4.1. Therapeutic indications

Epilepsy:

Female patients:

• For all female patients aged under 55 years: For the treatment of generalised, partial or other epilepsy only when there is no other effective or tolerated treatment.

• For all female patients aged over 55 years: For the treatment of generalised, partial or other epilepsy.

Male patients:

• For all male patients aged under 55 years initiating treatment with valproate: For the treatment of generalised, partial or other epilepsy only when there is no other effective or tolerated treatment.

• For all male patients established on treatment with valproate or male patients aged over 55 years: For the treatment of generalised, partial or other epilepsy.

Bipolar disorder:

For the treatment of manic episode in bipolar disorder only when there is no other effective or tolerated treatment.

The continuation of treatment after manic episode could be considered in patients who have responded to Epival CR for acute mania.

4.2. Posology and method of administration

Posology

Epival CR prolonged-release tablets are a prolonged-release formulation of sodium valproate which reduces peak concentration and ensures more even plasma concentrations throughout the day.

Daily dosage requirements vary according to age and body weight. 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).

Female children and women of childbearing potential aged under 55 years

No new female patients aged under 55 years should be initiated on valproate unless two specialists independently consider and document that there is no other effective or tolerated treatment (see sections 4.3, 4.4 and 4.6).

Valproate must be supervised by a specialist experienced in the management of epilepsy or bipolar disorder.

Valproate should not be prescribed in female children and women of childbearing potential aged under 55 years unless two specialists independently consider and document that there is no other effective or tolerated treatment (see sections 4.3, 4.4 and 4.6).

Where possible, existing female children and women of childbearing potential aged under 55 years should be switched to another treatment unless two specialists independently consider and document there is no other effective or tolerated treatment. For those continuing to receive valproate, the benefits and risks of valproate should be carefully reconsidered at regular treatment reviews, at least annually (see section 4.4).

Valproate in any indication must be 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).

Male patients under 55 years

No new male children or men aged under 55 years should be initiated on valproate unless two specialists independently consider and document that there is no other effective or tolerated treatment or the risk of infertility or potential risk of testicular toxicity are not applicable (see sections 4.4 and 4.6).

The specialist should discuss and complete the risk acknowledgement form with the patient and/or carer at initiation to ensure all male children and men aged under 55 years are aware of the risk of infertility in males (see sections 4.4, 4.6 and 4.8) and of the data available showing testicular toxicity in animals exposed to valproate and the uncertain clinical relevance (see section 5.3).

Epilepsy:

Monotherapy

Usual requirements are as follows:

Adults

Dosage should start at 600 mg (5-10 mg/kg body weight) daily, followed by gradual increases of 5-10 mg/kg at 3-7 day intervals until control is achieved. This is generally within the dosage range 1000 mg to 2000 mg per day, i.e. 20-30 mg/kg body weight. Where adequate control is not achieved within this range, the dose may be further increased up to 2500 mg per day.

Paediatic population

For children the starting dose for sodium valproate is 10-20 mg/kg and the maintenance dose between 20 and 30 mg/kg; doses higher than 40 mg/kg daily may be required in individual cases. (See dosage table for orientation.)

Children over 20 kg

The recommended starting dose for Epival CR prolonged-release tablets is 300 mg/day with increases at 3-7 day intervals 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.

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

Children under 20 kg

An alternative formulation of valproate should be used in this group of patients, due to the need for dose titration.

Elderly patients

The pharmacokinetics of valproate may be altered in the elderly. Dosage should be determined by seizure control (see section 5.2).

The following daily doses for sodium valproate are recommended (table for orientation purposes):

Age

Body weight (kg)

Average dose (mg/day)

3 - 6 months

≈ 5.5 - 7.5

150

6 - 12 months

≈ 7.5 - 10

150 - 300

1 - 3 years

≈ 10 - 15

300 - 450

3 - 6 years

≈ 15 - 20

450 - 600

7 - 11 years

≈ 20 - 40

600 - 1200

12 - 17 years

≈ 40 - 60

1000 - 1500

Adults and elderly

≥ 60

1200 - 2100

Patients with renal insufficiency

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

Patients with hepatic insufficiency

Salicylates should not be used concomitantly with valproate 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 valproate, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4).

Combined therapy

When starting Epival CR prolonged-release tablets in patients already on other anticonvulsants, these should be tapered slowly; initiation of therapy with Epival CR prolonged-release tablets should then be gradual, with target dose being reached after about 2 weeks. In certain cases, it may be necessary to raise the dose by 5 to 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 Epival CR prolonged-release tablets. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2).

Manic episodes in bipolar disorder:

Adults

The daily dosage should be established and controlled individually by the treating physician.

The initial recommended daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. Prolonged-release formulations can be given once or twice daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient.

The mean daily dose usually ranges between 1000 and 2000 mg valproate. Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored.

Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.

Paediatric population

The efficacy of Epival CR prolonged-release tablets in children below 18 years of age in the treatment of manic episodes of bipolar disorder has not been established. With respect to safety information in children see section 4.8.

Method of administration

Epival CR prolonged-release tablets are for oral use.

Epival CR prolonged-release tablets should be given once or twice daily. The tablets should be swallowed whole with fluid and not crushed or chewed. If at the start or during treatment gastrointestinal irritation occurs, Epival CR prolonged-release tablets should be taken with or after food (see section 4.8).

4.3. Contraindications

Epival CR prolonged-release tablets is contraindicated in the following situations:

- Hypersensitivity to sodium valproate or to any other excipients listed in section 6.1.

- Active liver disease, or personal or family history of severe hepatic dysfunction, especially drug related.

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

- Porphyria.

- 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).

- Patients with uncorrected systemic primary carnitine deficiency (see section 4.4).

Treatment of epilepsy

- in pregnancy, unless two specialists independently consider and document that there is no other effective or tolerated treatment (see section 4.4 and 4.6).

- in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

Treatment of bipolar disorder

- in pregnancy (see section 4.4 and 4.6).

- in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

4.4. Special warnings and precautions for use

Female children, women of childbearing potential under the age of 55 years and pregnant women:

Pregnancy Prevention Programme

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk (11%) for congenital malformations and neurodevelopmental disorders (up to 30-40%) which may lead to permanent disability (see section 4.6).

Valproate must only be initiated by two specialists who independently consider and document that there is no other effective or tolerated treatment.

Epival CR is contraindicated in the following situations:

Treatment of epilepsy

- in pregnancy unless two specialists independently consider and document that there is no other effective or tolerated treatment (see sections 4.3 and 4.6).

- in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).

Treatment of bipolar disorder

- in pregnancy (see sections 4.3 and 4.6).

- in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.6).

Conditions of Pregnancy Prevention Programme:

The specialist must ensure that

- Individual circumstances should be evaluated in each case, involving the patient in the discussion, to support 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 which may lead to permanent disability, including the magnitude of these risks for children exposed to valproate in utero.

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

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

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

- the patient understands the need to consult her general practitioner (GP) for referral to a specialist as soon as she is planning a pregnancy to ensure timely discussion and switching to another treatment prior to conception, and before contraception is discontinued.

- the patient understands the need to urgently consult her GP for urgent referral to a specialist 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 apply to women who are not currently sexually active unless the specialist considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Female children

- The specialist must ensure that parents/caregivers of female children understand the need to contact their general practitioner once the female child using valproate experiences menarche. Their general practitioner will refer the patient back to the specialist.

- The specialist 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 which may lead to permanent disability, 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 other treatment options. If valproate is the only effective and tolerated 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 another treatment before they reach menarche.

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 support 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 and complete the annual risk acknowledgement form with the patient and/or carer 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 other treatment options. Every effort should be made to switch to an appropriate treatment prior to conception, and before contraception is discontinued (see section 4.6). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.

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

In case of pregnancy

If a woman using valproate becomes pregnant, she must immediately contact her GP to be referred to a specialist to re-evaluate treatment with valproate and consider switching to other treatment options. The patients with a valproate exposed pregnancy and their partners should be referred by their GP 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 pack dispensing and that the patients understand its content.

- the patients are advised not to stop valproate medication and to immediately contact their GP to be referred to 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 discussed and completed with the patient and/or carer 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 or bipolar disorder.

Male children and men

All male patients and/or carers should be made aware of the potential risk to children born to men treated with valproate in the 3 months before conception (see also section 4.6), of the risk of infertility in men (see sections 4.2, 4.6 and 4.8) and of the data available showing testicular toxicity in animals exposed to valproate and the uncertain clinical relevance (see section 5.3).

A retrospective observational study suggests an increased risk of neuro-developmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception compared to those born to men treated with lamotrigine or levetiracetam (see section 4.6).

As a precautionary measure, GPs and specialists should inform male patients about this potential risk (see section 4.6) and recommend the need for male patients and their female partner to use effective contraception, while using valproate and for at least 3 months after treatment discontinuation.

Male patients should not donate sperm during treatment or for at least 3 months after treatment discontinuation.

Male patients treated with valproate should be regularly reviewed by their GP or specialist. For male patients planning to conceive a child, the specialist should consider and discuss other suitable treatment options with the male patients. Individual circumstances should be evaluated in each case.

Educational materials are available for healthcare professionals and male patients. A patient guide should be provided to male patients using valproate.

For males aged under 55 years, at initiation of treatment, the specialist should discuss and complete the risk acknowledgement form with the patient and/or carer at initiation to ensure all male children and men aged under 55 years are aware of the potential risk to offspring and of the risk of infertility in males and testicular toxicity data in animals.

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been reported. Experience in epilepsy has indicated that patients most at risk are infants, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections 4.3 and 4.4) 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 of liver toxicity (see also section 4.5). Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing valproate, but the potential benefit of valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy (see sections 4.4 and 4.5).

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:

- 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 for patients at risk and those with a prior history of liver disease. Upon changes in concomitant medicinal products (dose increase or additions) that are known to impact the liver, liver monitoring should be restarted as appropriate (see section 4.5).

Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.

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

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).

Urea cycle disorders and risk of hyperammonaemia:

When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate (see sections 4.3 and 4.4).

Patients at risk of hypocarnitinaemia

Valproate administration may trigger occurrence or worsening of hypocarnitinaemia that can result in hyperammonaemia (that may lead to hyperammonemic encephalopathy). Other symptoms such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome have been observed, mainly in patients with risk factors for hypocarnitinaemia or pre-existing hypocarnitinaemia. Patients at increased risk for symptomatic hypocarnitinaemia when treated with valproate include patients with metabolic disorders including mitochondrial disorders related to carnitine (see section 4.4), impairment in carnitine nutritional intake, patients younger than 10 years old, concomitant use of pivalate-conjugated medicines or of other antiepileptics.

Patients should be warned to report immediately any signs of hyperammonaemia such as ataxia, impaired consciousness, vomiting. Carnitine supplementation should be considered when symptoms of hypocarnitinaemia are observed.

Patients with systemic primary carnitine deficiency and corrected for hypocarnitinaemia may only be treated with valproate if the benefits of valproate treatment outweigh the risks in these patients and there is no therapeutic alternative. In these patients, carnitine monitoring should be implemented.

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of an increased risk of rhabdomyolysis developing with valproate therapy. Carnitine supplementation should be considered in these patients. See also sections 4.5, 4.8 and 4.9.

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 concomitant anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.

Severe Cutaneous Adverse Reactions and Angioedema:

Severe Cutaneous Adverse Reactions (SCARs) such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and angioedema, have been reported in association with valproate treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. In case signs of SCARs or angioedema are observed, prompt assessment is needed, and treatment must be discontinued if diagnosis of SCARs or angioedema is confirmed.

Aggravated convulsions:

As with other antiepileptics, 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:

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for valproate.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Carbapenem agents:

The concomitant use of valproate and carbapenem agents is not recommended.

Precautions

Haematological 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).

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).

Patients with systemic lupus erythematosus:

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

Weight gain

Valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of this risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8).

Diabetic patients

Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positive results in the urine testing of possible diabetics.

Alcohol

Alcohol intake is not recommended during treatment with valproate.

Sodium

This medicinal product contains 42 mg sodium per prolonged-release tablet, equivalent to 2.1 % 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 valproate on other drugs

Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

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 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.

Clozapine and haloperidol

No significant interaction was observed when clozapine and haloperidol were administered concurrently with valproate.

Lithium

Valproate does not affect serum concentrations of lithium.

Olanzapine

Valproate may reduce plasma levels of olanzapine.

Phenobarbital

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.

Primidone

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.

Phenytoin

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

Carbamazepine

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

Lamotrigine

Valproate may reduce lamotrigine metabolism and increase its mean half-life by nearly two-fold. dosages should be adjusted (lamotrigine dosage decreased) when appropriate. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended, and dosage 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 coadministered with valproate, a reduction of the dose of propofol should be considered.

Zidovudine

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

Nimodipine

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

Temozolomide

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

Clozapine

Concomitant treatment of valproate and clozapine may increase the risk of neutropenia and clozapine-induced myocarditis. If concomitant use of valproate with clozapine is necessary, careful monitoring for both events is required.

Effects of other drugs on valproate

Antiepileptics

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

Anti-malaria agents

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 valproate may need adjustment.

Highly protein-bound agents

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

Vitamin K-dependent anticoagulants and acetylsalicylic acid

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 during oral anticoagulation.

Cimetidine, erythromycin

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 (e.g. panipenem, imipenem, 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 in about two days. 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 (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

Rifampicin

Rifampicin may decrease valproic acid blood levels, resulting in a lack of therapeutic effect. Therefore valproate dosage adjustment may be necessary if co-administered with rifampicin.

Protease inhibitors

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

Cholestyramine

Cholestyramine may lead to a decrease in plasma level of valproate 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.

Metamizole

Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (mood control) and consider monitoring valproate serum levels as appropriate.

Methotrexate

Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control) and consider monitoring valproate serum levels as appropriate.

Other interactions

Risk of liver damage

The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity (see section 4.4).

Concomitant use of valproate and multiple anticonvulsant therapy increases the risk of liver damage, especially in young children (see section 4.4).

Concomitant use with cannabidiol increases the incidence of transaminases enzyme elevation. In clinical trials in patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, ALT increases greater than 3 times the upper limit of normal have been reported in 19% of patients. Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters (see section 4.4).

Newer anti-epileptics (including topiramate and acetazolamide)

Caution is advised when using sodium valproate in combination with newer anti-epileptics 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.

Pivalate-conjugated medicines

Concomitant administration of valproate and pivalate-conjugated medicines (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to increased risk of carnitine depletion (see section 4.4). Patients in whom coadministration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinaemia.

Quetiapine

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Treatment of epilepsy

• Epival CR is contraindicated in pregnancy unless two specialists independently consider and document that there is no other effective or tolerated treatment (see section 4.3 and 4.4).

• Epival CR is contraindicated for use in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and the conditions of the pregnancy prevention programme are fulfilled (see sections 4.3 and 4.4).

Treatment of bipolar disorder

• Epival CR is contraindicated in pregnancy.

• Epival CR is contraindicated for use in women of childbearing potential aged under 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment and 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

In females, both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data show an increased risk of major congenital malformations and neuro-developmental disorders in both valproate monotherapy and polytherapy compared to the population not exposed to valproate.

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 from in utero exposure

A meta-analysis (including registries and cohort studies) showed that 11% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations. This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%.

The risk of major congenital malformations in children after in utero exposure to antiepileptic drug polytherapy including valproate is higher than that of anti-epileptic drug polytherapy not including valproate.

This risk is dose-dependent in valproate monotherapy, and available data suggests it is dose-dependent in valproate polytherapy. However, 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 effects, facial dysmorphia, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple malformations anomalities 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 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.

Neuro-developmental disorders from in utero exposure

Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk of neuro-developmental disorders which may lead to permanent disability (including that of autism) seems to be dose-dependent when valproate is used in monotherapy, but a threshold dose below which no risk exists cannot be established based on available data. When valproate is administered in polytherapy with other anti-epileptic drugs during pregnancy, the risks of neuro-developmental disorders which may lead to permanent disability in the offspring were also significantly increased as compared with those in children from the general population or born to untreated women with epilepsy.

The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.

When valproate is administered in monotherapy, studies in 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 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 during pregnancy, although the role of confounding factors related to intellectual disability 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 from a population-based study show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.

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, female adolescents and woman of childbearing potential aged under 55 years (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 section 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.

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

Pregnant women

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

If a woman using valproate becomes pregnant, she must be immediately referred by her GP 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 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 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 by their GP 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% and 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 Epival CR 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 sections 4.2, 4.4 and 4.8). Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited numbers of case reports suggest a dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown.

Males and potential risk of neuro-developmental disorders in children of fathers treated with valproate in the 3 months prior to conception

A retrospective observational study in 3 Nordic countries suggests an increased risk of neuro-developmental disorders (NDDs) in children (from 0 to 11 years old) born to men treated with valproate as monotherapy in the 3 months prior to conception compared to those born to men treated with lamotrigine or levetiracetam as monotherapy, with a pooled adjusted hazard ratio (HR) of 1.50 (95% CI: 1.09-2.07). The adjusted cumulative risk of NDDs ranged between 4.0% to 5.6% in the valproate group versus between 2.3% to 3.2% in the composite lamotrigine/levetiracetam group. The study was not large enough to investigate associations with specific NDD subtypes and study limitations included potential confounding by indication and differences in follow-up time between exposure groups. The mean follow-up time of children in the valproate group ranged between 5.0 and 9.2 years compared to 4.8 and 6.6 years for children in the lamotrigine/levetiracetam group.

Overall, an increased risk of NDDs in children of fathers treated with valproate in the 3 months prior to conception is possible however the causal role of valproate is not confirmed. In addition, the study did not evaluate the risk of NDDs to children born to men stopping valproate for more than 3 months prior to conception (i.e., allowing a new spermatogenesis without valproate exposure).

As a precautionary measure, GPs and specialists should inform male patients about this potential risk and recommend the need for male patients and their female partner to use effective contraception, while using valproate and for at least 3 months after treatment discontinuation (see section 4.4).

Male patients should not donate sperm during treatment or for at least 3 months after treatment discontinuation.

Male patients treated with valproate should be regularly reviewed by their GP or specialist. For male patients planning to conceive a child, the specialist should consider and discuss other suitable treatment options with the male patients. Individual circumstances should be evaluated in each case.

4.7. Effects on ability to drive and use machines

Use of Epival CR prolonged-release tablets may provide seizure control such that the patient may be eligible to hold a driving license.

However, patients should be warned when driving a vehicle or using machines of the risk of transient drowsiness especially in cases of anticonvulsant polytherapy or association with benzodiazepines.

4.8. Undesirable effects

The following CIOMS frequency rating is used, when applicable:

Very common

Common

Uncommon

Rare

Very rare

Not known

(≥ 1/10),

(≥ 1/100 to < 1/10),

(≥ 1/1,000 to < 1/100),

(≥ 1/10,000 to < 1/1,000),

(< 1/10,000),

(cannot be estimated from available data).

The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of Epival CR in the treatment of manic episodes have been identified.

System organ class

Very common

Common

Uncommon

Rare

Not known

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

myelodysplastic syndrome

Blood and lymphatic system disorders

anaemia, thrombocytopenia**

pancytopenia, leucopenia

bone marrow failure (including red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis)

Endocrine disorders

syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia and/or increased androgen level)

hypothyroidism

Metabolism and nutrition disorders

hyponatraemia, weight gain**

hyperammonaemia**, obesity

hypocarnitinaemia

Psychiatric disorders

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

abnormal behaviour, psychomotor hyperactivity, learning disorder

Nervous system disorders

tremor

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

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

reversible dementia associated with reversible cerebral atrophy, cognitive disorder

Eye disorders

diplopia

Ear and labyrinth disorders

deafness, a cause-and-effect relationship has not been established

Vascular disorders

haemorrhage

vasculitis

Respiratory, thoracic and mediastinal disorders

pleural effusion (eosinophilic)

Gastrointestinal disorders

nausea

vomiting, gingival disorder (especially gingival hyperplasia), stomatitis, gastralgia, diarrhoea**

pancreatitis, sometimes lethal (see section 4.4)

Hepatobiliary disorders

liver injury (see section 4.4)**

Skin and subcutaneous tissue disorders

Hypersensitivity, transient and/or dose-related alopecia (hair loss)**, nail and nail bed disorders

angioedema, rash, hair disorder (e.g. abnormal hair texture, change of hair colour, abnormal hair growth)

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

hyperpigmentation

Musculoskeletal and connective tissue disorders

decreased bone mineral density**, osteopenia**, osteoporosis and fractures**

systemic lupus erythematosus, rhabdomyolysis

Renal and urinary disorders

urinary incontinence

renal failure

enuresis, tubulo-interstitial nephritis, reversible Fanconi syndrome**

Reproductive system and breast disorders

dysmenorrhoea

amenorrhoea

male infertility, polycystic ovarian syndrome

General disorders and administration site conditions

hypothermia, non-severe peripheral oedema

Investigations

coagulation factors decreased**, abnormal coagulation tests**

** Description of selected adverse reactions

Hepatobiliary disorders

Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also sections 4.2, 4.3 and 4.4). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4).

Gastrointestinal disorders (nausea, vomiting, gingival disorder, stomatitis, gastralgia, diarrhoea) frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Epival CR with or after food.

Blood and lymphatic system disorders:

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

Isolated reduction of blood fibrinogen and/or increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (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 also section 4.6).

Metabolism and nutrition disorders

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

Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered (see sections 4.3 and 4.4).

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

Nervous system disorders

Sedation has been reported, usually when in combination with other anticonvulsants. In monotherapy it has 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 has 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.

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

Skin and subcutaneous tissue disorders

Transient hair loss has commonly been noted in some patients, but is dose dependent. Regrowth normally begins within six months, although the hair may become more curly than previously.

Musculoskeletal and connective tissue disorders

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

Renal and urinary disorders

A reversible Fanconi´s syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with valproate therapy has been reported, but the mode of action is as yet unclear.

Reproductive system and breast disorders

Very rarely, gynaecomastia has occurred.

Investigations

Coagulation factors may be decreased (at least one), abnormal coagulation tests (e.g. prolonged prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, or INR prolonged) are possible (see sections 4.4 and 4.6).

Congenital, familial and genetic disorders

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

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

Symptoms

Cases of accidental and deliberate valproate overdosage have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of acute massive overdose, i.e. plasma concentration 10 – 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.

However, the symptoms may be variable and seizures have been reported in the presence of very high plasma levels in patients with epilepsy (see section 5.2). Cases of intracranial hypertension related to cerebral oedema have been reported.

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

Management

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

In case of valproate overdose resulting in hyperammonaemia, carnitine can be given through IV route to attempt to normalize ammonia levels.

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.