This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Episenta® 1000 mg prolonged-release granules

2. Qualitative and quantitative composition

Each sachet of prolonged-release granules contains 1000 mg sodium valproate

Excipient(s) with known effect: 6 mmol (137.9 mg) sodium per dose

For the full list of excipients see section 6.1

3. Pharmaceutical form

Prolonged-release granules.

White or almost white, round, film-coated prolonged-release granules.

4. Clinical particulars
4.1 Therapeutic indications

Sodium valproate is used in the:

• treatment of all forms of 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 sodium valproate for acute mania.

4.2 Posology and method of administration

Female children and women of childbearing potential

Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated.

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

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

Posology

Treatment in all forms of epilepsy:

Dosage requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control. The daily dosage should be given in 1 – 2 single doses.

Monotherapy

Usual requirements are as follows:

Adults

Dosage should start at 600mg 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 daily. Where adequate control is not achieved within this range the dose may be further increased to a maximum of 2500mg per day.

Children over 20kg

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 35 mg/kg body weight per day.

Children under 20kg

20mg/kg body weight per day; in severe cases this may be increased up to 40mg/kg/day.

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 decreased 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 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 and 4.8).

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

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).

Combined Therapy

When starting Episenta® in patients already on anticonvulsants, these should be tapered slowly; initiation of Episenta® treatment 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 10mg/kg/day when used in combination with liver enzyme 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 barbiturate 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).

Manic episodes in bipolar disorder

Adults

The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg sodium 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 1,000 and 2,000 mg sodium valproate. Patients receiving daily doses higher than 45 mg/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.

Children and adolescents

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

Method of administration

For oral administration.

The contents of the sachet may be sprinkled or stirred into soft food or drinks and swallowed immediately without chewing, or crushing the prolonged- release granules. The food or drink should be cold or at room temperature. A mixture of the granules with liquid or soft food should not be stored for future use. If the contents of the sachet are taken in a drink, as some granules may stick to the glass after the drink has been finished, the glass should be rinsed with a small amount of water and this water swallowed as well. The prolonged-release granules should not be given in babies' bottles as they can block the teat.

When changing from sodium valproate enteric coated tablets to Episenta® it is recommended to keep the same daily dose.

4.3 Contraindications

Episenta® is contraindicated in the following situations:

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

• Active liver disease.

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

• Porphyria.

• Patients with known urea cycle disorders (see section 4.4).

Treatment of epilepsy

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

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

Treatment of bipolar disorder

• in pregnancy (see sections 4.4 and 4.6).

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

Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).

4.4 Special warnings and precautions for use

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.

NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

The concomitant use of sodium valproate and carbapenem is not recommended (see section 4.5).

Aggravated convulsions:

As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).

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).

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 and 5.2).

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).

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).

Pregnancy Prevention Programme

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

Episenta® is contraindicated in the following situations:

Treatment of epilepsy

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

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

Treatment of bipolar disorder

• in pregnancy (see sections 4.3 and 4.6).

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

Conditions of Pregnancy Prevention Programme:

The prescriber must ensure that

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

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

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

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

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

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

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

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

• the patient has received the patient guide.

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

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

Female children

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

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

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

Pregnancy test

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

Contraception

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

Annual treatment reviews by a specialist

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

Pregnancy planning

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

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

In case of pregnancy

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

Pharmacist must ensure that

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

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

Educational materials

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

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

Patients with known or suspected mitochondrial disease

Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG),e.g. Alpers-Huttenlocher Syndrome.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).

Diabetic patients

Sodium 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.

Alcohol

Alcohol intake is not recommended during treatment with valproate.

Granules in stools

The prolonged-release granules are surrounded by an indigestible cellulose shell through which the sodium valproate is released and these shells will be seen as white residues in the stools of the patient. There are no safety issues concerning such residues.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of Episenta® on other drugs

Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

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.

Phenobarbital

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.

Primidone

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

Episenta® decreases phenytoin total plasma concentration and increases the free form of phenytoin leading to possible overdosage symptoms. Therefore, clinical monitoring is recommended with the free form of phenytoin being measured, when phenytoin plasma levels are determined.

Carbamazepine

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

Lamotrigine

Episenta® reduces the metabolism of lamotrigine and increases the lamotrigine mean half life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

Felbamate

Valproic acid may decrease the felbamate mean clearance by up to 16%.

Zidovudine

Episenta® 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 valproate The prothrombin time should be closely monitored.

Temozolomide

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

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 Episenta® 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 be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

Carbapenem antibiotics such as imipenem, panipenem and meropenem: 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 within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

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.

Other interaction

Episenta® 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. careful monitoring of signs and symptoms is advised in particularly at- risk patients such as those with pre-existing encephalopathy.

Co-administration of Episenta® and quetiapine may increase the risk of neutropenia/leucopenia.

4.6 Fertility, pregnancy and lactation

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

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 from congenital malformations (95 % CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3 %. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.

Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.

Teratogenicity and Developmental Effects

Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.

Studies in preschool children exposed in utero to valproate show that up to 30-40 % experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.

Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.

There are limited data on the long term outcomes.

Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.

Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).

Female children and women of childbearing potential (see above and section 4.4)

If a woman plans a pregnancy

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

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

Pregnant women

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

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

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

• Use the lowest effective dose and divide the daily dose of valproate into several small doses to be taken throughout the day. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations (see section 4.2).

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

Risk in the neonate

• Cases of hemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This hemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

• Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.

• Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.

• Withdrawal syndrome (such as, in particular, agitation, irritability, hyper- excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.

Breastfeeding

Valproate is excreted in human milk with a concentration ranging from 1% to 10% of maternal serum levels. Hematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Episenta® 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 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.

4.8 Undesirable effects

Frequency categories are defined using the following convention:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Congenital, familial and genetic disorders

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

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Rare:

myelodysplastic syndrome

Hepato-biliary disorders

Common:

liver injury (see section 4.4)

Not known:

severe liver damage, including hepatic failure sometimes resulting in fatalities (see sections 4.2, 4.3 and 4.4)

Gastro-intestinal disorders

Very common:

nausea

Common:

vomiting, gingival disorder, (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea.

The above three adverse events frequently occur at the start of the treatment, but usually disappearing after a few days without discontinuing treatment. These problems can usually be overcome by taking Episenta® with or after food.

Uncommon:

pancreatitis, sometimes lethal (see section 4.4)

Psychiatric disorders

Common:

confusional state, aggression*, agitation*, disturbance in attention*

Rare:

abnormal behaviour*, psychomotor hyperactivity*, learning disorder*

*These ADRs are principally observed in the paediatric population.

Nervous system disorders:

Very common:

tremor

Common:

extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus

Uncommon:

coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paresthesia.

Rare:

reversible dementia associated with reversible cerebral atrophy, cognitive disorder, diplopia.

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 occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have uncommonly 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.

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

Endocrine disorders

Uncommon:

Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increased)

Rare:

hypothyroidism (see section 4.6)

Metabolism and nutrition disorders

Common:

hyponatraemia

Rare:

hyperammonaemia* (see section 4.4), obesity

*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, 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.

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4). In such cases further investigations should be considered.

Blood and lymphatic system disorders

Common:

anaemia, thrombocytopenia (see section 4.4)

Uncommon:

pancytopenia, leucopenia

The blood picture returned to normal when the drug was discontinued.

Rare:

bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis.

Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Episenta® 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).).

Skin and subcutaneous tissue disorders

Common:

hypersensitivity, transient hair loss, which may sometimes be dose-related. Regrowth normally begins within 6 months, although the hair may become more curly than previously.

nail and nail bed disorders

Uncommon:

angioedema, rash

Rare:

toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

Reproductive system and breast disorders

Common:

dysmenorrhea

Uncommon:

amenorrhea

Rare:

male infertility, polycystic ovaries

Very rare:

gynaecomastia

Vascular disorders

Common:

haemorrhage (see section 4.4. and 4.6)

Uncommon:

vasculitis

Ear and labyrinth disorders

Common:

deafness, a cause and effect relationship has not been established

Renal and urinary disorders

Rare:

enuresis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Episenta® therapy, but the mode of action is as yet unclear.

General disorders and administration site conditions

Uncommon:

non-severe oedema peripheral

Musculoskeletal and connective tissue disorders

Uncommon:

bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with Episenta®. The mechanism by which Episenta® affects bone metabolism has not been identified.

Rare:

systemic lupus erythematosus (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Uncommon:

pleural effusion

Investigations

Common:

weight increased*

Rare:

coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged).

*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).

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 (see details below).

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Fatty acid derivatives

ATC code: N03AG01

The mode of action of valproic acid 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.

The increased expression of drug efflux transporters at the blood-brain barrier can results in lower concentrations of their respective substrate, i. e. the active substance, in the brain compared to its free concentration in plasma, and thereby reduce the concentration of antiepileptics at the site of action. This can lead to pharmacoresistance and thus to the development of a treatment-resistant status epilepticus or treatment-resistant epilepsy. However, in vitro data suggest that sodium valproate is not a substrate for transporters such as ATP-binding cassette (ABC) transporters (e. g. P-glycoprotein (Pgp)) or multidrug resistance-associated proteins (MRP1, MRP2 and MRP5). The development of pharmacoresistance against valproate by these transporters is therefore considered unlikely.

5.2 Pharmacokinetic properties

With peroral administration 90-100 % of the dose is rapidly absorbed.

Maximal plasma concentration is achieved with Episenta® within 6.5 ± 3.3 hours. The half-life is 12-16 h in most patients but can in exceptional cases be considerably lower. Impaired renal function prolongs the half-life. In infants under 2 months the half-life can be prolonged up to 60 hours but in older children it is the same as in adults.

Steady-state concentration is normally achieved after treatment in 3-5 days. A satisfactory effect is most often achieved at 50-100 µg/mL, but the patient's overall situation must be considered.

The relation between the dose and effect, and between plasma concentrations and effect, has not been fully clarified.

The cerebrospinal fluid concentration is up to 10 % of the plasma concentration. About 90 % of sodium valproate is bound to plasma protein (mainly to albumin), which may entail a risk of clinically significant interactions with other antiepileptics, primarily phenytoin. Protein binding decreases at higher dosages. Plasma protein binding is lower in elderly patients and in patients with kidney or liver dysfunction. In one study, elevated levels of the free drug (8.5 % up to more than 20 %) were observed in patients with significantly reduced renal function.

However, if hypoproteinaemia is present, the total concentration of valproic acid (free and protein-bound substance) can be essentially unchanged, although it may also be reduced due to the increased metabolism of the free portion.

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 of 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.

5.3 Preclinical safety data

Testicular atrophy, degeneration of the vas deferens and inadequate spermatogenesis as well as changes to the lungs and prostate gland have been observed in chronic toxicity studies with high oral dosages (250 mg/kg in rats and 90 mg/kg in the dog).

Mutagenicity tests in bacteria, rats and mice yielded no evidence of mutagenic potential.

Long-term studies have been conducted in rats and mice. At very high doses, the rate of subcutaneous fibrosarcomas was increased in male rats. Animal studies have shown valproic acid to be teratogenic.

6. Pharmaceutical particulars
6.1 List of excipients

Prolonged–release granule:

Calcium stearate

Colloidal anhydrous silicon dioxide, methylated

Ammonium methacrylate copolymer (Type B)

Sorbic acid

Sodium hydroxide

Granule coating:

Ethyl cellulose

Dibutyl sebacate

Oleic acid

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 30° C. Store in the original package.

6.5 Nature and contents of container

50, 100 or 200 Clay coated kraftpaper/Aluminium/PE sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

DESITIN ARZNEIMITTEL GMBH

WEG BEIM JAEGER 214

HAMBURG

D-22335 GERMANY

8. Marketing authorisation number(s)

PL 14040/0027

9. Date of first authorisation/renewal of the authorisation

01/08/2006

10. Date of revision of the text

18/12/2018