DYZANTIL 500 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

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

1 NAME OF THE MEDICINAL PRODUCT

Dyzantil 500 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 333 mg sodium valproate and 145 mg valproic acid equivalent to 500 mg sodium valproate.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Violet coloured, oblong shaped, film-coated tablet, 17.2 × 9.7 mm and plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of generalised, partial or other epilepsy.

4.2 Posology and method of administration

Dyzantil is a prolonged release formulation which reduces peak concentration and ensures more even plasma concentrations throughout the day. Dyzantil may be given once or twice daily. The tablets should be swallowed whole and not crushed or chewed. Daily dosage requirements vary according to age and body weight.

Dosage

Usual requirements are as follows:

Adults

Dosage should start at 600 mg daily increasing by 200 mg at three-day intervals until control is achieved. This is generally within the dosage range 1000 – 2000 mg per day, i.e. 20 – 30 mg/kg/day body weight. Where adequate control is not achieved within this range, the dose may be further increased to 2500 mg per day.

Children over 20 kg

Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 – 30 mg/kg body weight per day.

Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight per day.

Children under 20 kg

An alternative formulation of sodium valproate should be used in this group of patients, due to the tablet size and the need for dose titration. Liquid formulations of sodium valproate are available which would be more suitable for this patient group.

Elderly

Although the pharmacokinetics of sodium valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. 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.

Haematological tests

Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy.

Renal impairment

It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Sodium valproate is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4).

Hepatic impairment

Salicylates should not be used concomitantly with Dyzantil since they employ the same metabolic pathway (see sections 4.4 and 4.8).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 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 4.4.1).

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 (see sections 4.3, 4.4 and 4.6).

Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see sections 4.3 and 4.4). The benefits and risks should be carefully reconsidered at regular treatment reviews (see section 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).

Combined Therapy

When starting Dyzantil in patients already on other anticonvulsants, these should be tapered slowly; initiation of Dyzantil therapy 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 – 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Dyzantil. When barbiturates are being administered concomitantly, and particularly if sedation is observed (particularly in children), the dosage of barbiturate should be reduced.

NB: 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

Dyzantil 500 mg prolonged-release tablets are for oral administration.

4.3 Contraindications

Dyzantil is contraindicated in the following situations:

In pregnancy unless there is no suitable alternative treatment (see section 4.4 and 4.6).

In women ofchildbearing potential unless the conditions of the pregnancy prevention programme are fulfilled (see sections 4.4 and

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

Suggestive signs:

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

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

– in patients with epilepsy, recurrence of seizures.

These are an indication for immediate withdrawal of the drug.

Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations, including clinical examination and biological assessment of liver function, should be undertaken immediately.

Detection:

Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.

Tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.

Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Dyzantil therapy.

As a precaution, concomitant 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; this may be 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, 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, valporate should be discontinued.

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).

Dyzantil 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 prescriber must ensure that:

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

The 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 have experienced menarche, the prescribing specialist must annually reassess the need for valproate therapy and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch 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 childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a healthcare 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 review at least annually 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.

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 treatment options. The patients with 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).

Pharmacists must ensure that:

The Patient Card is provided with every valproate dispensation and that patients understand its content.

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, provide guidance regarding use of valproate in women of childbearing potential and provide 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.

Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of epilepsy.

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).

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 showed a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data does 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.

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur. These are usually transient and should not lead to treatment discontinuation. However, they may present clinically as vomiting, ataxia, and clouding of consciousness. Should these symptoms occur, Dyzantil should be discontinued. Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered.

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.

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

Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.

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

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

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to, unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, 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).

4.4.2 PrecautionsHaematological tests:

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).

Although immune disorders have only rarely been noted during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus (see section 4.8).

When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with sodium valproate (see section 4.3).

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.

Weight gain is a factor for polycystic ovarian syndrome.

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

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

Alcohol intake is not recommended during treatment with valproate.

4.5 Interaction with other medicinal products and other forms of interaction

5.4.1 Effects of sodium valproate on other drugs

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

In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

Sodium valproate has no effect on serum lithium levels.

Valproic acid may decrease the olanzapine plasma concentration.

Sodium valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

Sodium valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

Sodium valproate decreases phenytoin total plasma concentration. Moreover, sodium valproate increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

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

Lamotrigine

Sodium valproate 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.

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

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, particularly in children, as this effect is larger in this population.

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

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

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.

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

5.4.2 Effects of other drugs on sodium valproateAntiepileptics

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital,

carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.

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 sodium valproate decreases valproic acid clearance by 22% – 50% and consequently increase the valproic acid plasma concentrations. Sodium valproate dosage should be monitored.

Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of sodium valproate may need adjustment.

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

The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.

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

Carbapenem antibiotics (such as 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.

Rifampicin may decrease the valproic acid 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 such as lopinavir and ritonavir decrease valproate plasma level when co-administered.

Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.

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.

Conversely, valproate has no enzyme inducing effect; valproate does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception.

Co-administration of sodium valproate with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of sodium valproate with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and sodium valproate are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

5.4.3 Other interactions

Caution is advised when using Dyzantil in combination with newer antiepileptics whose pharmacodynamics may not be well established.

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

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

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 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.

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

In animals: teratogenic effects have been demonstrated in mice, rats and rabbits (see section 5.3).

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.

In utero exposure to valproate may result in eye malformations (including colobomas, microphthalmos) that have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.

Developmental disorders

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

Studies in preschool children exposed in utero to valproate show that up to 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 anti-epileptics. 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.

Available data from another population-based study show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperac­tivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.

Female children and woman 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

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

Use the lowest effective dose and divide the daily dose valproate into several small doses to be taken throughout the day.

The use of a prolonged-release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations (see section 4.2).

All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised 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 haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic 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.

Breast-feeding

Valproate is excreted in human milk with a concentration ranging from 1% – 10% of maternal serum levels. Haematological 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 Dyzantil 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 Dyzantil may provide seizure control such that the patient may be eligible to hold a driving licence.

Patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with other Medicaments and Other Forms of Interaction).

4.8 Undesirable effects

Tabulated list of adverse reactions

The following CIOMS frequency rating is used, when applicable: 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).

1 Includes pure red cell aplasia, agranulocytosis, macrocytic anaemia and macrocytosis.

2 Includes hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase.

3 Includes abnormal hair texture, hair colour changes and/or abnormal hair growth.

4 Includes prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged and/or INR prolonged.

Description of selected adverse reactions

Blood and lymphatic system disorders:

The haematological profile returned to normal when the drug was discontinued.

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 (sodium valproate 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 section 4.4).

Gastrointestinal disorders:

Common gastrointestinal adverse events, such as nausea and vomiting, frequently occur at the start of treatment, but usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking sodium valproate with or after food.

Hepatobiliary disorders:

Increased liver enzymes are common, particularly early in treatment, and may be transient. Severe liver damage, including hepatic failure sometimes resulting in death, has been reported.

Skin and subcutaneous tissue disorders:

Hair regrowth normally begins within six months, although the hair may become curlier than previously.

Musculoskeletal and connective tissue disorders:

There is a higher risk of osteoporosis and fractures in patients on long-term therapy with sodium valproate. Risk factors include a history of osteoporosis and concomitant steroid use.

Paediatric population:

The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see Section 4.4). Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population. Based on a limited number of post-marketing cases, Fanconi Syndrome, enuresis and gingival hyperplasia have been reported more frequently in paediatric patients than in adult patients.

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 Yellow Card Scheme at: 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 sodium valproate overdose have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of acute massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual, however some deaths have occurred following massive overdose.

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

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

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

Haemodialysis and haemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.

In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Sodium valproate and valproic acid are anticonvulsants.

The most likely mode of action for sodium valproate is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

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

The reported effective therapeutic range for plasma valproic acid levels is 40 – 100 mg/litre (278 – 694 micromol/li­tre). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of sodium valproate may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

Metabolism

The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7.

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

Above the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. In paediatric patients below the age of 10 years, the systemic clearance of valproate varies with age. In neonates and infants up to 2 months of age, valproate clearance is decreased when compared to adults and is lowest directly after birth. In a review of the scientific literature, valproate half-life in infants under two months showed considerable variability ranging from 1 to 67 hours. In children aged 2–10 years, valproate clearance is 50% higher than in adults.

Renal insufficiency

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels.

If measurement of plasma levels is considered necessary, the pharmacokinetics of Dyzantil make the measurement of plasma levels less dependent upon time of sampling than with conventional and modified release sodium valproate formulations.

5.3 Preclinical safety data

Valproate was neither mutagenic in bacteria, nor in the mouse lymphoma assay in vitro and did not induce DNA repair in primary rat hepatocyte cultures. In vivo, however, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route of administration in humans, valproate did not induce chromosome aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand-breaks and chromosomal damage in rodents. In addition, increased sister-chromatid exchanges in epileptic patients exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in epileptic patients treated with valproate with those in untreated epileptic patients. The clinical relevance of these DNA/chromosome findings is unknown.

Non-clinical data reveal no special hazard for humans based on conventional carcinogenicity studies.

Reproductive and developmental toxicity

Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.

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

Behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioural changes have also been observed in the second generation and those were less pronounced in the third generation of mice following acute in utero exposure of the first generation to teratogenic valproate doses. The underlying mechanisms and the clinical relevance of these findings are unknown.

In repeat-dose toxicity studies, testicular degeneration/a­trophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.

In juvenile rats, a decrease in testes weight was only observed at doses exceeding the maximum tolerated dose (from 240 mg/kg/day by intraperitoneal or intravenous route) and with no associated histopathological changes. No effects on the male reproductive organs were noted at tolerated doses (up to 90 mg/kg/day). Based on these data, juvenile animals were not considered more susceptible to testicular findings than adults. Relevance of the testicular findings to paediatric population is unknown.

In a fertility study in rats, valproate at doses up to 350 mg/kg/day did not alter male reproductive performance. However, male infertility has been identified as an undesirable effect in humans (see sections 4.6 and 4.8).

6.1 List of excipients

Hypromellose, ethylcellulose, silicon dioxide

Film Coat

Violet coat (Opadry OY-S-6705), containing: titanium dioxide (E171), erythrosine aluminium lake (E127), indigo carmine aluminium lake (E132), iron oxide black (E172), hypromellose (E464), macrogol 400.

6.2 Incompatibilities

None

6.3 Shelf life

36 months

6.4 Special precautions for storage

Sodium valproate is hygroscopic. The tablets should not be removed from their foil until immediately before they are taken. Where possible, blister strips should not be cut. Store in the original package to protect from moisture and light. Store in a dry place below 30°C.

6.5 Nature and contents of container

Polyamide/alu­minium/PVC – aluminium foil blister packs.

Pack sizes:

14, 30, 48, 72, 90, 100 prolonged-release tablets.

Not all pack sizes may be marketed.