In the treatment of generalised, partial or other epilepsy.

Depakine Syrup is for oral administration.

Daily dosage requirements vary according to age and body weight. Depakine Syrup may be given twice daily. If it is necessary to dilute Depakine Syrup, the recommended diluent is Syrup BP, but syrup containing SO₂ as a preservative should not be used. The diluted product will have a 14 day shelf life.

In patients where adequate control has been achieved Depakine Chrono formulations are interchangeable with other Depakine conventional or prolonged release formulations on an equivalent daily dosage basis.

Dosage

Usual requirements are as follows:

Adults

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

Children over 20 kg

Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 – 30 mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight per day.

Children under 20 kg

20 mg/kg of body weight per day; in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Use in the elderly

Although the pharmacokinetics of Depakine are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

In patients with renal insufficiency

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2).

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with Depakine 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 Depakine, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1).

Female children and women of childbearing potential

Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.3, 4.4 and 4.6).

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

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

Combined Therapy

When starting Depakine in patients already on other anti-convulsants, these should be tapered slowly: initiation of Depakine therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 – 10 mg/kg/day when used in combination with anti-convulsants 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 Depakine. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

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

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

Depakine is contraindicated in the following situations: • Pregnancy unless there is no suitable alternative treatment (see section 4.4 and 4.6). • Women of child-bearing potential, unless the conditions of the Pregnancy Prevention Program are fulfilled (see section 4.4 and 4.6). • History of hypersensitivity to valproate, valproate semisodium, valpromide or to any of the excipients listed in section 6.1. • Acute hepatitis. • Chronic hepatitis. • Patient or family history of severe hepatitis, especially drug-related. • Hepatic porphyria. • Patients with known urea cycle disorders (see section 4.4). • Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase gamma (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). • Combination with St John’s Wort (see section 4.5)

1.1.    Special warnings

Pregnancy Prevention Program

 

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6). Valproate should not be used in female children and women of child-bearing potential unless other treatments are ineffective or not tolerated. If no other treatment is possible, the Pregnancy Prevention Program below must be complied with.

 

Depakine is contraindicated in the following situations:

 

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

 

•        In women of child-bearing potential, unless the conditions of the Pregnancy Prevention Program are fulfilled (see sections 4.3 and 4.6).

 

Conditions of Pregnancy Prevention Program

 

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 minimize the risks.

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

•        the patient has received the patient guide.

 

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

 

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

 

Female children

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

 

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

 

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

 

Pregnancy test

 

Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of child-bearing potential without a negative result from a plasma pregnancy test with a sensitivity of at least 25 mIU/ml, confirmed by a healthcare provider, to rule out unintended use in pregnancy. This pregnancy test must be repeated at regular intervals during treatment.

 

Contraception

 

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

 

Annual treatment reviews by a specialist

 

The specialist should at least annually review whether valproate is the most suitable treatment for the patient. The specialist should discuss the Annual Risk Acknowledgement Form, at initiation and during each annual review and ensure that the patient has understood its content. The Risk Acknowledgement Form must be duly completed and signed by the prescriber and patient (or her legal representative).

 

Pregnancy planning

 

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

 

In case of pregnancy

 

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

 

Pharmacist must ensure that

 

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

 

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

 

Educational materials

 

In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorization Holder has provided educational materials to reinforce the warnings concerning the teratogenicity (congenital malformations) and fetotoxicity (neurodevelopmental disorders) of valproate and provide guidance regarding use of valproate in women of child-bearing potential and the details of the Pregnancy Prevention Program. A patient guide and patient card should be provided to all women of child-bearing potential using valproate.

 

An Annual Risk Acknowledgement Form needs to be used and duly completed and signed at the time of treatment initiation and during each annual review of valproate treatment by the specialist and the patient (or her legal representative).

 

Exacerbation of seizures

 

As with other antiepileptics, administration of valproate may, instead of improvement, lead to a reversible exacerbation of seizure frequency and severity (including status epilepticus), or the onset of a new type of seizure. Patients should be advised to consult their physician immediately if exacerbation of seizures occurs (see section 4.8). These seizures should be differentiated from those that may occur due to a pharmacokinetic interaction (see section 4.5), toxicity (liver disease or encephalopathy - see sections 4.4 and 4.8) or overdose.

 

Since this medicinal product is metabolized into valproic acid, it should not be combined with other medicinal products undergoing the same transformation to avoid an overdose of valproic acid (e.g. valproate semisodium, valpromide).

 

Liver disease

 

Conditions of onset

 

Exceptional cases of liver damage with a severe or sometimes fatal outcome have been reported. Infants and young children under the age of 3 with severe epilepsy and, in particular, epilepsy associated with brain damage, mental retardation and/or a genetic metabolic or degenerative disease are the most at risk. Over the age of 3, the incidence of onset is significantly reduced and gradually decreases with age.

 

In the great majority of cases, such liver damage has been observed within the first 6 months of treatment, usually between the 2nd and 12th week and generally during antiepileptic polytherapy.

 

Warning signs

 

Early diagnosis is based above all on clinical findings. It is particularly important to take into consideration, and especially in high-risk patients (see Conditions of onset), two types of manifestations which may precede jaundice:

•        firstly,  non-specific  systemic  signs,  generally  of  sudden  onset,  such  as  asthenia,  anorexia, exhaustion, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain,

•        secondly, a recurrence of epileptic seizures despite proper treatment compliance.

 

Patients, or their families if the patient is a child, should be advised to consult their physician immediately if these symptoms occur. In addition to a physical examination, liver function tests should immediately be performed.

 

Detection

 

During the first 6 months of treatment, liver function should be monitored periodically.

 

The most pertinent of the conventional tests are those reflecting protein synthesis and, in particular, PT (prothrombin time). Confirmation of abnormally  low PT values, especially if there are also other abnormal laboratory findings (significant reduction in fibrinogen and coagulation factors, elevated bilirubin, elevated transaminase levels - see section 4.4), should lead to discontinuation of treatment (and, as a precaution, discontinuation of salicylate derivatives if they are concomitantly prescribed, since they use the same metabolic pathway).

 

Pancreatitis

 

Pancreatitis with a sometimes fatal outcome has very rarely been reported. This can be observed irrespective of age and treatment duration, with young children appearing to be particularly at risk.

 

Pancreatitis with an unfavorable outcome is generally observed in young children or in patients with severe epilepsy, brain damage or those taking antiepileptic polytherapy.

 

If pancreatitis occurs along with liver failure, the risk of fatal outcome is increased.

 

In the event of acute  abdominal  pain or gastrointestinal  signs such  as nausea, vomiting and/or anorexia, a diagnosis of pancreatitis must be considered and, in patients with elevated pancreatic enzymes, treatment discontinued, and the necessary alternative therapeutic measures implemented.

 

Risk of suicide

 

Suicidal ideation and behavior have been reported in patients treated with antiepileptics in several indications. A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs has also shown a slight increase in risk of suicidal ideation and behavior. The causes of this risk are unknown and the available data do not make it possible to rule out an increased risk with valproate.

 

Consequently, patients must be closely monitored for any signs of suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and their care providers) should be advised to seek medical advice if there are signs of suicidal ideation or behavior.

 

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 gene encoding the mitochondrial enzyme polymerase gamma (POLG).

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 POLG gene, 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).

 

Interaction with other medicinal products

 

Coadministration of this medicinal product with lamotrigine and penems is not recommended (see section 4.5).

 

As this medicine contains sucrose and sorbitol, it is not recommended in patients with fructose intolerance, glucose and galactose malabsorption syndrome or sucrase-isomaltase deficiency (rare hereditary diseases).

 

This medicinal product contains 13.88 mg of sodium per 100 mg of sodium valproate. This must be taken into account in patients following a strict low-sodium diet.

 

This medicinal product contains parahydroxybenzoate and can cause allergic reactions (possibly delayed).

 

Cognitive or extrapyramidal disorders

 

Cognitive or extrapyramidal disorders can be associated with imaging findings of cerebral atrophy. This type of clinical picture can thus be confused with dementia or Parkinson’s disease. These disorders are reversible on treatment discontinuation (see section 4.8).

 

Precautions for use

 

Liver function tests should be performed before starting treatment (see section 4.3) and then periodically for the first 6 months, particularly in patients at risk (see section 4.4).

 

It should be emphasized that, as with most antiepileptics, an isolated and transient, moderate elevation in transaminase levels may be observed, without any clinical signs, particularly at the start of treatment.

 

Should this occur, it is recommended that a more complete laboratory workup be performed (in particular, prothrombin time), that the dosage be re-evaluated if necessary, and that the tests be repeated based on changes in the parameters.

 

In children under the age of 3, it is recommended that valproate only be used as single-agent treatment, after having weighed the therapeutic value against the risk of liver disease and pancreatitis in patients in this age group (see section 4.4).

 

Blood tests (complete blood count including platelets, bleeding time and coagulation parameters) are recommended prior to treatment, then after 15 days and at the end of treatment, and also before any surgery, and in the event of hematomas or spontaneous bleeding (see section 4.8).

 

In children, the simultaneous prescription of salicylate derivatives should be avoided, due to the risk of hepatotoxicity (see section 4.4) and the risk of bleeding.

 

In patients with kidney failure, elevated circulating valproic acid concentrations in the blood should be taken into account and the dose reduced accordingly.

 

This medicinal product is contraindicated in patients with urea cycle enzyme deficiencies. A few cases of hyperammonemia with stupor or coma have been described in these patients (see section 4.3).

 

In children with a history of unexplained hepatic and gastrointestinal disorders (anorexia, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, mental retardation or with a family history of neonatal or infant death, metabolic tests and, in particular, fasting and post-prandial blood ammonia tests must be performed prior to any valproate treatment.

 

Although it is recognized that this medicinal product only causes immunological disturbances in exceptional cases, the benefit/risk ratio should be weighed in patients with systemic lupus erythematosus.

 

When initiating treatment, the patient should be informed of the risk of weight gain and of the appropriate measures which are mainly dietary to be taken to minimize this effect.

 

As valproate is excreted primarily in the urine, partly in the form of ketone bodies, tests for ketonuria may yield false positive results in patients with diabetes.

 

Patients with carnitine palmitoyltransferase type II (CPT-II) deficiency must be warned of the increased risk of rhabdomyolysis associated with valproate use.

 

Use of alcohol is not recommended throughout treatment with Depakine.

1.1.    Contraindicated combinations

 

+ St. John's Wort

 

Risk of reduced plasma concentrations and decreased efficacy of the anticonvulsant.

 

Inadvisable combinations

 

+ Lamotrigine

 

Higher risk of serious skin reactions (toxic epidermal necrolysis).

 

Furthermore,  an  increase  in  lamotrigine  plasma  concentrations  may occur  (decreased  hepatic metabolism by sodium valproate).

 

If coadministration proves necessary, close clinical monitoring is required.

 

+ Penems

Risk of seizures due to a rapid decrease in valproic acid plasma concentrations, which may become undetectable.

 

Combinations requiring precautions for use

 

+ Acetazolamide

 

Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters.

+ Aztreonam

 

Risk of seizures due to a decrease in valproic acid plasma concentrations.

 

Clinical monitoring, plasma assays and possible dose adjustment of the anticonvulsant during treatment with the anti-infective agent and after its discontinuation.

 

+ Carbamazepine

 

Increased plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, reduced valproic acid plasma concentrations due to its increased hepatic metabolism by carbamazepine.

 

Clinical monitoring, plasma assays and dose adjustment of both anticonvulsants.

 

+ Felbamate

 

Increased serum valproic acid concentrations with a risk of overdose.

 

Clinical  monitoring  and  monitoring  of  laboratory  parameters  and  possible  valproate  dose adjustment during treatment with felbamate and after its discontinuation.

 

+ Nimodipine (oral route and, by extrapolation, by injection)

Risk of a 50% increase in plasma nimodipine concentrations. Therefore, nimodipine dose reduction is necessary in hypotensive patients.

 

+ Phenobarbital, and by extrapolation primidone

 

Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters.

+ Phenytoin, and by extrapolation fosphenytoin

 

Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters.

+ Propofol

 

Possible increase in propofol blood levels. When coadministered with valproate, a reduction in propofol dose should be considered.

 

+ Rifampicin

 

Risk of seizures due to increased hepatic metabolism of valproate by rifampicin.

 

Clinical  monitoring  and  monitoring  of  laboratory  parameters  and  possible  anticonvulsant  dose adjustment during treatment with rifampicin and after its discontinuation.

 

+ Rufinamide

 

Possible increase in rufinamide concentrations, in particular in children weighing less than 30 kg. In children weighing less than 30 kg: the total dose of 600 mg/day after dose titration should not be exceeded.

 

+ Topiramate

 

Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters.

+ Zidovudine

 

Risk of increased adverse effects of zidovudine, particularly hematological effects, due to decrease in its metabolism by valproic acid.

 

Regular monitoring of clinical and laboratory parameters. A blood count should be performed to test for anemia during the first two months of the combination.

 

+ Zonisamide

 

Increased hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters.

Other forms of interaction

 

+ Oral contraceptives

 

As valproate has no enzyme-inducing activity, it does not reduce the efficacy of estrogen-progestogen hormonal contraception in women.

 

+ Lithium

 

Depakine has no effect on blood lithium levels.

 

Valproate is contraindicated (see sections 4.3 and 4.4):

•        during pregnancy unless there is no suitable alternative to treat epilepsy.

•        in women of child-bearing potential unless the conditions of the Pregnancy Prevention Program are fulfilled.

 

Pregnancy

 

Teratogenicity and neurodevelopmental effects

 

Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.

 

•        Congenital malformations

 

Data derived from a meta-analysis (including registries and cohort studies) have shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16 -13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose-dependent but a threshold dose below which no risk exists cannot be established.

 

Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects (approximately 2 to 3%), facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects (in particular, hypospadias), limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.

 

•        Neurodevelopmental disorders

 

Studies have shown that exposure to valproate in utero increases the risk of neurodevelopmental disorders in exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The period of risk could involve the entire pregnancy.

 

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

 

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

 

There are limited data on the long term outcomes.

 

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

 

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

 

Women of child-bearing potential

Depakine should not be used in women of child-bearing potential unless other treatments are ineffective or not tolerated. If no other treatment is possible, Depakine can only be initiated if the Pregnancy Prevention Program is complied with (see section 4.4), in particular:

 

•        the patient is not pregnant (plasma pregnancy test with a sensitivity of at least 25 mIU/ml negative at the start of treatment and at regular intervals during treatment).

 

•        the patient is using at least one effective method of contraception.

 

•        and the patient is informed of the risks associated with using valproate during pregnancy.

 

In women of child-bearing potential, the benefit-risk balance must be carefully reevaluated at regular intervals during treatment (at least annually).

 

If a woman plans a pregnancy

 

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

 

Folate supplementation before pregnancy and at the beginning of 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.

 

Pregnant women

 

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

 

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.

 

During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.

 

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

 

•        the lowest effective dose must be used

 

•        the daily dose of valproate should be divided into several small doses to be taken throughout the day.

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

 

All patients with a valproate-exposed pregnancy and their partners should be referred to a specialist experienced in teratology 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.

 

Before delivery

 

Coagulation tests should be performed in the mother before delivery, including in particular a platelet count, fibrinogen levels and coagulation time (activated partial thromboplastin time: aPTT).

 

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 vitamin K factor deficiency induced by phenobarbital and enzymatic inducers. Normal hemostasis test results in the mother do not make it possible to rule out hemostasis abnormalities in the neonate. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should  be investigated in neonates at birth.

 

•        Cases of hypoglycemia 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 (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.

 

Post-natal monitoring/monitoring of children

 

Close monitoring of the neurodevelopmental behavior must be implemented in children exposed to valproate during pregnancy and suitable treatment initiated as early as possible if necessary.

 

Breast-feeding

 

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

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depakine therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

 

Fertility

 

Amenorrhea, 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 (in particular, decreased sperm motility) (see section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

The attention of patients, particularly those who drive or use machines, must be drawn to the risk of drowsiness, especially in patients receiving anticonvulsant polytherapy or concomitant administration with other medicinal products that may increase drowsiness.

Classification of expected frequencies:

 

Very common (≥ 10%); Common (≥ 1% - < 10%); Uncommon (≥ 0.1% - < 1%); Rare (≥ 0.01% -

< 0.1%); Very rare (< 0.01%); Not known (cannot be estimated from the available data).

 

Congenital, familial and genetic disorders

 

•        Congenital malformations and neurodevelopmental disorders (see sections 4.4 and 4.6).

 

Blood and lymphatic system disorders

 

•        Common: anemia; thrombocytopenia.

•        Cases    of   dose-dependent   thrombocytopenia   have    been    reported,    generally    discovered systematically and without any clinical repercussions.

•        In patients with asymptomatic thrombocytopenia, if possible, given the platelet level and control of the disease, simply reducing the dose of this medicinal product usually leads to resolution of thrombocytopenia.

•        Uncommon: leukopenia, pancytopenia.

•        Rare:  bone  marrow  aplasia  or  pure  red  cell  aplasia,  agranulocytosis,  macrocytic  anemia, macrocytosis.

 

Investigations

 

•        Common: weight gain*,

•        Rare: decrease in at least one coagulation  factor,  abnormal  coagulation  test  results  (such  as increased prothrombin time, increased activated partial thromboplastin time, increased thrombin time, increased INR) (see sections 4.4 and 4.6), vitamin B8 (biotin) deficiency/biotinidase deficiency.

*as weight gain is a risk factor for polycystic ovary syndrome, patient weight must be carefully monitored (see section 4.4).

 

Nervous system disorders

•        Very common: tremor.

•        Common: extrapyramidal disorders**, stupor*, sedation, seizures,* memory disorders, headache, nystagmus, nausea or dizziness.

•        Uncommon:  coma*,  encephalopathy*,  lethargy*,  reversible  Parkinsonian  syndrome**,  ataxia, paresthesia.

•        Rare: cognitive disturbances of insidious and progressive onset (which may progress as far as complete dementia) and which are reversible a few weeks to a few months following treatment withdrawal**.

 

*Cases of stupor or lethargy, sometimes leading to transient coma (encephalopathy) have been observed with valproate, regressing on treatment discontinuation or dose reduction. These states most often occur during polytherapy (particularly with phenobarbital or topiramate) or following a sudden increase in valproate doses.

 

**These symptoms can be associated with imaging findings of cerebral atrophy.

 

Ear and labyrinth disorders

•        Common: hearing loss.

 

Respiratory, thoracic and mediastinal disorders

 

•        Uncommon: pleural effusion.

 

Gastrointestinal disorders

 

•        Very common: nausea.

•        Common: vomiting, gingival disorders (mainly  gingival  hyperplasia),  stomatitis,  epigastric  pain, diarrhea that may occur in some patients at the beginning of treatment, but that generally resolves after a few days without treatment discontinuation.

•        Uncommon: pancreatitis with possibly fatal outcome requiring early treatment discontinuation (see section 4.4).

 

Renal and urinary disorders

 

•        Uncommon: renal failure.

•        Rare: enuresis, urinary incontinence, tubulointerstitial nephritis.

 

Skin and subcutaneous tissue disorders

 

•        Common: transient and/or dose-dependent hair loss; nail and nail bed disorders.

•        Uncommon: angioedema, skin reactions, hair disorders (such as abnormal hair texture, change in hair color, abnormal hair growth).

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

 

Endocrine disorders

 

•        Uncommon: inappropriate antidiuretic hormone secretion syndrome (IADHS), hyperandrogenism (hirsutism, virilism, acne, androgenic alopecia and/or increase in androgen hormone levels).

•        Rare: hypothyroidism (see section 4.6).

 

Metabolism and nutrition disorders

 

•        Common: hyponatremia.

•        Rare: hyperammonemia* (see section 4.4), obesity.

 

*Isolated and moderate hyperammonemia with no changes in liver parameters can be observed, especially during polytherapy, and does not warrant treatment discontinuation.

However, cases of hyperammonemia with neurological symptoms (which may progress to coma) have also been reported, and require additional tests (see section 4.4).

 

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

 

•        Rare: myelodysplastic syndromes.

 

Vascular disorders

 

•        Common: bleeding (see sections 4.4 and 4.8).

 

General disorders and administration site conditions

 

•        Uncommon: hypothermia, non-severe peripheral edema.

 

Hepatobiliary disorders

 

•        Common: liver disease (see section 4.4).

 

Reproductive system and breast disorders

 

•        Common: menstrual irregularities.

•        Uncommon: amenorrhea.

•        Rare:  impact  on  spermatogenesis  (in  particular,  decreased  sperm  motility)  (see  section  4.6), polycystic ovaries.

 

Musculoskeletal and connective tissue disorders

•        Uncommon: decreased bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long-term treatment with  Depakine. The mechanism of action of Depakine on bone metabolism is not known.

•        Rare: acute systemic lupus erythematosus (see section 4.4), rhabdomyolysis (see section 4.4).

* These effects are mainly observed in children.

 

Psychiatric disorders

 

•        Common: confused state, hallucinations, aggressiveness,* agitation,* attention deficit disorders.*

•        Rare: behavioral disturbances,* psychomotor hyperactivity,* learning disabilities.*

*These effects are mainly observed in children.

 

To report any side effect(s):

• Saudi Arabia:

 

-          The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2340. o SFDA call center : 19999 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

·         Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

The clinical signs of massive acute poisoning usually include a calm coma, which may be more or less deep, with muscle hypotonia, hyporeflexia, miosis, reduced respiratory autonomy and metabolic acidosis, hypotension and collapsus/cardiovascular shock.

 

A few cases of intracranial hypertension related to cerebral edema have been described.

 

Patient management in a hospital setting includes: gastric lavage if indicated, maintenance of effective diuresis, cardiorespiratory monitoring. In very serious cases, extra-renal purification may be performed if necessary.

 

The prognosis for such poisoning is generally favorable. However, a few deaths have been reported.

 

In  the  event  of  overdose,  the  sodium  content  in  formulations  containing  valproate  can  lead  to hypernatremia.

 

Pharmacotherapeutic group: ANTIEPILEPTICS, ATC code: N03AG01.

 

Valproate is pharmacologically active primarily on the central nervous system.

 

The drug has an anticonvulsant effect on a very wide range of seizures in animals and epilepsy in humans.

 

Experimental and clinical studies on valproate suggest two types of anticonvulsant effect.

 

The first is a direct pharmacological effect related to valproate concentrations in the plasma and the brain.

The second appears to be indirect and is probably related to the metabolites of valproate, which remain in the brain, or to changes in neurotransmitters or direct membrane effects. The most widely accepted hypothesis is that of gamma-aminobutyric acid (GABA) levels, which increase following valproate administration.

 

Valproate reduces the duration of intermediate stages of sleep, with a concomitant increase in slow sleep.

The various pharmacokinetic studies conducted on valproate have shown that: The bioavailability in the blood following oral administration is close to 100%.

The volume of distribution is mainly limited to the blood and to the rapid-exchange extracellular fluids. Valproate circulates in the CSF and in the brain.

The half-life is 15 to 17 hours.

Therapeutic efficacy usually requires a minimum serum concentration of 40 to 50 mg/l, with a wide range from 40 to 100 mg/l. If higher plasma levels prove necessary, the expected benefits must be weighed against the risk of occurrence of adverse effects, particularly dose-dependent effects. However, levels remaining above 150 mg/l require a dose reduction.

The steady-state plasma concentration is reached in 3 to 4 days.

Valproate is highly protein-bound. Protein binding is dose-dependent and saturable.

Valproate is excreted mainly in the urine, following metabolization by glucuronide conjugation and beta- oxidation.

Valproate  can  be  dialyzed,  but  hemodialysis  only  affects  the  free  fraction  of  blood  valproate (approximately 10%).

 

Valproate does not induce enzymes involved in the metabolic system of cytochrome P 450 in contrast with most other antiepileptics. It therefore does not accelerate its own degradation or that of other substances, such as estrogen-progestogens and oral anticoagulants.

Not applicable.

Methyl  parahydroxybenzoate,  propyl  parahydroxybenzoate,  sucrose,  70%  sorbitol  solution,  glycerol, artificial cherry flavor, concentrated hydrochloric acid, sodium hydroxide, purified water.

 

Composition of the artificial cherry flavor: benzaldehyde, isoamyl alcohol, isoamyl butyrate, isoamyl acetate, cinnamic aldehyde, isoamyl propionate, ethyl butyrate, partially deterpenated essential oil of orange.

Not applicable.

• Before opening: 2 years. • After opening: 1 month.

Before opening: Do not store above 25°C. After opening: Do not store above 25°C.

150 ml (amber glass) bottles with (LDPE/polystyrene) oral syringe and (LDPE) adaptor.

150 ml (amber PVC) bottles with (LDPE/polystyrene) oral syringe and (LDPE) adaptor.

To open the bottle, press down and turn the child-proof safety cap. The bottle must be closed after each use.