Temporary treatment of epilepsies in adults and children, replacing the oral form when the latter is temporarily unusable.

Female children and women of childbearing potential
Valproate treatment should be initiated and monitored by a specialist physician experienced in the management of epilepsy.
Valproate should not be used in female children and women of childbearing potential, except in cases of ineffectiveness or intolerance to other treatments. In this case, valproate should be prescribed and dispensed in accordance with the valproate pregnancy prevention programme (see sections 4.3 and 4.4).
In a simple relay situation (for example in anticipation of a surgical intervention): between 4 and 6 hours after the last oral intake, intravenous administration of sodium valproate in an 0.9% sodium chloride solution for injection:
•either as a continuous infusion over 24 hours,
•or in a divided manner in 4 infusions of one hour per day, at the previous dosage (usual average dosage of 20 to 30 mg/kg/day).
In a situation that requires rapidly achieving and maintaining an effective plasma concentration: intravenous injection over 5 minutes of a bolus of 15 mg/kg; then carry out a relay with a continuous infusion, with a flow rate of 1 mg/kg/hour to be gradually adapted to reach a blood level of valproic acid around 75 mg/l. Then adjust the flow according to the evolution of the clinical situation.
As soon as the infusion is stopped, the resumption of treatment with the oral form will ensure immediate compensation for the quantities eliminated. It will be done either at the previous dosage or after dosage adjustment.
Appearance of the product after reconstitution: clear to slightly opalescent liquid.
Patients with kidney failure
In patients with kidney failure, it may be necessary to decrease the dosage, and in patients undergoing haemodialysis, it may be necessary to increase it. Sodium valproate is dialysable (see section 4.9). The dosage should be modified according to the patient’s clinical monitoring (see section 4.4).

•Pregnant women, unless there is no suitable therapeutic alternative (see sections 4.4 and 4.6). • of childbearing potential, unless all conditions of the pregnancy prevention programme are met (see sections 4.4 and 4.6). •History of hypersensitivity to valproate, divalproate, valpromide or to any of the ingredients of the medicinal product. •Acute hepatitis. •Chronic hepatitis. •Personal or family history of severe hepatitis, in particular medicine-induced. •Hepatic porphyria. •Patient with known urea cycle disorders (see section 4.4). •Patient with primary, uncorrected, systemic carnitine deficiency (see section 4.4 “Patients at risk of hypocarnitinaemia”). •Valproate is contraindicated in patients with known 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 the age of two years suspected of having a POLG-related disorder (see section 4.4). •Combination with St. John’s Wort (see section 4.5).

Special warnings
Pregnancy prevention programme
Valproate is a potent teratogen resulting in a high risk of congenital malformations and neurodevelopmental disorders in children exposed in utero to valproate (see section 4.6). Valproate should not be used in female children and women of childbearing potential, except in cases of ineffectiveness or intolerance to other treatments. If no other treatment is possible, follow the pregnancy prevention programme below.
DEPAKINE is contraindicated in the following cases:
•In pregnant women, unless there is no suitable therapeutic alternative (see sections 4.3 and 4.6).
•In women of childbearing potential, unless all conditions of the pregnancy prevention programme are met (see sections 4.3 and 4.6).
Conditions of the pregnancy prevention programme
The prescriber must ensure that:
•individual situations are assessed on a case-by-case basis, involving the patient in the discussion, in order to secure her commitment, to discuss treatment options, and to ensure that the patient has understood the risks and the steps needed to reduce those risks;
•the risk of pregnancy is assessed in all female patients;
•the patient fully understands and is aware of the risks of birth defects and neurodevelopmental disorders, including the magnitude of these risks for children exposed in utero to valproate;
•the patient understands the need to perform a pregnancy test before starting treatment and during treatment, as needed;
•the patient has been counselled on contraception, and is able to comply with the need to use effective contraception (for details, see the “Contraception” subsection of this box), without
interruption, throughout the duration of treatment with valproate;
•the patient understands the need for a specialist physician experienced in the management of epilepsy to regularly (at least annually) review the treatment;
•the patient understands the need to consult her doctor as soon as she considers pregnancy in order to discuss it in due time, and to seek alternative treatment options before conception. This should be done before stopping contraception;
•the patient understands the need to urgently consult her physician in the event of pregnancy;
•the patient has received the patient information leaflet;
•the patient acknowledged having understood the risks and necessary precautions associated with the use of valproate (annual care agreement form).
These conditions also concern women who are not sexually active, unless the prescriber considers that there are indisputable reasons indicating that there is no risk of pregnancy.
Female children
•Prescribers should ensure that parents/caregivers of a female child understand the need to contact the specialist physician as soon as the female child using valproate has her first period.
•The prescriber should ensure that parents/carers of a female child having her first period receive full information on the risks of congenital malformations and neurodevelopmental disorders, including the extent of these risks for children exposed to valproate in utero.
•For patients who have had their first period, the prescribing specialist physician should reassess the need for treatment with valproate annually, and consider all alternative treatment options. If valproate is the only appropriate treatment, the need to use effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist physician to switch to alternative treatment in female children. This should be done before puberty or adulthood.
Pregnancy test
Pregnancy must be excluded before initiating treatment with valproate. Valproate treatment should not be initiated in women of childbearing potential without obtaining a negative pregnancy test (plasma pregnancy test with a sensitivity of at least 25 mIU/ml), confirmed by a healthcare professional, in order to eliminate any possibility of unintended use of the product during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.
Contraception
Women of childbearing potential who receive valproate have to use effective contraception continuously and throughout the duration of valproate treatment. These patients should receive comprehensive information on pregnancy prevention, as well as contraceptive counselling if they are not using effective contraception. At least one effective method of contraception (preferably a method whose effectiveness does not depend on the user, such as an intra-uterine contraceptive device or an implant), or two complementary methods of contraception including a barrier method, must be used. When choosing the method of contraception, individual situations should be considered on a case-by-case basis, involving the patient in the discussion to ensure her commitment and compliance with the chosen measures. All advice on effective contraception should be followed, even in the case of amenorrhoea.
Medicinal products containing oestrogen
Concomitant use with medicinal products containing oestrogen, including hormonal contraceptives containing oestrogen, may potentially lead to a decrease in the efficacy of valproate (see section 4.5). Prescribers should monitor the clinical response (epilepsy control) to initiation or discontinuation of medicinal products containing oestrogen.
Conversely, valproate does not reduce the effectiveness of hormonal contraceptives.
Annual evaluation of the treatment by a specialist physician
The specialist physician should reassess, at least annually, the valproate treatment to check whether it is still the most appropriate treatment for the patient. The specialist physician should discuss the annual care agreement form when the treatment is initiated and at each annual assessment and should ensure that the patient has understood its content. The care agreement form must be duly completed and signed by the prescriber and the patient (or the patient’s legal representative).
Pregnancy planning
In women planning a pregnancy, a specialist physician experienced in the management of epilepsy should reassess treatment with valproate, and consider all alternative treatment options. Every effort should be made to switch to an appropriate alternative treatment prior to conception and before contraception is stopped (see section 4.6). If a therapy change is not possible, the patient should receive additional advice regarding the risks that valproate presents for the unborn child, in order to help her make an informed decision regarding her family planning.
In case of pregnancy
If a woman using valproate becomes pregnant, she should be referred immediately to a specialist physician to reassess valproate treatment, and to consider alternative options. Patients whose pregnancies have been exposed to valproate, as well as their partners, should be referred to a physician specialised or experienced in teratology for evaluation and advice (see section 4.6).
The pharmacist should ensure that:
•the patient card is given with each dispensation of valproate, and that patients understand its content;
•patients are advised not to stop valproate treatment on their own, and to contact a specialist physician immediately if they are planning or suspect pregnancy.
Information leaflets
To help healthcare professionals and patients avoid foetal exposure to valproate, the marketing authorisation holder should provide them with information leaflets to reinforce the teratogenicity (congenital malformations) and foetotoxicity (neurodevelopmental disorders) warnings for valproate and to provide recommendations to women of childbearing potential regarding the use of valproate, as well as details on the pregnancy prevention programme. A patient card and patient information leaflet should be provided to all patients using valproate.
An annual care consent form must be used and duly completed and signed at the time of treatment initiation and during each annual reassessment of valproate treatment by the specialist physician and the patient (or her legal representative).
Use in men of childbearing age
Data from a retrospective study conducted on Scandinavian registries suggest an increase in the risk of neurodevelopmental disorders in children whose fathers were treated with valproate in the 3 months prior to conception, compared to those whose fathers were treated with lamotrigine or levetiracetam. The limitations of this study do not allow conclusions to be drawn about this potential risk at this stage, and additional data are necessary.
As a precautionary measure, the prescriber should inform patients able to father children of this potential risk. The prescriber must discuss the following with them:
•the need to implement effective contraceptive measures during treatment and for at least three months after treatment discontinuation,
•the possibility of therapeutic alternatives for patients planning to conceive a child,
•not to donate sperm during treatment with valproate, and for at least three months after discontinuing it (see section 4.6).
The risk of neurodevelopmental disorders for children conceived by men stopping valproate more than three months before conception is not known.
Worsening of seizures
As with other antiepileptic medicinal products, valproate may be followed, instead of improvement, by reversible worsening of seizure frequency and severity (including status epilepticus) or the development of new seizure types in the patient. In case seizures worsen, the patient should be advised to consult their physician immediately (see section 4.8).
These seizures can be distinguished from those that may occur during a pharmacokinetic interaction (see section 4.5), toxicity (hepatopathy or encephalopathy – see sections 4.4 and 4.8) or overdose.
As this medicinal product transforms into valproic acid in the body, it should not be combined with other medicinal products undergoing this same transformation in order to avoid a valproic acid overdose (for example: divalproate, valpromide).
Risk of local tissue necrosis
Intravenous administration should be strictly carried out. Do not inject intramuscularly.
Severe liver damage
Conditions of occurrence
Liver damage, which is severe and sometimes fatal, has been reported exceptionally.
Infants and young children under 3 years of age with severe epilepsy, including epilepsy associated with brain damage, mental retardation and (or) Carnitine deficiency a congenital metabolic disease, including mitochondrial disorders, such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections 4.3 and 4.4) or a degenerative disease of genetic origin, are most at risk. Beyond the age of 3 years, the incidence of occurrence decreases significantly and gradually decreases with age.
In the vast majority of cases, hepatic damage was observed during the first 6 months of treatment, most often between the 2nd and 12th week and generally during antiepileptic combination therapy.
Suggestive signs
Early diagnosis is still mainly clinical. In particular, two types of manifestations which may precede jaundice should be taken into consideration, especially in patients at risk (see “Conditions of occurrence”):
•on the one hand, non-specific general signs that usually appear suddenly such as asthenia, anorexia, depression, somnolence, sometimes accompanied by repeated vomiting and abdominal pain,
•on the other hand, a reappearance of epileptic seizures while the treatment is properly followed.
It is advisable to inform the patient, or their family if it is a child, that the appearance of such a clinical picture must immediately motivate a consultation. This will include, in addition to the clinical examination, the immediate performance of a liver function panel.
Detection
Liver function should be monitored before the start of treatment and regularly during the first 6 months of treatment, especially in patients at risk.
In the event of a change in the combined treatments known for their liver toxicity (increase in dose or new treatment), laboratory liver monitoring should be repeated (see also section 4.5 on the risk of hepatic damage with salicylates, other anticonvulsants including cannabidiol).
Among the standard examinations, tests reflecting protein synthesis and in particular PT (prothrombin time ratio) are the most relevant. Confirmation of an abnormally low prothrombin time ratio, especially if it is accompanied by other laboratory abnormalities (significant decrease in fibrinogen and coagulation factors, increased bilirubin, elevated transaminases – see section “Precautions for use”) should lead to discontinuation of treatment with this medicinal product (as a precaution, this also applies to salicylate derivatives if they are co-prescribed, since they use the same metabolic pathway).
Pancreatitis
Cases of pancreatitis, which is sometimes fatal, have been very rarely reported. They can be observed regardless of age and duration of treatment, as young children seem particularly exposed to this risk.
Pancreatitis of an unfavourable course is generally observed in young children, or in patients with severe epilepsy, brain lesions or antiepileptic combination therapy.
Liver failure associated with pancreatitis increases the risk of fatal progression.
In the event of acute abdominal pain syndrome, such as in case of gastrointestinal disorders such as nausea, vomiting and/or anorexia, it is necessary to suggest the diagnosis of pancreatitis and in case of elevated pancreatic enzymes, interrupt the treatment by implementing the alternative therapeutic measures that are necessary.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic medicinal products in several indications. A meta-analysis of randomised, placebo-controlled trials on antiepileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The causes of this risk are not known and the available data do not rule out the possibility of an increase of such a risk due to valproate.
Therefore, patients should be closely monitored for any signs of suicidal ideation and behaviour, and appropriate treatment should be considered. It must be recommended to patients (and their caregiver) to seek medical advice in the case of the onset of signs of suicidal ideation and behaviour.
Patients with known or suspected mitochondrial disease
Valproate may trigger or worsen clinical signs of underlying mitochondrial illness caused by mitochondrial DNA mutations, as well as in the nuclear gene encoding the mitochondrial DNA polymerase gamma (POLG).
Notably, cases of valproate-induced acute liver failure and 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 of or symptoms suggestive of a POLG-related disorder including, but not limited to, unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus on presentation, developmental delays, psychomotor regression, sensorimotor axonal neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or a complicated migraine with occipital aura. For a diagnostic evaluation of such disorders, a test for POLG mutations should be performed, according to current clinical practice (see section 4.3).
Interaction with other medicinal products
Taking this medicinal product in combination with lamotrigine and/or penems (carbapenems) is not recommended (see section 4.5).
Cognitive or extrapyramidal disorders
Cognitive or extrapyramidal disorders may be associated with scans showing cerebral atrophy. The clinical picture may thus be confused with dementia-like diseases or Parkinson’s disease. These disorders are reversible upon discontinuation of treatment (see section 4.8).
Information related to the presence of sodium
This medicinal product contains 55 mg sodium per bottle, equivalent to 2.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken into account for patients adhering to a strict low-sodium diet.
Precautions for use
Perform a liver function panel before the start of treatment (see section 4.3), then perform periodic monitoring during the first 6 months, especially in patients at risk (see section 4.4, “Severe hepatic damage – Detection”).
It should be emphasised that, as with most antiepileptic medicinal products, we can observe, particularly at the start of treatment, a moderate, isolated and transient increase of transaminases, without any clinical signs.
In this case, it is advisable to perform a more complete laboratory panel (prothrombin time ratio, in particular), to potentially reconsider the dosage and to reinforce controls based on the evolution of the parameters.
A haematology exam (FBC including platelets, bleeding time and coagulation panel) is recommended prior to treatment, then at 15 days and at the end of treatment, as well as before a surgical procedure and in the case of haematoma or spontaneous bleeding (see section 4.8).
In patients with kidney failure, the increase in free serum concentrations of valproic acid should be taken into account and the dosage reduced accordingly.
Urea cycle disorders and risk of hyperammonaemia
This medicinal product is contraindicated in patients with urea cycle enzyme deficiency. A few cases of hyperammonaemia associated with stupor or coma have been described in these patients (see sections 4.3 and 4.4, “Patients at risk of hypocarnitinaemia” and “Severe liver damage”).
Patients at risk of hypocarnitinaemia
Administration of valproate may trigger the onset or worsening of hypocarnitinaemia, which may lead to hyperammonaemia (which may cause hyperammonemic encephalopathy). Other symptoms, such as liver toxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, Fanconi syndrome, have been observed, mainly in patients with risk factors for hypocarnitinaemia or pre-existing hypocarnitinaemia. Patients at increased risk of symptomatic hypocarnitinaemia when treated with valproate are patients with metabolic disorders, including carnitine-related mitochondrial disorders (see also section 4.4 Patients with known or suspected mitochondrial disease and Urea cycle disorders and risk of hyperammonaemia), patients with impaired carnitine nutritional intake, patients under 10 years of age and patients treated concomitantly with pivalate-conjugated medicinal products or other antiepileptics.
Patients should be instructed to immediately report any signs of hyperammonaemia, such as ataxia, altered consciousness, vomiting. Carnitine supplementation should be considered when symptoms of hypocarnitinaemia are observed.
Patients with primary systemic carnitine deficiency and corrected hypocarnitinaemia can only be treated with valproate if the benefits of treatment with valproate outweigh the risks incurred for these patients and in the absence of an alternative treatment. In these patients, carnitine monitoring should be implemented.
Patients with underlying carnitine palmitoyltransferase (CPT) II deficiency should be cautioned about the increased risk of rhabdomyolysis when taking valproate. Carnitine supplementation should be considered in these patients. See also sections 4.5, 4.8 and 4.9. Although this medicinal product is recognised as
only exceptionally leading to immune system disorders, its use in a subject with disseminated lupus erythematosus should be weighed based on the benefit/risk balance.
At the initiation of treatment, patients must be informed of the risk of weight gain and of appropriate measures, primarily dietary, which must be taken in order to minimise it.
The excretion of valproate is essentially urinary, partly in the form of ketone bodies; ketonuria testing may give false positives in diabetic patients.
Alcohol consumption is not recommended for the duration of the treatment with DEPAKINE.
Paediatric population
In children under 3 years of age, it is recommended that valproate be used as monotherapy only, after assessing the therapeutic benefit in relation to the risk of hepatopathy and pancreatitis in patients in this age group prior to initiation of treatment (see section 4.4 “Severe hepatic damage” and also section 4.5).
In children under 3 years of age, avoid simultaneously prescribing salicylates, given the risk of hepatotoxicity (also see section 4.4) and the risk of haemorrhage.
In children with a history of unexplained hepato-gastrointestinal disorders (anorexia, vomiting, bout of cytolysis), bout of lethargy or coma, intellectual disability or in the case of a family history of neonatal deaths or deaths during childhood, metabolic tests and in particular NPO and postprandial ammonia plasma level tests must be performed before any treatment with valproate.

Contraindicated combinations
+ St John’s Wort
Risk of decreased plasma concentrations and the efficacy of the anticonvulsant.
Inadvisable combinations
+ Lamotrigine
Increased risk of serious skin reactions (Lyell’s syndrome).
Also, an increase in lamotrigine plasma concentrations (decrease in its hepatic metabolism by sodium valproate).
If the combination is necessary, close clinical monitoring should be carried out.
+ Penems (carbapenems)
Risk of the onset of seizures due to a rapid decrease in plasma concentrations of valproic acid, which may become undetectable.
Administration of valproic acid in combination with carbapenems resulted in a decrease in plasma concentrations of valproic acid of 60 to 100% in approximately two days. Due to the rapid onset and the significance of the decrease in plasma concentrations, the simultaneous administration of carbapenems in patients stabilised on valproic acid that cannot be monitored should therefore be avoided (see section 4.4).
Combinations requiring precautions for use
+ Acetazolamide
Increased hyperammonaemia, with increased risk of encephalopathy.
Regular clinical and laboratory monitoring.
+ Aztreonam
Risk of the onset of seizures due to decreased plasma concentrations of valproic acid.
Clinical monitoring, plasma assays and possible anticonvulsant dose adjustment during and after treatment with the anti-infective medicinal product.
+ Carbamazepine
Increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose. Also, a decrease in plasma concentrations of valproic acid due to an increase in its hepatic metabolism by carbamazepine.
Clinical monitoring, plasma assays and dosage adjustment of both anticonvulsants.
+ Felbamate
Increased plasma concentrations of valproic acid, with risk of overdose.
Clinical monitoring, laboratory tests and possible valproate dosage adjustment during and after treatment with felbamate.
+ Medicinal products containing oestrogen, including hormonal contraceptives containing oestrogen
Oestrogens are inducers of the isoforms of UDP-Glucuronosyltransferase (UGT) involved in the glucuronidation of valproate and may increase its clearance; this may result in decreased serum concentration of valproate and potentially decreased efficacy (see section 4.4). Consider monitoring serum concentrations of valproate.
Conversely, due to the lack of enzyme-inducing effect, valproate does not decrease the efficacy of oestro-progestogens in women on hormonal contraception.
+ Metamizole
Metamizole may decrease serum concentrations of valproate when co-administered, which may lead to a potential decrease in the clinical efficacy of valproate.
Monitoring of clinical response (seizure control or mood control) and considering monitoring of serum concentrations of valproate, if applicable.
+ Methotrexate
In some cases, a significant decrease in serum valproate levels is reported after administration of methotrexate, with the occurrence of convulsions.
Prescribers should monitor clinical response (seizure control or mood control) and consider appropriate monitoring of serum valproate levels.
+ Nimodipine (oral and by extrapolation, injectable)
Risk of increased plasma concentrations of nimodipine by 50%. Therefore, the dosage of nimodipine should be reduced in case of hypotension.
+ Phenobarbital, and by extrapolation primidone
Increased hyperammonaemia, with increased risk of encephalopathy.
Regular clinical and laboratory monitoring.
+ Phenytoin, and by extrapolation fosphenytoin
Increased hyperammonaemia, with increased risk of encephalopathy.
Regular clinical and laboratory monitoring.
+ Propofol
Possible increase in blood concentrations of propofol. A dose reduction of propofol should be considered when combined with valproate.
+ Rifampicin
There is a risk of seizures due to an increase in the hepatic metabolism of valproate by rifampicin.
Clinical and laboratory monitoring and possible anticonvulsant dosage adjustment during and after treatment with rifampicin.
+ Rufinamide
Possible increase in rufinamide concentrations, especially in children weighing less than 30 kg.
In children weighing less than 30 kg: do not exceed the total dose of 600 mg/d after the titration period.
+ Topiramate
Increased hyperammonaemia, with increased risk of encephalopathy.
Regular clinical and laboratory monitoring.
+ Zidovudine
Risk of increased undesirable effects, particularly haematological effects, of zidovudine due to a decrease in its metabolism by valproic acid.
Regular clinical and laboratory monitoring. A complete blood count to screen for anaemia should be performed during the first two months of the combination.
+ Zonisamide
Increased hyperammonaemia, with increased risk of encephalopathy.
Regular clinical and laboratory monitoring.
Other forms of interaction
+ Lithium
DEPAKINE has no effect on serum lithium.
+ Risk of liver damage
Concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of hepatic toxicity (see section 4.4).
Simultaneous use of valproate and other anticonvulsants increases the risk of liver damage, especially in young children (see section 4.4).
Use in combination with cannabidiol increases the incidence of elevated transaminases. In clinical trials in patients of any age receiving cannabidiol at doses of 10–25 mg/kg and valproate simultaneously, an increase in ALT of more than 3 times the upper normal limit was reported in 19% of patients. Appropriate liver monitoring should be performed when valproate is used in combination with other potentially hepatotoxic anticonvulsants, including cannabidiol.
Dose reductions or therapy cessation should be considered in case of significant abnormalities in hepatic parameters (see section 4.4).
+ Pivalate-conjugated medicinal products
Concomitant administration of valproate and pivalate-conjugated medicinal products (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to the increased risk of decreased carnitine (see section 4.4 Patients at risk of hypocarnitinaemia). Patients for whom concomitant administration cannot be avoided should be closely monitored for any signs or symptoms of hypocarnitinaemia.
 

Valproate is contraindicated (see sections 4.3 and 4.4):
• during pregnancy, unless there is no appropriate alternative therapy;
•in women of childbearing potential, unless all conditions of the pregnancy prevention programme are met.
Use in men of childbearing age: see section 4.4 «Warnings» and paragraph «Male of childbearing age» below.
Pregnancy
Teratogenicity and neurodevelopmental effects
The use of valproate, whether as monotherapy or in combination with other antiepileptic medicinal products, is frequently associated with abnormal pregnancy outcomes. The available data show an increased risk of major congenital malformations and neurodevelopmental disorders, both when valproate is used as monotherapy as well as in combination therapy, compared to the population not exposed to valproate. Valproate has been shown to cross the placental barrier in animals and 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 born to mothers with epilepsy treated with valproate monotherapy during pregnancy had major congenital malformations. This is greater than the risk of major malformations encountered in the general population (approximately 2–3%).
The risk of major congenital malformations in children exposed in utero to antiepileptic combination therapy including valproate is higher than the risk associated with antiepileptic combination therapy without valproate.
This risk is dose-dependent during monotherapy with valproate, and the available data suggest that it is dose-dependent during combination therapy with valproate. However, no threshold dose excluding this risk could be determined.
Available data show an increased incidence of minor and major malformations. The most common malformations encountered include neural tube defects (between 2 and 3%), facial dysmorphisms, cleft lips and cleft palates, craniostenosis, renal, urogenital, and heart malformations (including hypospadias), malformations of the limbs (including bilateral radial aplasia) and polymalformative syndromes affecting different parts of the body.
In utero exposure to valproate may also lead to hearing impairment or deafness due to nose and/or ear malformations (side effect), and/or direct toxicity to auditory function. Cases describe unilateral and bilateral hearing impairment or deafness. Developments were not reported for all cases. When developments were reported, there was no recovery in the majority of cases.
In utero exposure to valproate may lead to eye malformations (including coloboma and microphthalmia), which have been reported in conjunction with other congenital malformations. These eye malformations may affect vision.
•Neurodevelopmental disorders
Studies show that valproate leads to an increased risk of neurodevelopmental disorders in children exposed in utero. The risk of neurodevelopmental disorders (including autism) appears to be dose-dependent when valproate is used as monotherapy, but the available data do not make it possible to determine a dose excluding this risk.
When valproate is administered in combination with other antiepileptic medicinal products during pregnancy, the risks of neurodevelopmental disorders in children were also significantly increased, compared to children from the general population or those born to untreated epileptic mothers.
The risk period for these effects is uncertain and the possibility of a risk throughout the pregnancy cannot be excluded.
When valproate is administered as monotherapy, studies in nursery school-age children exposed to valproate in utero show that up to 30–40% of them experience developmental delays in early childhood,
such as delays in the acquisition of speech and walking, reduced intellectual abilities, reduced verbal (speaking and understanding) abilities, as well as memory disturbances.
The intelligence quotient (IQ) of primary school-age children (6 years) exposed to valproate in utero was on average 7 to 10 points lower than that of children exposed to other antiepileptic medicinal products. Although the role of confounding factors cannot be excluded, it is proven that this decrease in IQ observed in children exposed in utero is independent of maternal IQ.
Data on the course of these long-term disorders are limited.
Available data from a study based on the population show that children exposed to valproate in utero have an increased risk of having autism spectrum disorders (about 3 times more common) and childhood autism (about 5 times more common), compared to the unexposed population in the study.
Available data from another study based on the population show that children exposed to valproate in utero have an increased risk of developing attention deficit/hyperactivity disorder (ADHD) (about 1.5 times more common), compared to the unexposed population in the study.
Women of childbearing potential
In women of childbearing potential, DEPAKINE treatment should not be used, except in cases of ineffectiveness or intolerance to other treatments. If no other treatment is possible, DEPAKINE can only be initiated if the pregnancy prevention programme is followed (see section 4.4), including:
•Not being pregnant (negative plasma pregnancy test with a sensitivity of at least 25 mIU/ml at treatment initiation and at regular intervals during treatment);
•Using at least one effective method of contraception;
•Being informed of the risks of using valproate during pregnancy.
In these women, the benefit/risk balance should be carefully reassessed at regular intervals during treatment (at least annually).
Medicinal products containing oestrogen:
Medicinal products containing oestrogen, including hormonal contraceptives containing oestrogen, may increase the clearance of valproate, which may result in decreased serum concentrations of valproate and potentially decreased efficacy (see sections 4.4 and 4.5).
If pregnancy is planned:
In women planning a pregnancy, a specialist physician experienced in the management of epilepsy should reassess treatment with valproate, and consider all alternative treatment options. Every effort should be made to switch to an appropriate alternative treatment prior to conception and before contraception is stopped (see section 4.4). If a therapy change is not possible, the patient should receive additional advice regarding the risks that valproate presents for the unborn child, in order to help her make an informed decision regarding her family planning.
Folic acid supplementation before and at the beginning of pregnancy may decrease the risk of developing neural tube defects inherent in any pregnancy. For information, the available data do not show any preventive action of folic acid on valproate-related malformations.
Pregnant women
Valproate used in the treatment of epilepsy is contraindicated during pregnancy, unless there is no appropriate therapeutic alternative (see sections 4.3 and 4.4).
In the event of pregnancy in a woman using valproate, she must be immediately referred to a specialist physician in order to consider all alternative treatment options.
During pregnancy, tonic-clonic epilepsy and status epilepticus with hypoxia in the mother can lead to serious or even fatal consequences for the mother and the unborn child.
If, in exceptional circumstances, despite the known risks associated with the use of valproate during pregnancy, and after careful evaluation of alternative treatments, valproate absolutely had to be maintained to control epilepsy in a pregnant woman:
•it is essential to use the minimum effective dose,
•it is recommended that the daily dosage be divided into several smaller doses during the day. The use of a sustained release formulation may be preferable to other formulations in order to avoid plasma peaks (see section 4.2).
All patients whose pregnancies have been exposed to valproate, and their partners, should be referred to a physician specialised or experienced in teratology for evaluation and counselling regarding the exposed pregnancy:
•Specialised prenatal monitoring should be initiated to detect possible abnormalities involving the neural tube or other malformations.
Before delivery
Perform a coagulation panel including in particular platelet count, fibrinogen assay and coagulation time (activated partial thromboplastin time, aPTT) in the mother before delivery.
Risk in the newborn child
Very rare cases of bleeding tendency have been reported in newborn children of mothers treated with valproate during pregnancy. This bleeding tendency is related to thrombocytopenia, hypofibrinogenemia, and/or a decrease in other coagulation factors. Afibrinogenemia has also been reported and can be fatal. However, this syndrome must be distinguished from a vitamin K factor deficiency induced by phenobarbital and enzyme inducers. A normal haemostasis assessment in the mother does not exclude haemostasis abnormalities in the newborn child. Therefore, at birth, newborn children should undergo an assessment including a platelet count, fibrinogen assay, coagulation factors and tests.
Cases of hypoglycaemia have been reported in newborn children whose mothers were treated with valproate during the third trimester of pregnancy.
Cases of hypothyroidism have been reported in newborn children whose mothers were treated with valproate during pregnancy.
Withdrawal syndrome (particularly agitation, irritability, hyperexcitability, nervousness, hyperkinesia, muscle tone disorders, tremors, seizures, and feeding disorders) may occur in newborn children whose mothers were treated with valproate during the third trimester of pregnancy.
Postnatal/child follow-up
In the case of exposure during pregnancy, a close follow-up of neurobehavioral development in the child is to be started and appropriate management should be implemented as early as possible if needed.
Men of childbearing age:
Risk for the children of fathers treated with valproate
Data from a retrospective study conducted on Scandinavian registries suggest an increase in the risk of neurodevelopmental disorders in children (from 0 to 11 years) whose fathers were treated with valproate in the 3 months prior to conception, compared to those whose fathers were treated with lamotrigine or levetiracetam.
The limitations of this study do not allow conclusions to be drawn about this potential risk at this stage, and additional data are necessary.
As a precautionary measure, the prescriber should inform patients of childbearing age of this potential risk.
The prescriber must discuss the following with them:
•the need for effective contraceptive measures during treatment, and for at least three months after discontinuing it,
•the possibility of therapeutic alternatives for patients who are planning to conceive a child,
•do not donate sperm during treatment with valproate and for at least three months after stopping treatment (see section 4.4).
The risk of neurodevelopmental disorders for children conceived by men stopping valproate more than three months before conception is not known.
Breast-feeding
Valproate is excreted in human milk at a concentration between 1% and 10% of maternal serum levels. Haematological disorders have been observed in breastfed newborns/infants of treated women (see section 4.8).
The decision to discontinue breast-feeding or to discontinue DEPAKINE therapy should take into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
Cases of amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women treated with valproate (see section 4.8). In men, the administration of valproate may also impair fertility (reduced sperm mobility in particular) (see section 4.8). In some cases, these fertility disorders are reversible after at least 3 months of therapy cessation. In a limited number of cases, it has been reported that a significant dose reduction is likely to improve fertility. However, in other cases, the reversibility of these male fertility disorders is not known.

Attention is drawn, particularly in vehicle drivers and machine operators, to the risk of somnolence, particularly in cases of anticonvulsant combination therapy or combination with other medicinal products that may increase somnolence.

Classification of expected frequencies:
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1 000 to < 1/100); Rare (≥ 1/10 000 to < 1/1 000); Very rare (< 1/10 000); Not known (cannot be estimated from the available data).
Congenital, familial and genetic disorders
•Congenital malformations, neurodevelopmental disorders (see sections 4.4 and 4.6).
Blood and lymphatic system disorders
•Common: anaemia, thrombocytopenia.
Cases of dose-dependent thrombocytopenia, usually discovered systematically and without clinical impact, have been described.
In the case of asymptomatic thrombocytopenia, if the platelet count and disease control allow for this, simply reducing the dose of this medicinal product most often results in the regression of this thrombocytopenia.
•Uncommon: leukopenia, pancytopenia.
•Rare: general aplasia bone marrow or pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis.
Investigations
•Common: weight gain*.
•Rare: decrease in at least one coagulation factor, abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased INR) (see sections 4.4 and 4.6), vitamin B8 deficiency (biotin)/biotinidase deficiency.
*as weight gain is a risk factor for polycystic ovarian syndrome, patients’ weight must be carefully monitored (see section 4.4).
Nervous system disorders
•Very common: tremors
•Common: extrapyramidal disorders**, stupor*, sedation, seizures*, memory disturbance, headache, nystagmus, nausea or dizziness
•Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism**, ataxia, paraesthesia
•Rare: diplopia, cognitive disorders of insidious and progressive onset (possibly leading to a full clinical picture of dementia) that are reversible a few weeks to a few months after therapy cessation**
*Cases of stupor or lethargy, sometimes leading to transient coma (encephalopathy) have been observed during treatment with valproate, resolving upon therapy cessation or after a dose reduction. These conditions are most likely to occur during combination therapy (with phenobarbital or topiramate in particular) or after a sudden increase in the dose of valproate.
**These symptoms may be associated with scans showing cerebral atrophy.
Ear and labyrinth disorders
•Common: hearing loss.
Respiratory, thoracic and mediastinal disorders
•Uncommon: pleural effusion.
Gastrointestinal disorders
•Very common: nausea.
•Common: vomiting, gum disorders (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhoea that may occur in some patients at the start of treatment, but which usually resolve after a few days without interruption of treatment.
•Uncommon: pancreatitis, which can be fatal and requires early discontinuation of treatment (see section 4.4).
Renal and urinary disorders
•Common: urinary incontinence.
•Uncommon: renal failure.
•Rare: enuresis, tubulointerstitial nephritis, Fanconi syndrome.
Skin and subcutaneous tissue disorders
•Common: transient and/or dose-dependent hair loss, nail and nail bed disorders.
•Uncommon: angioedema, skin reactions, capillary disorders (such as abnormal hair texture, changes in hair colour, abnormal hair growth).
•Rare: Lyell’s syndrome, Stevens-Johnson syndrome, erythema multiforme, DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome, or drug-induced hypersensitivity syndrome.
Endocrine disorders
Uncommon: syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilism, acne, androgenic alopecia and/or increased levels of androgens).
•Rare: hypothyroidism (see section 4.6).
Metabolism and nutrition disorders
•Common: hyponatraemia.
•Rare: hyperammonaemia* (see section 4.4), obesity.
*Isolated and moderate hyperammonaemia without changes in liver laboratory tests may be observed, especially in the case of combination therapy, and should not cause treatment interruption.
However, cases of hyperammonaemia with neurological symptoms (possibly leading to coma) have also been reported, requiring additional investigations (see sections 4.3 and 4.4: “Urea cycle disorders and risk of hyperammonaemia and Patients at risk of hypocarnitinaemia”).
•Not known: hypocarnitinaemia (see sections 4.3 and 4.4).
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
•Rare: Myelodysplastic syndrome.
Vascular disorders
•Common: haemorrhage (see sections 4.4 and 4.8).
•Uncommon: skin vasculitides, mainly leukocytoclastic vasculitis.
General disorders and administration site conditions
•Uncommon: hypothermia, non-severe peripheral oedema.
•Not known: risk of local tissue necrosis if injections are received repeatedly.
Hepatobiliary disorders
•Common: hepatopathy (see section 4.4).
Reproductive system and breast disorders
•Common: menstrual irregularity.
•Uncommon: amenorrhoea.
•Rare: male fertility disorders, (see section 4.6), polycystic ovaries.
Musculoskeletal and connective tissue disorders
•Uncommon: decreased bone mineral density, osteopaenia, 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).
Psychiatric disorders
•Common: confusional state, hallucinations, aggressiveness*, agitation*, impairment of attention*.
•Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disabilities*.
*These reactions are mostly seen in the paediatric population.
Paediatric population
The safety profile of valproate in the paediatric population is comparable to that in adults, but some undesirable effects are more serious, or are mainly seen in the paediatric population. There is a particular risk of severe hepatic damage in infants and young children, especially before the age of 3 years. Young children also have a particular risk of pancreatitis. These risks decrease with age (see section 4.4). Psychiatric disorders, such as aggression, agitation, impairment of attention, abnormal behaviours, psychomotor hyperactivity and learning disabilities, are mainly observed in the paediatric population.
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.
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
• SFDA call center : 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

The picture of massive acute intoxication usually includes a more or less deep calm coma, with muscle hypotonia, hyporeflexia, miosis, decreased respiratory autonomy, metabolic acidosis, hypotension, and cardiovascular collapse/shock.
Some cases of intracranial hypertension associated with cerebral oedema have been described.
The measures to be taken in a hospital setting are: gastric emptying if indicated, maintenance of effective diuresis, cardiorespiratory monitoring. In very severe cases, extrarenal purification may be performed.
The prognosis of these intoxications is generally favourable, however some deaths have been reported.
The presence of sodium in formulations containing valproate may lead to hypernatraemia in the event of overdose.
Treatment
In the event of a valproate overdose resulting in hyperammonaemia, carnitine may be given IV to attempt to normalise ammonium levels.

Pharmacotherapeutic group: ANTIEPILEPTIC, ATC code: N03AG01.
Valproate exerts its pharmacological effects primarily in the central nervous system.
These anticonvulsant properties are exercised against a wide variety of seizures in animals and epilepsies in humans.
Experimental and clinical studies of valproate suggest two types of anticonvulsant action.
The first is a direct pharmacological effect in relation to plasma and brain concentrations of valproate.
The second is apparently indirect and probably related to persistent valproate metabolites in the brain or with neurotransmitter changes or direct membrane effects. The most generally accepted hypothesis is the gamma-aminobutyric acid (GABA) hypothesis, whose levels increase after administration of valproate.
Valproate decreases the duration of intermediate sleep stages with a concomitant increase in NREM sleep.

The different pharmacokinetic studies performed for valproate showed that:
•The blood bioavailability of valproate after oral or IV administration is close to 100%.
•The volume of distribution is limited primarily to blood and rapidly exchanged extracellular fluids. Valproate diffuses in the CSF and in the brain.
•Crossing of the placental barrier (see section 4.6):
Valproate crosses the placental barrier in animals and in humans:
oin animals, valproate crosses the placenta, in a way that is similar to humans,
oIn humans, several publications have evaluated the concentration of valproate in the umbilical cord of newborns at delivery. The serum concentration of valproate in the umbilical cord, representing the serum concentration of valproate in foetuses, was similar or slightly higher than that of the mothers.
•Its half-life is from 15 to 17 hours.
•Therapeutic efficacy usually requires a minimum serum concentration of 40–50 mg/l, with a wide range between 40 to 100 mg/l. If higher plasma levels are necessary, the expected benefits must be weighed against the risk of undesirable effects, particularly dose-dependent ones. However, levels that remain above 150 mg/l require a dose reduction.
•By the oral route, steady-state plasma concentration is reached in 3 to 4 days; with the injectable form, it can be reached in a few minutes and maintained by venous infusion.
•The protein binding of valproate is very significant. It is dose-dependent and saturable.
•The major pathway of valproate metabolism is glucuronidation (approximately 40%), primarily via UGT1A6, UGT1A9 and UGT2B7.
•The excretion of valproate is essentially urinary after metabolism by glucuronidation and beta-oxidation.
•The valproate molecule is dialysable, but haemodialysis only affects the free fraction of blood valproate (approximately 10%).
•Valproate is not an inducer of enzymes involved in the cytochrome P 450 metabolic system: unlike most other antiepileptic medicinal products, it does not accelerate its own degradation or that of other substances such as oestro-progestogens and vitamin K antagonists.
Paediatric population
From the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. In paediatric patients under 10 years of age, systemic valproate clearance varies with age. In newborn children and infants up to 2 months of age, valproate clearance is reduced compared to that in adults, and is lowest immediately after birth.
In a review of the scientific literature, the half-life of valproate in infants under two months of age showed considerable variability ranging from 1 to 67 hours.
In children aged 2 to 10 years, valproate clearance is 50% higher than in adults

Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
In vitro, valproate was not mutagenic in bacteria or in mouse lymphoma trials and did not induce DNA repair in primary cultures of rat hepatocytes. However, in vivo, conflicting results were obtained at teratogenic doses depending on the route of administration. After oral administration, the most common route in humans, valproate did not induce chromosomal aberrations in rat bone marrow or major lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand breaks and chromosomal aberrations in rodents. In addition, an increase in sister chromatid exchanges in patients with epilepsy exposed to valproate has been reported in published studies compared to healthy untreated subjects. However, conflicting results were obtained by comparing data from patients with epilepsy treated with valproate with data from 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 studies of carcinogenicity.
Reproductive toxicity
Valproate induced teratogenic effects (malformations of several organ systems) in mice, rats and rabbits.
Behavioural abnormalities were reported in first-generation offspring of mice and rats after in utero exposure. Some behavioural changes were also observed in the second generation and were less pronounced in the third generation of mice after acute in utero exposure of the first generation to teratogenic doses of valproate. The underlying mechanisms and clinical relevance of these findings are unknown.
In studies on repeated dose toxicity, testicular degeneration/atrophy, abnormal spermatogenesis and a decrease in testicular weight were reported in adult rats and dogs following oral administration of doses of 400 mg/kg/day and 150 mg/kg/day, respectively. The no-observable-adverse-effect levels (NOAELs) associated with testicular effects are 270 mg/kg/day in adult rats and 90 mg/kg/day in adult dogs. On the basis of extrapolations of AUCs (area under curves) in rats and dogs, there might not be a safety margin for humans.
In juvenile rats, the decrease in testicular weight was only observed at doses exceeding the maximum tolerated dose (from 240 mg/kg/day intraperitoneally or intravenously) and without associated histopathological changes. No effects on the male reproductive organs were observed at the tolerated doses (up to 90 mg/kg/day). Based on these data, juvenile animals were not considered more likely than adults to have testicular disorders. The clinical relevance of these results regarding the testes for the paediatric population is still unknown.
In a fertility study in rats, the administration of valproate at doses of up to 350 mg/kg/day did not impair reproductive performance in males. However, male fertility disorders have been identified as an undesirable effect in humans (see sections 4.6 and 4.8).

Solvent: water for injections.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in reference in 4.2.

3 years After opening/reconstitution/dilution: the product should be used immediately.

This medicinal product does not require any special storage conditions.

Powder in (colourless glass) bottle + 4 ml solvent in (colourless glass) ampoule. Box of 1, 4 or 80.
Not all pack sizes may be marketed.

No special requirements.
Appearance of the product after reconstitution: clear to slightly opalescent liquid.