DEPAKOTE 500 MG TABLETS - summary of medicine characteristics

Summary of medicine characteristics - DEPAKOTE 500 MG TABLETS

SUMMARY OF PRODUCT 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

Depakote 500mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Containing 538.20 mg of valproate semisodium* per tablet (equivalent to 500 mg of valproic acid).

*Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. It is also known as divalproex sodium (USAN).

Excipient(s) with known effect:

Sodium 39.93 mg (see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gastro-resistant tablet.

Oval, lilac pink gastro-resistant tablets

4.1 Therapeutic indications

For the treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated.

For the continuation of treatment after manic episode could be considered in patients who have responded to Depakote for acute mania.

4.2 Posology and method of administration

Posology

The daily dosage should be established according to age and body weight. The wide variation in individual sensitivity to Depakote should also be considered.

Dosage

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 2 – 3 divided doses. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. 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 – 2000 mg valproate. Patients receiving daily doses higher than 45 mg/kg/day body weight should be carefully monitored.

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

Elderly

Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response.

Paediatric population

The efficacy of Depakote 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.

Renal impairment

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).

Hepatic impairment

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 of age (see aspirin/salicylate product information on Reye’s syndrome). In addition, in conjunction with valproate, concomitant use in children under 3 years of age 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 bipolar disorder. Valproate should not be used in female children or 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 (see section 4.5)

When starting Depakote in patients already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Depakote therapy should then be gradual, with target dose being reached after about 2 weeks. Faster titration may be permissible if plasma level monitoring is available. 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 control on a reduced dose of Depakote. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.

When using Depakote with other psychotropics, a reduced dose may be required (see section 4.5.1).

Optimum dosage is mainly determined by control. 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

For oral administration. The tablets should be swallowed whole with a drink of water, and not crushed or chewed.

4.3 Contraindications

Depakote is contraindicated in the following situations:

In pregnancy (see sections 4.4 and 4.6).

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

Hypersensitivity to valproate semisodium or 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 y (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).

4.4 Special warnings and precautions for use

To ensure the correct medication is prescribed for the patient’s condition, care must be taken not to confuse Depakote with Epilim or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets which clearly indicate specific indications for these differing medications.

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

4.4.1 Special Warnings

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye’s syndrome).

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.

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 treatment.

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

Increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

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

Pancreatitis:

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

Female children, women of childbearing potential and pregnant women:

Pregnancy Prevention Programme

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

Depakote is contraindicated in the following situations:

In pregnancy (see sections 4.3 and 4.6).

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

Conditions of Pregnancy Prevention Programme:

The prescriber must ensure that:

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

The potential for pregnancy is assessed for all female patients.

The patient has understood and acknowledged the risks of congenital malformations and neuro-developmental 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 bipolar disorder.

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 neuro-developmental 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 (mood 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.

Pregnancy planning

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

In case of pregnancy

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative 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 bipolar disorder.

Aggravated convulsions:

As with other anti-epileptic drugs, some patients with epilepsy 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 does not exclude the possibility of an increased risk for valproate semisodium.

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.

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 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, 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).

Excipients with known effect

Sodium: This medicinal product contains 39.93 mg sodium per tablet, equivalent to 2.00% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Ponceau 4R (E124): This colourant (azo dye) may cause allergic reactions including asthma in some people. You are more likely to have an allergy if you are also allergic to aspirin.

4.4.2 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 section 4.8).

Urea cycle disorders:

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 section 4.3).

Weight gain:

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

Diabetic patients:

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.

Carnitine palmitoyltransferase (CPT) type II deficiency:

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

Alcohol:

Alcohol intake is not recommended during treatment with valproate.

4.5 Interaction with other medicinal products and other forms of interaction

4.5.1 Effects of Depakote 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 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.

– Clozapine and haloperidol

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

– Lithium

Co-administration of valproate and lithium does not appear to affect the steady state kinetics of lithium. Valproate has no effect on serum lithium levels.

Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

– Phenobarbital

Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur. 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 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.

– 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 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 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 sodium valproate and nimodipine the exposure to nimodipine can 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.

4.5.2 Effects of other drugs on Depakote

– Anti-epileptics

Antiepileptics with enzyme inducing effects (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-malarial agents

Mefloquine and chloroquine increase valproic acid metabolism. 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 factor anticoagulants

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.

– Cimetidine or 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 (such as panipenem, imipenem and meropenem)

Decreases in blood levels of valproic acid have been reported when it is coadministered 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 (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level should be performed.

– Rifampicin

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

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 glucuoronidation 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.

4.5.3 Other interactions

– Newer anti-epileptics (including topiramate and acetazolamide)

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

Quetiapine

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

4.6 Fertility, pregnancy and lactation

Valproate is contraindicated as treatment for bipolar disorder during pregnancy.

Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.3 and 4.4).

Teratogenicity and developmental effects

Pregnancy exposure risk related to valproate

Both valproate monotherapy and valproate polytherapy including other anti-epileptics are frequently associated with abnormal pregnancy outcomes. Available data 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

A meta-analysis (including registries and cohort studies) showed that approximately 11% of children of women with epilepsy exposed to valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations in the general population (approximately 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 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.

Neuro-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 of neuro-developmental disorders (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 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. 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 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 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 section 4.4 and 4.5).

If a woman plans a pregnancy

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy (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.

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 common to 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, hyperexcitability, 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 valproate 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). Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation. Limited number of case reports suggest that a strong dose reduction may improve fertility function. However, in some cases, the reversibility of male infertility was unknown.

4.7 Effects on ability to drive and use machines

Patients should be warned of the risk of transient drowsiness, especially in cases of polytherapy or association with benzodiazepines (see section 4.5).

4.8 Undesirable effects

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 estimatedfrom 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 Depakote in the treatment of manic episodes have been identified.

Congenital malformations and developmental disorders: (see sections 4.4 and 4.6).

Hepatobiliary disorders:

Common: liver injury (see section 4.4.1)

Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment and may be transient (see section 4.4.1).

Gastrointestinal disorders:

Very common: nausea

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

The above adverse events 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 Depakote with or after food.

Uncommon: pancreatitis, sometimes lethal (see section 4.4)

Nervous system disorders:

Very common: tremor

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

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

Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder

Sedation has been reported occasionally. In monotherapy it occurred early in treatment on rare occasions and is usually transient.

Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have 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 anti-convulsants, 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.

Psychiatric disorders:

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

Rare: abnormal behaviour, psychomotor hyperactivity, learning disorder

Metabolism and nutrition disorders:

Common: hyponatraemia, weight increased

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

Rare: hyperammonaemia (see section 4.4.2), obesity

*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, but they 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 (see section 4.4.2). In such cases further investigations should be considered.

Endocrine disorders:

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

Rare: hypothyroidism (see section 4.6)

Blood and lymphatic system disorders:

Common: anaemia, thrombocytopenia (see section 4.4.2)

Uncommon: pancytopenia, leucopenia

Rare: bone marrow failure, including red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis

The blood picture 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 (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 4.6).

Skin and subcutaneous tissue disorders:

Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.

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

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

Reproductive system and breast disorders:

Common: dysmenorrhea

Uncommon: amenorrhea

Rare: polycystic ovaries, male infertility (see section 4.6)

Very rarely gynaecomastia has occurred.

Vascular disorders:

Common: haemorrhage (see sections 4.4.2 and 4.6)

Uncommon: vasculitis

Eye disorders:

Rare: diplopia

Ear and labyrinth disorders:

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

Renal and urinary disorders:

Common: urinary incontinence

Uncommon: renal failure

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

General disorders and administration site conditions:

Uncommon: hypothermia, non-severe peripheral oedema

Musculoskeletal and connective tissue disorders:

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

Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2)

Respiratory, thoracic and mediastinal disorders:

Uncommon: pleural effusion

Investigations:

Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see sections 4.4 and 4.6)

Neoplasms benign, malignant and unspecified (including cysts and polyps): Rare: myelodysplastic syndrome

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

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 functions and metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual. However, some deaths have occurred following massive overdose.

Symptoms may however be variable, and seizures have been reported in the presence of very high plasma levels in patients with epilepsy. Cases of intracranial hypertension related to cerebral oedema have been reported.

The presence of sodium content in the Depakote 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 – 12 hours following ingestion.

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

Pharmacotherapeutic group: Psycholeptics, Antipsychotics, Other Antipsychotics, ATC code: N05AX.

Mechanism of action

Depakote exerts its effects mainly on the central nervous system.

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

Clinical efficacy

The effectiveness of Depakote in acute mania was demonstrated in two, 3 week, double-blind, placebo-controlled trials conducted in bipolar patients. Depakote was initiated at a dose of 250 mg tid and subsequently titrated up to a maximum daily dose not exceeding 2500 mg; the concomitant use of a benzodiazepine was allowed during the first 10 days of treatment to manage associated symptoms such as severe agitation.

Pharmacological studies have demonstrated activity in experimental models of animal behaviour in mania.

5.2 Pharmacokinetic properties

Following oral administration of Depakote, the absolute bioavailability of valproic acid approaches 100%. Mean terminal half-life is about 14 hours, steady state conditions usually being achieved within 3 – 4 days. Peak plasma concentrations are achieved within 3 – 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.

Distribution

Plasma protein binding of Depakote ranges from 85 – 94% over plasma drug concentrations of 40 – 100 ^g/ml. It is concentration-dependent, and the free fraction increases non-linearly with plasma drug concentration.

Placental transfer (see section 4.6)

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

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

In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentrations in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.

Metabolism

Depakote is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from ^-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 – 0.6L/h and is independent of hepatic blood flow.

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

Interaction with oestrogen-containing products

Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.

Special populations

In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response.

Haemodialysis reduces serum valproic acid concentrations by about 20%.

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 patients with epilepsy exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in patients with epilepsy treated with valproate with those in untreated patients with epilepsy. 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Silicone dioxide

Starch pre-gelatinised

Povidone

Titanium dioxide (E171)

Hypromellose

Polyethylene glycol 6000

Methacrylic acid- ethyl acrylate copolymer (1:1)

Triethyl citrate

Ponceau 4R aluminium lake (E124)

Indigotine aluminium lake (E132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

None.

6.5 Nature and contents of container

Aluminium/aluminium blister packs containing 30, 60 or 90 tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited

410 Thames Valley Park Drive

Reading

Berkshire

RG6 1PT

Trading as:

Sanofi