely gynaecomastia has occurred.

Vascular disorders:

The occurrence of vasculitis has occasionally been reported.

Ear disorders:

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

Renal and urinary disorders:

There have been isolated reports of reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phospaturia, and uricosuria) associated with sodium valproate therapy, but the mode of action is as yet unclear. Very rare cases of enuresis have been reported.

Immune system disorders:

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

General disorders:

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

Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 Special warnings and precautions for use).

When using Episenta^® intravenously, transient nausea or dizziness may occur.

Cases of accidental and deliberate overdosage with oral therapy 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, 10 to 20 times the maximum therapeutic levels, there may be serious CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favourable outcome is usual, however some deaths have occurred following massive overdose.

The symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension related to cerebral oedema have been reported. A number of deaths have occurred following large overdoses. Hospital management of overdose includes induced vomiting, gastric lavage, assisted ventilation and other supportive measures. Haemodialysis and haemoperfusion have been used successfully. Intravenous naloxone has also been used sometimes in association with activated charcoal given orally.

ATC no: N03AG01

The mode of action of valproic acid in epilepsy is not fully understood but may involve an elevation of gamma-amino butyric acid levels in the brain.

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

Per definition, with intravenous injection the bioavailability amounts to 100. The half-life is 8 – 20 h in most patients but can in exceptional cases be considerable lower. It is usually shorter in children. In infants under 2 months the half-life can be prolonged up to 60 hours. In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free serum valproic acid levels.

Steady-state concentration is normally achieved after treatment in 3 - 5 days. A satisfactory effect is most often achieved at 40 – 100mg/litre (278 – 694 micromol/litre), but the patient's overall situation must be considered. The reported range may depend on time of sampling and presence of co-medication. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of Episenta^® may not be clearly correlated with the total or free (unbound) plasma valproic acid levels. The CFS concentration is up to 10% of the plasma concentration. The percentage of free (unbound) drug is usually between 6 and 15% of the total plasma levels. Sodium valproate is metabolised to a great extent and is excreted in the urine as conjugated metabolites. Sodium valproate crosses the placental barrier and concentrations in foetal plasma are comparable to those in the mother.

Valproic acid passes into breast milk but is not likely to influence the child when therapeutic doses are used.

Acute toxicity

Depending on the species of the animal and mode of administration the LD₅₀ is between 0.5 – 1.5g/kg body weight. The symptoms observed included, for example, ataxia, sedation, hypothermia, catalepsy, co-ordination disorders and vomiting.

Chronic toxicity

Carcinogenic and mutagenic potential

Carcinogenic studies have been conducted in the rat and mouse. At very high doses, increased subcutaneous fibrosarcoma was observed in male rats.

Studies of mutagenic potential have shown no mutagenic effect.

Reproduction toxicology

Valproic acid has been found to be teratogenic in mice, rats, hamsters, monkeys and rabbits. The effects occur primarily as skeletal (palatal cleft, costal and vertebral fusion) and renal malformations, in mice also as encephalocele and malformation of the neural tube. Malformations have also been observed in neurulation studies in chicken embryo in vitro.

Disodium edetate

Water for injections

Episenta^® solution for injection should not be administered via the same intravenous line with other drugs.

Shelf life of the medicinal product as packaged for sale: 3 years.

Shelf life after dilution or reconstitution according to the directions: Chemical and physical in-use stability has been demonstrated for 3 days at 20 - 22°C. From a microbiological point of view, the product should be used immediately after opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally be not longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not freeze.

Glass ampoule containing 3 ml or 10 ml solution for injection.

For infusion of Episenta^® solution for injection it may be diluted in 0.9% saline or 5% dextrose. Tests with the recommended infusion solutions over three days at 20 - 22ºC show compatibility.

Prior to use Episenta^® solution for injection and the diluted solution should be visually inspected. Only clear solutions without particles should be used.

Beacon Pharmaceuticals Ltd

85, High Street

Tunbridge Wells

Kent TN1 1YG

UK

PL 18157/0027

Date of first authorisation: 28^th July 2006

Date of last renewal: 17^th February 2009

1^st April 2011