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® solution for injection

2. Qualitative and quantitative composition

Sodium valproate 100mg/ml

One ampoule with 3 ml solution for injection contains 300 mg of sodium valproate (equivalent to 260.28 mg of valproic acid).

One ampoule with 10 ml solution for injection contains 1,000 mg of sodium valproate (equivalent to 867.6 mg of valproic acid).

Excipient(s) with known effect:

1 ampoule with 3 ml solution for injection contains 1.81 mmol (41.6 mg) sodium.

1 ampoule with 10 ml solution for injection contains 6.0 mmol (138.8 mg) sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection

4. Clinical particulars
4.1 Therapeutic indications

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.

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. 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. 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.

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 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 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 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).

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 IV additives.

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.

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)

- 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).

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:

• 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).

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.

• 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.

Oestrogen-containing products

Concomitant use with oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (seizure control) when initiating, or discontinuing oestrogen-containing products.

On the opposite, valproate does not reduce efficacy of hormonal contraceptives.

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.

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.

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.

Carnitine palmitoyltransferase (CPT) type II deficiency

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking Episenta®.

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).

Alcohol

Alcohol intake is not recommended during treatment with valproate.

Sodium content

This medicinal product contains 41.6 mg sodium per 3 mL ampoule, equivalent to 2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 138.8 mg sodium per 10 mL ampoule, equivalent to 7 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

Lithium

Episenta® has no effect on serum lithium levels.

Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

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%.

Rufinamide

Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.

Propofol

Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.

Zidovudine

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

Nimodipine

In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50 %. The nimodipine dose should therefore be decreased in case of hypotension.

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

Antiepileptics with enzyme inducing effects e.g. phenytoin, phenobarbital, carbamazepine, decrease valproate plasma levels. Plasma levels should be monitored and dosage adjusted accordingly.

Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.

On the other hand, combination of felbamate and Episenta decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Episenta dosage should be monitored.

Anti-malaria agents

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

Highly protein bound agents

Free valproate levels may be increased in the case of concomitant use with highly protein bound agents e.g. acetylsalicylic acid.

Cimetidine or erythromycin

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

Colestyramine may decrease the absorption of valproate.

Rifampicin

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.

Protease inhibitors

Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.

Oestrogen-containing products, including oestrogen-containing hormonal contraceptives

Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.

On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.

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.

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

Concomitant administration of valproate and topiramate or acetazolamide 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.

4.6 Fertility, pregnancy and lactation

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

Teratogenicity and Developmental Effects

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate may be associated with a greater risk of congenital malformations than valproate monotherapy.

Valproate was shown to cross the placental barrier both in animal species and in humans (see section 5.2).

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.

In utero exposure to valproate may also result in hearing impairment or deafness due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases did not recover.

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)

Oestrogen-containing products

Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see sections 4.4 and 4.5).

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.

Pregnant women

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 (including cysts and polyps)

Rare:

myelodysplastic syndrome

Hepato-biliary disorders

Common:

liver injury (see section 4.4); increased liver enzymes, particularly early in treatment, and may be transient (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, occurs a few minutes after intravenous injection with spontaneous resolution within a few minutes

Common:

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

These frequently occur at the start of the treatment, but usually disappearing after a few days without discontinuing treatment.

Uncommon:

pancreatitis, sometimes lethal (see section 4.4)

Psychiatric disorders

Common:

confusional state, hallucinations, 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, dizziness may occur a few minutes after intravenous injection; it disappears spontaneously within a few minutes.

Uncommon:

coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paresthesia, aggravated convulsions (see section 4.4)

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, weight increased*

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

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 and/or dose related alopecia (hair loss). Regrowth normally begins within 6 months, although the hair may become more curly than previously.

nail and nail bed disorders

Uncommon:

angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)

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

Common:

urinary incontinence

Uncommon:

renal failure

Rare:

enuresis, tubulointerstitial nephritis, 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:

hypothermia, 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), rhabdomyolysis (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Uncommon:

pleural effusion

Investigations

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).

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.

The presence of sodium content in the Episenta® formulations may lead to hypernatraemia when taken in overdose.

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10–12 hours following ingestion. 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

ATCcode: 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.

5.2 Pharmacokinetic properties

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 – 100 mg/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.

Placental transfer (see section 4.6)

Valproate crosses the placental barrier in animal species and in humans:

• In animal species, valproate crosses the placenta to a similar extent as in humans.

• In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery.

Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.

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

5.3 Preclinical safety data

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

Testicular atrophy, degeneration of the vas deferens and insufficient spermatogenesis as well as lung and prostate gland changes have been observed in chronic toxicity studies at dosages of more than 250 mg/kg in rats and 90 mg/kg in the dog. In rats, at 200 mg/kg p.o., morphological hepatocytes changes were seen. At 750 mg/kg i.p., functional liver disorders and, among other things, hyperammonaemia, occurred.

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.

Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.

6. Pharmaceutical particulars
6.1 List of excipients

Disodium edetate

Water for injections

6.2 Incompatibilities

Episenta® solution for injection should not be administered via the same intravenous line as other IV additives.

6.3 Shelf life

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.

6.4 Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

Glass (type I) ampoule with silicone coating on the inside containing 3 ml or 10 ml solution for injection.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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 - 22°C 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.

The contents of the vial are for single use only

7. Marketing authorisation holder

Desitin Arzneimittel GmbH

Weg beim Jäger 214

D-22335 Hamburg

Germany

8. Marketing authorisation number(s)

PL 14040/0028

9. Date of first authorisation/renewal of the authorisation

17/02/2009

10. Date of revision of the text

22/01/2020