Depakin chrono® 500 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPAKINE CHRONO® 500 mg (DEPAKINE CHRONO® 500 mg)

Composition:

Active substances: sodium valproate and valproic acid;

One tablet contains sodium valproate 333 mg, valproic acid 145 mg (equivalent to 500 mg of sodium valproate);

Excipients: hypromellose, ethylcellulose, colloidal anhydrous silicon dioxide, colloidal hydrated silicon dioxide, sodium saccharin;

Coating: hypromellose, polyethylene glycol, talc, titanium dioxide (E 171), polyacrylate dispersion.

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical characteristics: elongated, almost white tablets with a score line, coated with a film coating.

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03AG01.

Pharmacological Properties.

Pharmacodynamics.

The pharmacological activity of valproate is primarily directed at the central nervous system. It demonstrates anticonvulsant properties against a broad spectrum of seizures in animals and epilepsy in humans.

Two mechanisms of anticonvulsant action of valproate have been identified in experimental and clinical studies.

The first is a direct pharmacological effect dependent on the concentration of valproate in plasma and brain tissue.

The second is an indirect mechanism, possibly related to valproate metabolites that remain in the brain, or to modifications of neurotransmitters, or to a direct effect on the membrane.

The most likely hypothesis is that following administration, valproate increases the level of gamma-aminobutyric acid (GABA).

Pharmacological studies in animals have shown that sodium valproate has anticonvulsant properties in various models of experimental epilepsy (with generalized and focal seizures).

Similarly, studies have demonstrated that sodium valproate exerts antiepileptic effects in various forms of human epilepsy. This action is likely based on GABA-ergic (gamma-aminobutyric acid-mediated) activity, which prevents or limits the spread of discharges. The active form of sodium valproate, whether administered intravenously or orally, is valproic acid.

In some in vitro studies, sodium valproate was observed to stimulate replication of HIV-1; however, this effect is weak and has not been reproducible in most studies. The clinical implications of this effect in patients infected with HIV-1 are unknown. When administering sodium valproate to patients infected with HIV-1, this information should be taken into account for proper interpretation of viral load test results.

Valproate reduces the duration of intermediate sleep stages with a simultaneous increase in slow-wave sleep.

Pharmacokinetics.

Various pharmacokinetic studies conducted with valproate have shown the following results.

After oral administration of Depakine Chrono® 500 mg, its bioavailability in plasma approaches 100%.

In plasma, Depakine Chrono® 500 mg exists in the form of valproic acid. The absorption of Depakine Chrono® 500 mg, film-coated prolonged-release tablets, in the gastrointestinal tract begins immediately and proceeds in a uniform and prolonged manner. This results in the absence of peaks in plasma concentration of the active substance and better maintenance of therapeutic concentrations of valproic acid over time.

Distribution. The volume of distribution of valproic acid is primarily limited to blood and rapidly exchanging extracellular fluids. Valproate penetrates into cerebrospinal fluid and brain tissue. Information on placental transfer is provided in the section "Use during pregnancy or breastfeeding".

Valproate crosses the placental barrier in both animals and humans:

• in animals, valproate crosses the placental barrier in amounts similar to those in humans;
• several publications have evaluated the concentration of valproate in umbilical cord blood of newborns during delivery in women: the concentration of valproate in umbilical cord serum, corresponding to fetal serum concentration, was equal to or slightly higher than that in maternal serum.

The elimination half-life is 15–17 hours.

Binding to blood proteins occurs mainly with albumin and is dose-dependent and saturable. At a total plasma concentration of valproic acid of 40–100 mg/L, the free fraction typically constitutes 6–15%. In patients with renal impairment, there is a tendency toward increased free fraction due to decreased albumin levels and, consequently, reduced number of available binding sites.

The concentration of valproic acid in cerebrospinal fluid is similar to the concentration of its free fraction in plasma (approximately 10%).

Valproic acid is removed during dialysis, but the volume of the fraction removed is significantly reduced due to its binding to albumin (approximately 10%).

Sodium valproate crosses the placental barrier. Valproic acid passes into breast milk (1–10% of total serum concentration) in women who received Depakine Chrono® 500 mg during lactation.

Maximum plasma concentration under fasting conditions is reached on average 5–7 hours after administration. These time intervals may increase by 2–4 hours if the drug is taken with food.

After initiation of long-term therapy with Depakine Chrono® 500 mg, steady-state serum concentration of valproic acid is achieved approximately within 3–4 days, although in some cases it may take longer.

The minimum serum concentration of valproate required for therapeutic effect is usually 40–50 mg/L. The therapeutic plasma concentration of valproic acid generally ranges between 40–100 mg/L (278–694 µmol/L). If higher concentrations are necessary, the expected benefit should be weighed against the likelihood of adverse effects, particularly dose-dependent ones. If the total plasma concentration of valproic acid remains above 150 mg/L (1040 µmol/L), the daily dose should be reduced.

Metabolism. Depakine Chrono® 500 mg is primarily metabolized in the liver. The main metabolic pathways are glucuronidation and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate either its own breakdown or that of other substances such as estrogen and progesterone. This property is reflected in the absence of any inducing effect on enzymes involved in the cytochrome P450 system. There are more than 10 known metabolites, some of which have demonstrated anticonvulsant properties in animal studies. The primary metabolic pathway of valproate is glucuronidation (approximately 40%), occurring mainly via UGT1A6, UGT1A9, and UGT2B7 enzymes. Enterohepatic recirculation is present.

Excretion. With continuous administration of valproic acid, its average elimination half-life in plasma in adults is 10.6 hours (although it may range from 5 to 20 hours), necessitating twice-daily dosing. The drug is primarily excreted by the kidneys after metabolism via conjugation with glucuronic acid and beta-oxidation: 70% as glucuronide and ±7% as unchanged valproic acid. Residual amounts are excreted via the respiratory tract and feces. The elimination half-life in preterm neonates is significantly prolonged, reaching 30–70 hours depending on the degree of prematurity (compared to 20–30 hours in full-term neonates and infants during the first month of life), gradually approaching values typical for children and adults, i.e., 8–22 hours with a mean of 12 hours.

The valproate molecule is dialyzable, but hemodialysis is effective only for the free fraction of valproate in blood (approximately 10%). Valproate does not induce enzymes of the cytochrome P450 metabolic system; therefore, unlike most other antiepileptic drugs, it does not accelerate its own degradation or that of other substances such as estrogen-progestogen agents and oral anticoagulants.

Valproic acid is excreted primarily by the kidneys. A small fraction is excreted unchanged, while the majority of the administered dose is excreted as metabolites.

Pharmacokinetics in specific patient groups

Renal impairment. Reduced binding to albumin occurs. One should be aware of the possibility of increased serum concentration of the free fraction of valproic acid. In such cases, the dose should be appropriately reduced.

Elderly patients. Changes in pharmacokinetic parameters have been observed, but they were not particularly significant. Therefore, the dose should be determined based on clinical response (i.e., seizure control).

Compared to the gastro-resistant formulation of valproate, this prolonged-release dosage form at equivalent doses demonstrates the following characteristics:

• elimination of the absorption lag time;
• prolonged absorption;
• identical bioavailability;
• lower total maximum plasma concentration (Cmax) and free fraction plasma concentration (Cmax approximately 25% lower, with a relatively stable plateau between 4–14 hours after administration); this "peak smoothing" effect provides more stable and more evenly distributed concentrations of valproic acid over a 24-hour period: when administered twice daily at the same dose, the extent of plasma concentration fluctuations is reduced by half;
• more linear correlation between dose and total plasma concentration and free fraction plasma concentration.

Children. In children from the age of 10 years, valproate clearance is similar to that in adults. In patients under 10 years of age, systemic clearance of valproate varies with age.

In neonates and infants up to 2 months of age, valproate clearance is reduced compared to adults and is lowest immediately after birth. According to a review of medical literature, the elimination half-life of valproate in infants under 2 months of age is highly variable—ranging from 1 to 67 hours.

In children aged 2 to 10 years, valproate clearance is 50% higher than in adults.

Preclinical safety data

Animal studies have shown that in utero exposure to valproate causes physical and functional disturbances of the auditory system in rats and mice.

In vitro, valproate did not show mutagenic effects on bacteria or mouse lymphoma cells and did not activate DNA repair in primary rat hepatocyte cultures. However, in vivo results were conflicting when teratogenic doses were administered via different routes. After oral administration—the primary route used in humans—valproate did not induce chromosomal aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand breaks and chromosomal aberrations in rodents. Furthermore, published studies have reported increased sister chromatid exchanges in epileptic patients exposed to valproate compared to healthy subjects not receiving such treatment. However, conflicting results were observed when comparing data from epileptic patients treated with valproate to those from untreated epileptic patients. The clinical significance of these findings regarding DNA/chromosome effects is unknown.

Preclinical data from conventional carcinogenicity studies do not indicate a specific risk for humans.

Reproductive toxicity

Valproate caused teratogenic effects (malformations in several organ systems) in mice, rats, and rabbits.

Behavioral disturbances in offspring of mice and rats in the first generation after in utero exposure have been reported. In mice, certain behavioral changes were also observed in the second and third generations, although less pronounced in the third generation, following acute in utero exposure of the first generation to teratogenic doses of valproate. The primary mechanisms and clinical significance of these findings are unknown.

Fertility. In subchronic and chronic toxicity studies with repeated dosing, testicular degeneration/atrophy or abnormalities in spermatogenesis and reduced testicular weight were reported in adult rats and dogs after oral administration at doses of 400 mg/kg/day and 150 mg/kg/day, respectively, with no observed adverse effect at 270 mg/kg/day for testes in adult rats and 90 mg/kg/day in adult dogs. In a rat fertility study, valproate at doses up to 350 mg/kg/day did not affect male reproductive function. No effect on male reproductive organs was observed at maximally tolerated doses (up to 90 mg/kg/day). Reduced testicular weight was observed only at highly toxic doses (from 240 mg/kg/day intraperitoneally or intravenously) without associated histopathological changes. The sensitivity of testes to valproate exposure in the pediatric rat population is unknown.

Clinical characteristics.

Indications.

The primary indication for the use of Depakine Chrono® 500 mg, preferably as monotherapy, is primary generalized epilepsy: absence seizures/absence epilepsy, generalized bilateral myoclonic seizures, tonic-clonic seizures with or without myoclonia, and photosensitive forms of epilepsy.

Depakine Chrono® 500 mg is also effective, either as monotherapy or in combination with other antiepileptic drugs, in the following conditions:

• Secondary generalized epilepsy, particularly West syndrome (infantile spasms) and Lennox-Gastaut syndrome;
• Partial epilepsy with simple or complex symptomatology (psychosensory forms, psychomotor forms);
• Mixed forms of epilepsy (generalized and partial).

Treatment of manic episodes associated with bipolar affective disorders in adult patients when contraindications to, or intolerance of, lithium exist.

Prophylaxis of relapses of dysthymic episodes in adult patients with bipolar disorders who have responded therapeutically to valproate during treatment of manic episodes.

Contraindications.

Treatment of epilepsy

Contraindicated in pregnant women, except in cases where no alternative treatment options are available and after thorough patient counseling regarding risks (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Contraindicated in female children and women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Treatment and prophylaxis of bipolar disorders

Contraindicated in pregnant women (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Contraindicated in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

All indications

Hypersensitivity to valproate, sodium valproate, divalproex sodium, valpromide, or to any component of the medicinal product in the patient's history.

Acute hepatitis.

Chronic hepatitis.

Pancreatitis (see section "Special precautions for use").

Severe hepatitis in personal or family history, particularly if drug-induced.

Hepatic porphyria.

Combination with mefloquine and St. John's wort extract (see section "Interaction with other medicinal products and other types of interactions").

Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the gene encoding mitochondrial gamma-polymerase enzyme, such as Alpers-Huttenlocher syndrome; in children under two years of age suspected of having a disorder associated with gamma-polymerase; and in patients with a history of urea cycle disorders (see section "Special precautions for use").

Deficiency of enzymes of the urea cycle (see section "Special precautions for use").

Known systemic primary carnitine deficiency with uncorrected hypocarnitinemia (see section "Special precautions for use").

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations

St. John's wort. Risk of decreased plasma concentrations and reduced efficacy of the antiepileptic agent.

Not recommended combinations

Lamotrigine. Increased risk of serious skin reactions (Stevens-Johnson syndrome). Additionally, possible increase in lamotrigine plasma concentrations (due to reduced hepatic metabolism by sodium valproate).

If concomitant use cannot be avoided, careful clinical monitoring of the patient is required.

Penems (carbapenems). Risk of seizures due to rapid decrease in valproic acid plasma concentrations, which may fall below the detection threshold.

Concomitant administration of valproic acid and carbapenems has led to a reduction in valproic acid plasma concentration by approximately 60–100% within about two days. Due to the rapid onset and extent of the concentration decline, concomitant use of carbapenems should be avoided in patients whose condition is stabilized on valproic acid and who cannot be closely monitored (see section "Special precautions for use").

Combinations requiring special precautions during use

Acetazolamide. Possible enhancement of hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Aztreonam. Risk of seizures due to decreased valproic acid plasma concentration. Clinical monitoring of the patient, measurement of plasma drug concentrations, and possibly dose adjustment of the anticonvulsant during and after antibiotic therapy are necessary.

Carbamazepine. Possible increase in plasma concentration of the active metabolite of carbamazepine with signs of overdose. Additionally, decreased valproic acid plasma concentrations due to enhanced hepatic metabolism by carbamazepine. Clinical monitoring, measurement of plasma drug concentrations, and dose adjustment of both anticonvulsants are indicated.

Felbamate. Possible increase in serum valproic acid concentrations with risk of overdose. Clinical monitoring, laboratory testing, and possible dose adjustment of valproate are indicated during and after felbamate therapy.

Estrogen-containing medicinal products, including hormonal contraceptives containing estrogens. Estrogens are inducers of UDP-glucuronosyltransferase (UGT) isoenzymes involved in valproate glucuronidation and may increase valproate clearance, which in turn may lead to decreased serum valproate concentrations and potentially reduce its efficacy (see section "Special precautions for use"). Monitoring of serum valproate levels should be considered. Conversely, valproate does not induce enzymes; therefore, valproate does not reduce the efficacy of estrogen-progestogen hormonal contraceptives in women.

Metamizole. Metamizole may reduce serum valproate concentrations when used concomitantly with other medicinal products, potentially reducing the clinical efficacy of valproate.

Clinical response (seizure control or mood stability) should be monitored, and serum valproate concentration monitoring should be considered if necessary.

MTX (methotrexate). Several reports describe a significant decrease in serum valproate levels after methotrexate administration, leading to seizures. Physicians prescribing these drugs should monitor clinical response (seizure control or mood stability) and consider monitoring serum valproate levels if necessary.

Nimodipine (oral and, by extrapolation, parenteral). Risk of 50% increase in nimodipine plasma concentration. Therefore, nimodipine dosage should be reduced in patients with arterial hypotension.

Phenobarbital and, by extrapolation, primidone. Possible enhancement of hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Phenytoin and, by extrapolation, fosphenytoin. Possible enhancement of hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Propofol. Possible increase in blood propofol levels. When used concomitantly with valproate, a reduction in propofol dosage should be considered.

Rifampicin. Risk of seizures due to enhanced hepatic metabolism of valproate. Clinical monitoring, laboratory testing, and possible dose adjustment of the anticonvulsant during and after rifampicin therapy are indicated.

Rufinamide. Possible increase in rufinamide concentrations, especially in children with body weight less than 30 kg. For children weighing less than 30 kg, the total daily dose should not exceed 600 mg after titration.

Topiramate. Possible increase in hyperammonemia and increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Zidovudine. Risk of increased zidovudine adverse reactions, particularly hematological, due to reduced metabolism by valproic acid. Regular monitoring of clinical and laboratory parameters is indicated. Complete blood count to detect anemia should be performed monthly during the first two months of combination therapy.

Zonisamide. Enhanced hyperammonemia with increased risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Other types of interactions

Pivaloyl-conjugated medicinal products. Concomitant use of valproate and pivalate-conjugated drugs, which reduce carnitine levels (e.g., cefditoren pivoxil, adefovir dipivoxil, pivmecillinam, and pivampicillin), may lead to the development of hypocarnitinemia (see section "Special precautions for use. Patients at risk of developing hypocarnitinemia"). Concomitant use of these medicinal products with valproate is not recommended. Patients who cannot avoid concomitant use should be carefully monitored for signs and symptoms of hypocarnitinemia.

Lithium. Depakine Chrono® 500 mg does not affect serum lithium levels.

Risk of liver injury

Concomitant use of salicylates in children under 3 years of age should be avoided due to the risk of toxic liver injury (see section "Special precautions for use").

Concomitant use of valproate with multiple anticonvulsant therapies increases the risk of liver injury, especially in younger children (see section "Special precautions for use").

Combination with cannabidiol increases the frequency of transaminase elevations.

In 19% of patients of various ages receiving cannabidiol at doses of 10 to 25 mg/kg and valproate concomitantly in clinical trials, ALT elevations greater than three times the upper limit of normal were reported. Appropriate liver monitoring is required when valproate is used concomitantly with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and consideration should be given to dose reduction or discontinuation of the drug in case of significant deviations in liver function tests (see section "Special precautions for use").

Special precautions for use.

Pregnancy prevention programme

Valproate is a potent human teratogen with a high risk of congenital malformations and neurodevelopmental disorders in infants exposed to valproate in utero (see section “Use in pregnancy or breastfeeding”).

Depakine Chrono® 500 mg is contraindicated in the following situations:

Treatment of epilepsy

• During pregnancy, except when alternative treatment options are unavailable and after thorough patient counselling on the risks (see sections “Contraindications” and “Use in pregnancy or breastfeeding”).
• In female children and women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections “Contraindications” and “Use in pregnancy or breastfeeding”).

Treatment and prevention of bipolar disorders

• In pregnant women (see sections “Contraindications” and “Use in pregnancy or breastfeeding”).
• In women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections “Contraindications” and “Use in pregnancy or breastfeeding”).

Conditions of the Pregnancy Prevention Programme

The prescribing physician must:

• Assess individual circumstances in each case, involve the patient in discussions, ensure her engagement, discuss treatment options, and guarantee understanding of the risks and necessary measures to minimise them;
• Evaluate the possibility of pregnancy in all female patients;
• Ensure the patient fully understands the risks of congenital malformations and neurodevelopmental disorders, particularly the significance of these risks for children exposed to valproate in utero;
• Ensure the patient understands the necessity of a pregnancy test prior to starting treatment and during treatment if required;
• Advise the patient to use contraception and verify her ability to adhere to continuous use of effective contraceptive methods (additional information is provided in the “Contraception” subsection of this boxed warning) throughout the entire course of valproate treatment;
• Ensure the patient understands the need for regular (at least annual) review by a specialist experienced in treating epilepsy or bipolar disorders;
• Ensure the patient understands the necessity of consulting her physician if she plans a pregnancy, to allow timely discussion and transition to alternative treatments before conception and before discontinuation of contraception;
• Ensure the patient understands the necessity of urgent consultation with her physician if pregnancy occurs;
• Provide the Patient Information Leaflet;
• Ensure the patient understands the dangers and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).

These conditions also apply to women who are currently not sexually active, except when, in the physician’s opinion, there are compelling reasons to consider the risk of pregnancy negligible.

Female children

• The prescribing physician must ensure that parents/guardians of female children understand the necessity of consulting a specialist immediately after the onset of menstruation in a female child receiving valproate.
• The prescribing physician must ensure that parents/guardians of female children receive comprehensive information about the risks of congenital malformations and neurodevelopmental disorders, including the extent of these risks for children exposed to valproate during their in utero development.
• In patients who have already started menstruation, the prescribing physician must annually reassess the necessity of valproate treatment and consider the possibility of alternative treatments. If valproate remains the only acceptable treatment, the necessity of effective contraception and all other conditions of the Pregnancy Prevention Programme must be discussed. The specialist should take all possible measures to transition female children to alternative treatments before they reach sexual maturity or adulthood.

Pregnancy testing. Pregnancy must be excluded before initiating valproate therapy. Valproate treatment must not be initiated in women of childbearing potential without a negative pregnancy test result using blood plasma with a sensitivity of at least 25 mIU/mL, confirmed by a healthcare professional, to prevent inadvertent exposure during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.

Contraception. Women of childbearing potential prescribed valproate must use effective contraception continuously throughout the entire treatment period. These patients must receive comprehensive information on pregnancy prevention and be referred for contraceptive counselling if they are not using effective contraceptive methods. At least one effective contraceptive method (preferably user-independent, such as an intrauterine device or implant) or two complementary methods, one of which must be a barrier method, should be used. The choice of contraceptive method must be individualised, involving the patient in the discussion to ensure active participation and adherence to the chosen preventive measures. Even in patients with amenorrhoea, all recommendations for effective contraception must be followed.

Estrogen-containing medicines. Concomitant use of Depakine Chrono® 500 mg with estrogen-containing medicines, including estrogen-containing hormonal contraceptives, may potentially reduce the efficacy of valproate (see section “Interaction with other medicinal products and other forms of interaction”). Physicians prescribing Depakine Chrono® 500 mg must monitor clinical response (seizure control) when initiating or discontinuing estrogen-containing agents. However, valproate does not reduce the efficacy of hormonal contraceptives.

Annual specialist review of treatment. A specialist must reassess at least annually whether valproate remains the most appropriate treatment for the patient. The specialist must discuss the Annual Risk Acknowledgement Form at the beginning of treatment and during each annual review, ensuring the patient understands the information provided. The Annual Risk Acknowledgement Form must be properly completed and signed by both the prescribing physician and the patient (or her legal representative).

Planning pregnancy. If a woman plans to become pregnant, a specialist experienced in managing epilepsy must reassess valproate treatment and consider alternative treatment options. All possible measures should be taken to transition the patient to suitable alternative treatments before conception and before discontinuation of contraception (see section “Use in pregnancy or breastfeeding”). If such transition is not possible, the woman should receive additional counselling on the risks associated with valproate for the unborn child to ensure she is adequately informed for making decisions regarding family planning.

Regarding use in bipolar disorders, if a woman plans to become pregnant, consultation with a specialist experienced in treating bipolar disorder is required, and valproate therapy should be discontinued and, if necessary, replaced with alternative treatment (pharmacological or non-pharmacological) before conception and before discontinuation of contraception.

Pregnancy. If a woman taking valproate becomes pregnant, she must be immediately referred to a specialist for reassessment of valproate treatment and consideration of alternative treatment options. Pregnant patients who received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding treatment during pregnancy (see section “Use in pregnancy or breastfeeding”).

The pharmacist must ensure that:

• With each dispensing of valproate, the patient receives a patient card and understands the information provided;
• Patients are advised not to discontinue valproate and to seek immediate specialist consultation if pregnancy is planned or suspected.

Educational materials. To assist healthcare professionals and patients in avoiding valproate use during pregnancy, the marketing authorisation holder provides educational materials to further highlight the warnings regarding teratogenicity (the ability to cause congenital malformations) and fetotoxicity (the ability to cause neurodevelopmental disorders) of valproate and to provide instructions on the use of valproate in women of childbearing potential and detailed information on the requirements of the Pregnancy Prevention Programme. The Patient Information Leaflet and patient card must be provided to all women of childbearing potential receiving valproate.

The specialist and the patient (or her legal representative) must use, properly complete, and sign the Annual Risk Acknowledgement Form at the start of treatment and during each annual review of valproate treatment.

Congenital malformations and neurodevelopmental disorders following in utero exposure to Depakine Chrono® 500 mg (see sections “Use in pregnancy or breastfeeding” and “Side effects”). Clinical study data show that valproate use is associated with a high risk of congenital malformations (incidence of 11% in children exposed to valproate in utero).

Additionally, children exposed to valproate in utero have a high risk of neurodevelopmental disorders (with an incidence of up to 30–40%) (see sections “Use in pregnancy or breastfeeding” and “Side effects”).

Use in male patients of reproductive potential

Data from a retrospective observational study conducted in two countries indicate a trend towards an increased risk of neurodevelopmental disorders in children born to male patients who received valproate during the three months before and/or during conception, compared to those who received lamotrigine or levetiracetam (see section “Use in pregnancy or breastfeeding”). The risk for children conceived by male patients who discontinued valproate at least three months before conception (to allow for a complete new spermatogenesis cycle without valproate exposure) is unknown.

Despite the limitations of the study, as a precautionary measure, the prescribing physician must inform the male patient about this potential risk and the preventive measures required. The physician should discuss with the patient the necessity of effective contraceptive methods, including for the partner, during valproate use and for three months after discontinuation. The physician must also inform the male patient about the following:

• Not to donate sperm during valproate use and for three months after discontinuation;
• The necessity of consulting a specialist if the male patient plans to conceive a child, prior to discontinuing contraception, to discuss alternative treatment options;
• The need to consult appropriate physicians together with the partner as soon as possible if pregnancy occurs, when the child was conceived during the father’s valproate use or within three months after discontinuation, for risk assessment and recommendations.

Male patients should also be informed about the necessity of regular (at least annually) review of treatment by a specialist experienced in treating epilepsy or bipolar disorder. The specialist must reassess at least annually whether valproate remains the most effective treatment for the patient. During such a review, the specialist must ensure the patient fully understands the risks, has comprehended the information provided, and is aware of the necessary precautions when using valproate. An updated version of the instructions for use should be provided to all male patients of reproductive potential receiving valproate. The patient must sign the Annual Risk Acknowledgement Form, which includes confirmation of receipt of the instructions for use, at the beginning of treatment and during each annual specialist review. Educational materials are available for healthcare professionals and male patients. The patient card is issued with each new prescription of valproate.

Exacerbation of seizures. As with other antiepileptic drugs, valproate may paradoxically cause a reversible worsening of seizure frequency and severity (including status epilepticus) or the emergence of new seizure types, instead of improving the condition. Patients should be advised to seek immediate medical attention if seizures worsen (see section “Side effects”).

These seizures must be differentiated from those that may occur due to pharmacokinetic interactions (see section “Interaction with other medicinal products and other forms of interaction”), toxicity (hepatic injury or encephalopathy, see sections “Special precautions for use” and “Side effects”) or overdose.

Since this medicinal product is metabolised to valproic acid, it must not be combined with other medicinal products undergoing the same transformation to avoid valproic acid overdose (e.g., sodium valproate, valpromide).

Severe liver injury

Conditions of occurrence. Rare cases of severe liver injury, sometimes leading to fatal outcomes, have been reported. Experience shows that the highest risk occurs in infants and children under 3 years of age with severe epilepsy. This particularly applies to children with brain damage, intellectual disability, and/or genetically determined metabolic or degenerative disorders, including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, mutations in the mitochondrial DNA polymerase gamma (POLG) gene, and during complex antiepileptic therapy, including the use of cannabidiol.

In children aged 3 years and older, the risk significantly decreases and progressively diminishes with age.

In most cases, such liver injury occurred within the first 6 months of treatment, usually within 2–12 weeks.

Clinical features and diagnosis. Early diagnosis primarily depends on clinical and biological monitoring. Symptoms that may precede jaundice, especially in high-risk patients (see above “Conditions of occurrence”), should be considered, particularly if they occur suddenly:

• Non-specific general symptoms, such as:
• Somnolence, lethargy, indifference, impaired consciousness, confusion, agitation, abnormal movements, malaise, asthenia;
• Anorexia, nausea, sometimes accompanied by repeated vomiting and abdominal pain;
• Bruising, epistaxis;
• Localised or generalised oedema;
• In patients with epilepsy – recurrence of epileptic seizures, increased frequency or severity of seizures.

The patient (or their caregivers, if the patient is a child) should be informed about the necessity of seeking immediate medical attention if these symptoms occur.

The patient must be immediately examined, including clinical assessments and laboratory tests of liver function. Fatal cases have been reported with normal liver function tests shortly after the onset of clinical symptoms. Therefore, normal laboratory results do not exclude liver injury in a patient with clinical signs of liver dysfunction.

Before initiating valproate therapy, a detailed medical history must be obtained, particularly regarding metabolic disorders, liver, pancreas, and coagulation disorders. Metabolic disorders, liver, pancreas, and coagulation disorders in the patient and family members (see section “Contraindications”). Liver function should be tested in all patients, with periodic monitoring for 6 months, especially in high-risk patients (see sections “Special precautions for use. Clinical features and diagnosis” and “Interaction with other medicinal products and other forms of interaction. Risk of liver injury”).

It should be emphasised that isolated and transient elevations of transaminase levels without clinical signs are frequently observed, particularly at the beginning of therapy. In such cases, a more comprehensive laboratory evaluation is recommended (see below), dose adjustment should be considered if necessary, and tests should be repeated to monitor trends.

In addition to routine tests, the most informative are those reflecting protein synthesis, particularly prothrombin levels. If pathologically low prothrombin levels are confirmed, especially in conjunction with other abnormal biological parameters (marked decrease in fibrinogen and coagulation factors, increased bilirubin and liver enzymes), valproate therapy must be discontinued immediately.

Concomitant use of cannabidiol.

In patients receiving both valproate and cannabidiol, serum transaminase and total bilirubin levels should be measured at 2 weeks, 1 month, 2 months, 3 months, and 6 months after initiation of combination therapy, and regularly thereafter or as clinically indicated.

Pancreatitis. Very rare cases of severe pancreatitis, which could lead to fatal outcomes, have been reported. The risk is particularly high in young children, but pancreatitis may occur regardless of patient age or duration of treatment.

Unfavourable clinical outcomes from pancreatitis are generally observed in younger children or in patients with severe seizures, neurological impairments, or those receiving polytherapy with antiepileptic drugs.

The risk of fatal outcome is significantly increased when liver failure occurs with pancreatitis.

In the event of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting, and/or loss of appetite, pancreatitis should be considered, and the drug must be discontinued and appropriate alternative therapy initiated in patients with elevated pancreatic enzyme levels.

Children under 3 years of age Valproate should only be used as monotherapy. Treatment in this age group should only be initiated after careful consideration of clinical benefits versus the risk of liver injury or pancreatitis (see sections “Special precautions for use. Risk of liver injury” and “Interaction with other medicinal products and other forms of interaction”).

Concomitant administration of salicylate derivatives to children should be avoided due to the risk of hepatotoxicity and bleeding (see section “Interaction with other medicinal products and other forms of interaction”).

In children with a history of unexplained liver and gastrointestinal disorders (loss of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, developmental delay, or a family history of neonatal or infant death, metabolic assessments, particularly blood ammonia levels in fasting and postprandial states, should be performed before initiating any valproate therapy.

Estrogen-containing medicines. Valproate does not reduce the efficacy of hormonal contraceptives. However, estrogen-containing medicines, including estrogen-containing hormonal contraceptives, may increase valproate clearance, potentially leading to decreased serum valproate concentrations and reduced efficacy of valproate.

Prescribing physicians must monitor clinical response (seizure control or mood control) at the initiation or discontinuation of estrogen-containing medicines. Monitoring of serum valproate levels is recommended (see section “Interaction with other medicinal products and other forms of interaction”).

Suicidal thoughts and behaviour. Reports of suicidal thoughts and behaviour have been received in patients receiving antiepileptic drugs for various indications. A meta-analysis of data from randomised placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behaviour. The mechanism of this effect is unknown, and currently available data do not allow exclusion of an increased risk with valproate use.

Therefore, patients should be monitored for early detection of suicidal thoughts and behaviour, and appropriate therapy should be initiated. Patients (and caregivers) should be warned that if signs of suicidal thoughts or behaviour occur, immediate medical attention should be sought.

Patients with known or suspected mitochondrial disorders. Valproate may trigger or worsen clinical manifestations of existing mitochondrial disorders caused by mitochondrial DNA mutations or nuclear gene mutations encoding the mitochondrial enzyme DNA polymerase gamma (POLG).

In particular, in patients with hereditary neurometabolic syndromes caused by POLG gene mutations (e.g., Alpers-Huttenlocher syndrome), cases of valproate-induced acute liver failure and death due to liver dysfunction have been reported. POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or those with symptoms suggestive of such disorders, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Testing for POLG mutations should be performed according to current clinical practice for diagnostic evaluation of such disorders (see section “Contraindications”).

Renal impairment. In patients with renal impairment, increased blood concentrations of valproic acid should be considered, and the dose should be adjusted accordingly.

Blood tests. Blood tests (complete blood count including platelet count, assessment of bleeding time and coagulation parameters including fibrinogen, activated partial thromboplastin time (aPTT), factor VIII and related factors) are recommended before initiating treatment, at 3 and 6 months of treatment, and before any surgical procedures, especially if the dose exceeds 30 mg/kg/day, and in case of bruising or spontaneous bleeding (see sections “Side effects. Blood and lymphatic system disorders”, “Side effects. Laboratory test results”).

Urea cycle disorders and risk of hyperammonaemia. This medicinal product is contraindicated in patients with deficiencies of urea cycle enzymes. Hyperammonaemia with stupor or coma has been reported in such patients (see sections “Contraindications” and “Patients at risk of developing hypocarnitinaemia” and “Severe liver injury” in this section).

Patients at risk of developing hypocarnitinaemia. Valproate may reduce tissue and plasma carnitine concentrations, thereby altering mitochondrial metabolism, impairing fatty acid beta-oxidation and the urea cycle.

Carnitine deficiency may develop or worsen during valproate treatment. This deficiency may lead to hyperammonaemia (which may result in hyperammonaemic encephalopathy) (see sections “Side effects” and “Overdose”). Other reported symptoms include hepatotoxicity, hypoketotic hypoglycaemia, myopathy, cardiomyopathy, rhabdomyolysis and/or Fanconi syndrome, particularly in patients with risk factors for carnitine deficiency and/or pre-existing carnitine deficiency.

Patients at increased risk of symptomatic carnitine deficiency during valproate treatment include those with metabolic disorders, including carnitine-related mitochondrial disorders (see sections “Special precautions for use. Patients with known or suspected mitochondrial disorders” and “Special precautions for use. Urea cycle disorders and risk of hyperammonaemia”), patients with inadequate dietary carnitine intake, patients under 10 years of age, patients receiving pivalate-conjugated medicinal products, or those on combination therapy with other antiepileptic drugs (see sections “Interaction with other medicinal products and other forms of interaction” and “Overdose”).

Patients should be advised to immediately report any signs of hyperammonaemia (such as ataxia, confusion, vomiting, headache, tremor/asterixis) for immediate further evaluation.

If clinical symptoms of carnitine deficiency occur, additional carnitine supplementation should be considered. Carnitine levels in blood may not necessarily be reduced in such cases. Additional investigations may be required to identify carnitine deficiency.

Valproate should be used in patients with primary systemic carnitine deficiency, whose deficiency has been corrected, only if the benefit of valproate treatment outweighs the risk for these patients and no alternative treatment options are available. Patients with secondary systemic carnitine deficiency should be treated with the medicinal product after correction of the deficiency and with particular caution. These patients should be closely monitored for recurrence of carnitine deficiency.

Carnitine-palmitoyltransferase (CPT) type II deficiency. Patients with primary carnitine-palmitoyltransferase (CPT) type II deficiency should be warned about the increased risk of rhabdomyolysis during valproate use. Carnitine supplementation should be considered in these patients; see also sections “Interaction with other medicinal products and other forms of interaction”, “Side effects”, “Overdose”.

Patients with systemic lupus erythematosus. Although immunological disorders have been reported in rare cases during use of this medicinal product, the benefit-risk ratio should be considered in patients with systemic lupus erythematosus.

Weight gain. At the beginning of treatment, patients should be informed about the risk of weight gain, and appropriate measures, primarily related to diet, should be taken to minimise this effect.

Effect of long-term treatment on bone metabolism. Cases of decreased bone mineral density, which may indicate osteopenia or osteoporosis and even lead to atypical fractures, have been reported in patients undergoing long-term treatment with valproic acid. The mechanism of valproic acid’s effect on bone metabolism is not yet fully understood (see section “Side effects”).

Interaction with other medicinal products. This medicinal product is not recommended for concomitant use with lamotrigine and penems (carbapenems) (see section “Interaction with other medicinal products and other forms of interaction”).

Cognitive or extrapyramidal disorders. Cognitive or extrapyramidal disorders may be accompanied by signs of brain atrophy on imaging studies. This may lead to misinterpretation of the clinical picture as dementia or Parkinson’s disease. These disorders are reversible after discontinuation of the drug (see section “Side effects”).

Alcohol. Alcoholic beverages should not be consumed during valproate treatment.

Effect on laboratory and diagnostic tests. Since valproate is primarily excreted by the kidneys, partially as ketone bodies, urine ketone testing may yield false-positive results in patients with diabetes mellitus.

Sodium. This medicinal product contains 47 mg of sodium per tablet, equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for adults. This should be considered by patients on a strict low-sodium diet.

Use in pregnancy or breastfeeding.

Valproate is contraindicated (see sections “Contraindications” and “Special precautions for use”):

• During pregnancy, except when alternative treatment options for epilepsy are unavailable;
• For treatment of bipolar disorder during pregnancy;
• In female children and women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme.

Pregnancy

Teratogenicity and effects on fetal development following exposure in male and female patients. In women, valproate use as monotherapy or in combination therapy, including with other antiepileptic drugs, is frequently associated with unfavourable pregnancy outcomes. Available data indicate an increased risk of severe congenital malformations and central nervous system disorders with valproate monotherapy or combination therapy compared to the general population not exposed to valproate. Valproate has been shown to cross the placental barrier in both animals and humans (see section “Pharmacokinetics”). Teratogenic effects of valproate have been demonstrated in mice, rats, and rabbits (see section “Preclinical safety data”).

Risk for children born to male patients receiving valproate. Data from a retrospective observational study of electronic medical records conducted in three Nordic countries indicate a trend towards an increased risk of neurodevelopmental disorders in children (aged 0–11 years) born to male patients who received valproate during the three months before and/or during conception, compared to those who received lamotrigine or levetiracetam. The cumulative risk of neurodevelopmental disorders, adjusted for major risk factors and parental risk factors, ranged from 4.0% to 5.6% in the group of fathers receiving valproate and from 2.3% to 3.2% in the group of fathers receiving lamotrigine or levetiracetam monotherapy, depending on the country. The adjusted risk ratio, combined across the three countries (including all subtypes), was 1.50 (95% CI: 1.09–2.07) in the meta-analysis.

Due to study limitations, it is not possible to determine which of the investigated subtypes of neurodevelopmental disorders (autism spectrum disorders, intellectual disability, speech disorders, attention deficit/hyperactivity, musculoskeletal disorders) contribute to the overall increased risk.

Physicians must inform male patients of reproductive potential about this potential risk and the preventive measures required, including the necessity of effective contraception during valproate use and for three months after discontinuation. The physician should discuss alternative treatment options with the patient at the beginning of treatment and during each annual review of drug use (see section “Special precautions for use”).

Congenital malformations following in utero exposure. A meta-analysis including registry studies and cohort studies showed that approximately 11% of children born to women with epilepsy who received valproate monotherapy during pregnancy had severe congenital malformations. This risk of major malformations is higher than in the general population, where the risk is approximately 2–3%. The risk of severe congenital malformations in children exposed to combination antiepileptic therapy including valproate is higher than with combination therapy without valproate. This risk is dose-dependent with valproate monotherapy, and available data suggest it is also dose-dependent with combination therapy including valproate. However, a threshold dose below which the risk is absent cannot be established.

Available data indicate an increased incidence of minor or major malformations. The most common malformations include neural tube defects (approximately 2–3%), facial dysmorphisms, cleft lip and palate, craniosynostosis, heart, kidney, and urogenital system malformations (particularly hypospadias), limb malformations (including bilateral radial aplasia), and multiple anomalies affecting various organ systems.

In utero exposure to valproate may also lead to hearing impairments or loss due to ear and/or nose malformations (secondary effect) and/or direct toxic effects on auditory function. Cases of unilateral or bilateral deafness or hearing impairments have been reported. Not all cases reported outcomes. In most reported cases with outcomes, these hearing impairments were irreversible.

In utero exposure to valproates may lead to eye malformations (including colobomas, microphthalmia), reported in combination with other congenital malformations. These eye malformations may affect vision.

Neurodevelopmental disorders. Available data indicate that in utero exposure to valproate increases the risk of neurodevelopmental disorders in exposed children. This risk of neurodevelopmental disorders (including autism) is likely dose-dependent with valproate monotherapy, but a threshold dose below which the risk is absent cannot be established based on available data.

When valproate is used in combination with other antiepileptic drugs during pregnancy, the risk of neurodevelopmental disorders in children is also significantly increased compared to risks in children in the general population or children born to women with untreated epilepsy.

The exact period of pregnancy during which these effects pose a risk is not defined, and the possibility of risk throughout the entire pregnancy cannot be excluded.

Studies involving preschool-aged children exposed to valproate in utero as monotherapy showed that approximately 30–40% experienced developmental delays in early childhood, such as delayed speech and walking, reduced intellectual functions, inadequate language skills (expressive and receptive language), and memory impairments.

The intelligence quotient (IQ) measured in school-aged children (6 years old) exposed to valproate in utero was on average 7–10 points lower than in children exposed to other antiepileptic drugs. Although the role of other factors cannot be excluded, there is evidence that the risk of reduced intellectual function in valproate-exposed children may not depend on maternal IQ.

Data on long-term outcomes are limited.

Available data indicate that children exposed to valproate in utero have an increased risk of general psychological developmental disorders (autism spectrum disorders) (approximately 3 times) and childhood autism (approximately 5 times) compared to the general study population.

Available data from another population study show that children exposed to valproate in utero have an increased risk of attention deficit hyperactivity disorder (ADHD) (approximately 1.5 times) compared to the non-exposed study population.

Estrogen-containing medicines. Medicines containing estrogens, including estrogen-containing hormonal contraceptives, may increase valproate clearance, which is believed to lead to decreased serum valproate concentrations and potentially reduce the efficacy of valproate (see sections “Special precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

If a woman plans pregnancy. Valproate treatment in women planning pregnancy or who are pregnant must be reassessed by a specialist experienced in treating epilepsy, and all alternative treatment options should be considered. All possible measures should be taken to replace the drug in women planning pregnancy with an appropriate alternative treatment before conception and before discontinuation of contraception (see section “Special precautions for use”). If such transition is not possible, the woman should receive additional counselling on the risks of valproate use for the unborn child to ensure she is adequately informed for making decisions regarding family planning.

Regarding the indication for bipolar disorders, if a woman plans pregnancy, consultation with a specialist experienced in treating bipolar disorder is required, and valproate treatment should be discontinued and, if necessary, replaced with alternative treatment (pharmacological or non-pharmacological) before conception and before discontinuation of contraception.

Pregnant women. The use of valproate for the treatment of epilepsy is contraindicated during pregnancy, except when no appropriate alternative treatment is available (see sections “Contraindications” and “Special precautions for use”). For the treatment of bipolar disorder, valproate use is contraindicated during pregnancy.

If a woman taking valproate becomes pregnant, she must be immediately referred to a specialist for consideration of alternative treatment options.

During pregnancy, tonic-clonic seizures and status epilepticus with hypoxia in the woman may be associated with a particular risk of death for both the pregnant woman and the unborn child.

If, in exceptional circumstances, despite the known risks associated with valproate use during pregnancy and after careful evaluation of alternative treatment options, a pregnant woman must use valproate to control epilepsy, the following is recommended.

The lowest effective dose should be used, and the daily valproate dose should be divided into several doses throughout the day. The use of a prolonged-release formulation is preferred over other formulations to avoid high peak plasma concentrations (see section “Posology and method of administration”).

All pregnant patients who received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding pregnancy during treatment.

Specialised prenatal monitoring should be performed to detect possible fetal neural tube defects or other malformations.

Folic acid supplementation before and at the beginning of pregnancy may reduce the risk of neural tube defects, which are common in all pregnancies. However, available data do not confirm that this prevents birth defects or malformations due to valproate exposure.

Before delivery. Before delivery, the woman should undergo tests to assess coagulation parameters, including platelet count, fibrinogen levels, and coagulation time (activated partial thromboplastin time, aPTT).

Risk in the neonatal period. Very rare cases of haemorrhagic syndrome have been reported in newborns whose mothers took valproate during pregnancy. This haemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenaemia, and/or decreased levels of other coagulation factors. Afibrinogenaemia, which may lead to fatal outcomes, has also been reported. However, this syndrome must be differentiated from vitamin K deficiency caused by phenobarbital and enzyme inducers. Normal coagulation test results in the mother do not exclude coagulation disorders in her newborn. Therefore, newborns should have platelet count, plasma fibrinogen levels, coagulation tests, and coagulation factors assessed immediately after birth.

Cases of hypoglycaemia have been reported in newborns whose mothers took valproate during the third trimester of pregnancy.

Cases of hypothyroidism have been reported in newborns whose mothers took valproate during pregnancy.

In newborns whose mothers took valproate during the last trimester of pregnancy, withdrawal syndrome may develop (manifested by nervous excitability, irritability, increased excitability, increased neuromuscular reflex excitability, hyperkinesia, tonic disorders, tremor, seizures, and sucking disorders).

Monitoring of newborns/older children. Children exposed to valproate during their in utero development should undergo careful monitoring of neurodevelopmental parameters, and appropriate treatment should be initiated as early as necessary.

Breastfeeding. Valproate is excreted in human breast milk at concentrations of 1 to 10% of the mother’s serum levels. Blood disorders have been observed in newborns/infants whose mothers received treatment with this medicinal product (see section “Side effects”).

The decision whether to discontinue breastfeeding or to discontinue/abstain from taking Depakine Chrono® 500 mg should be made considering the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility. Cases of amenorrhoea, polycystic ovary syndrome, and elevated testosterone levels have been reported in women taking valproate (see section “Side effects”). Valproate use may also lead to impaired fertility in men (including reduced sperm motility) (see section “Side effects”). In some cases, impaired fertility is reported to be reversible and resolves at least three months after discontinuation of treatment. Limited reported cases indicate that spermogram abnormalities were not reversible even several months later. In other cases, the consequences of these abnormalities are unknown (see sections “Side effects” and “Pharmacological properties. Fertility”).

Ability to affect reaction speed when driving or operating machinery.

Due to possible adverse effects, Depakine Chrono® 500 mg may negatively affect the ability to drive vehicles and operate machinery.

Patients, particularly those who drive or operate machinery, should be warned about the risk of somnolence, especially if they are receiving combination antiepileptic therapy or concomitant therapy with other medicinal products that may enhance somnolence.

Method of Administration and Dosage

Epilepsy Treatment

Female children, women of childbearing potential, and pregnant women

Valproate therapy should be initiated and supervised by a specialist experienced in the treatment of epilepsy.

Valproate should not be used in female children, adolescents, women of childbearing potential, or pregnant women, except in cases where alternative treatments are ineffective or not tolerated. In such cases, valproate must be prescribed in accordance with the requirements of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Depakine Chrono® 500 mg is a prolonged-release formulation of Depakine, which provides lower peak plasma concentrations and more stable plasma levels throughout the day.

Due to its active ingredient content, this medicinal product is intended for use only in adults and children with body weight above 17 kg.

This dosage form is not suitable for use in children under 6 years of age (risk of aspiration during swallowing).

Among oral dosage forms, syrup, oral solution, and prolonged-release granules are most appropriate for administration to children under 11 years of age.

Dosage

The initial daily dose is 10–15 mg/kg, which should then be increased until the optimal dose is achieved (see "Initiation of Treatment").

The average dose of the drug is 20–30 mg/kg body weight per day. However, if seizures remain uncontrolled at this dose, the dose may be increased with careful patient monitoring.

The most commonly recommended daily doses are:

• 25 mg/kg for children; 20–25 mg/kg for adolescents;
• 20 mg/kg for adults;
• 15–20 mg/kg for elderly patients.

The daily dose should be determined based on the patient’s age and body weight; however, it should be noted that the range of individual sensitivity to valproate is quite wide.

A clear correlation between daily dose, plasma concentrations, and therapeutic effect has not been established: the dose should primarily be determined based on clinical response.

If seizure control cannot be achieved or if adverse effects are suspected, in addition to clinical monitoring, measurement of valproic acid plasma concentrations is recommended. The effective therapeutic range is generally between 40 and 100 mg/L (300 to 700 µmol/L).

Method of Administration

Oral administration

This medicinal product should be taken daily in one or two doses, preferably with food. Once-daily administration may be considered in patients with well-controlled epilepsy.

The tablet must be swallowed whole, without crushing or chewing.

Initiation of Treatment

In patients who have achieved adequate disease control with immediate-release formulations of Depakine, it is recommended to maintain the corresponding daily dose when switching to Depakine Chrono® 500 mg.

If the patient is already receiving treatment and taking other antiepileptic drugs, treatment with Depakine Chrono® 500 mg should be initiated gradually, reaching the optimal dose over approximately 2 weeks, after which concomitant drug doses may be reduced as needed, depending on treatment efficacy.

If the patient is not taking any other antiepileptic drugs, the dose should preferably be increased stepwise every 2 or 3 days to achieve the optimal dose within approximately 1 week.

If combination therapy with other antiepileptic drugs is required, they should be introduced gradually (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Patients with renal impairment may require dose reduction or dose adjustment. Sodium valproate is dialyzable (see section "Overdose"). The dose should be adjusted based on clinical monitoring of the patient (see section "Special Warnings and Precautions for Use").

Manic episodes associated with bipolar affective disorders. Valproate treatment should be initiated and supervised by a specialist experienced in the treatment of bipolar disorders. For women of childbearing potential and pregnant women, see section "Contraindications".

The recommended initial dose is 20 mg/kg/day. This dose should be increased as rapidly as possible until the minimum therapeutic dose that achieves the desired clinical effect is reached.

The desired clinical effect is generally achieved with plasma valproate concentrations between 45 and 125 µg/mL.

The recommended maintenance dose in the treatment of bipolar disorder is 1000–2000 mg/day. Rarely, the dose may be increased up to the maximum level of 3000 mg/day. The dose should be adjusted according to individual clinical response.

Prevention of relapse of manic episodes in bipolar disorders. The dose for relapse prevention corresponds to the lowest effective dose that adequately controls symptoms of acute mania in the individual patient. The maximum daily dose of 3000 mg should not be exceeded.

Children.

The drug is prescribed for epilepsy in children with body weight above 17 kg. This dosage form is not recommended for children under 6 years of age (risk of aspiration during swallowing).

Among oral dosage forms, syrup, oral solution, and prolonged-release granules are most appropriate for administration to children under 11 years of age.

The safety and efficacy of valproate in the treatment of manic episodes associated with bipolar affective disorders have not been established in patients under 18 years of age.

Overdose.

At plasma concentrations 5–6 times higher than the therapeutic maximum, nausea, vomiting, and dizziness may occur.

Signs of acute massive overdose typically include: superficial or deep coma without agitation, muscular hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, arterial hypotension, circulatory collapse/shock. Several cases of intracranial hypertension associated with cerebral edema have been reported. Fatal outcomes have occurred following massive overdose. However, the prognosis in cases of overdose is generally favorable.

Emergency hospital management should include, if necessary, gastric lavage, maintenance of adequate diuresis, and continuous monitoring of cardiovascular and respiratory functions. In very severe cases, extracorporeal blood purification should be performed if necessary.

The prognosis in such poisoning is generally favorable. However, several fatal cases have been reported.

Symptoms of overdose may vary, and seizures may occur in the presence of very high plasma levels of the active substance.

The sodium content in valproate may lead to hypernatremia in cases of overdose.

In cases of valproate overdose leading to hyperammonemia, intravenous carnitine may be administered in an attempt to normalize ammonia levels.

Adverse Reactions

Adverse reactions are categorized by organ systems. The frequency of occurrence is defined as follows: very common ≥ 10%; common ≥ 1% and < 10%; uncommon ≥ 0.1% and < 1%; rare ≥ 0.01% and < 0.1%; very rare < 0.01%; unknown (cannot be estimated from available data).

Congenital, familial and genetic disorders

Congenital malformations and developmental disorders of the nervous system (see sections "Special precautions for use" and "Use in pregnancy or breastfeeding").

Disorders of the blood and lymphatic system

Common: anaemia, thrombocytopenia.

Cases of dose-dependent thrombocytopenia have been reported, which typically occurred in a predictable manner and had no clinical consequences.

In patients with asymptomatic thrombocytopenia, simple dose reduction, if possible, considering platelet levels and disease control, usually leads to resolution of thrombocytopenia.

Uncommon: pancytopenia, leukopenia.

Rare: bone marrow aplasia, erythroid aplasia, agranulocytosis; macrocytic anaemia, macrocytosis.

Frequency unknown: acquired Pelger-Huët anomaly (predominantly, but not exclusively, observed in myelodysplastic syndrome).

Investigations

Common: weight gain*.

Rare: decreased levels of coagulation factors (at least one), pathological coagulation test results (e.g., prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio (INR)) (see sections "Special precautions for use" and "Use in pregnancy or breastfeeding"), vitamin B8 (biotin) deficiency / biotinidase deficiency.

* Since weight gain is a risk factor for polycystic ovary syndrome, body weight should be carefully monitored in female patients (see section "Special precautions for use").

Disorders of the nervous system

Very common: tremor.

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

Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism**, ataxia, paraesthesia.

Rare: diplopia, cognitive disorders with gradual onset and progressive development (which may progress to full dementia), which were reversible within several weeks or months after discontinuation of the drug**.

* Cases of stupor and lethargy have been reported, sometimes leading to transient coma (encephalopathy) during valproate treatment. Symptoms improved after discontinuation or dose reduction of valproate. These effects most frequently occur during combination therapy (especially with phenobarbital or topiramate) or after a rapid increase in valproate dose.

** These symptoms may be accompanied by signs of cerebral atrophy on imaging studies.

Disorders of the ear and labyrinth

Common: hearing loss.

Disorders of the respiratory system, thoracic organs and mediastinum

Uncommon: pleural effusion.

Gastrointestinal disorders

Very common: nausea.

Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhoea, which may occur at the beginning of treatment and usually resolve within a few days without the need to discontinue the drug.

Uncommon: pancreatitis, sometimes fatal, requiring immediate discontinuation of the drug (see section "Special precautions for use").

Disorders of the kidneys and urinary tract

Common: urinary incontinence.

Uncommon: renal failure.

Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome.

Disorders of the skin and subcutaneous tissue

Common: transient and/or dose-dependent alopecia, nail and nail bed disorders.

Uncommon: angioneurotic oedema, skin reactions, abnormal hair growth (such as unusual hair texture, hair colour changes, abnormal hair growth).

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) or drug hypersensitivity syndrome.

Endocrine disorders

Uncommon: syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilization, acne, androgenic alopecia and/or increased androgen hormone levels).

Rare: hypothyroidism (see section "Use in pregnancy or breastfeeding").

Metabolic and nutritional disorders

Common: weight gain. Since weight gain may worsen clinical symptoms of polycystic ovary syndrome, body weight should be carefully monitored.

Common: hyponatraemia.

Rare: hyperammonaemia* (see section "Special precautions for use"), obesity.

* Isolated cases of mild hyperammonaemia without changes in standard liver function tests have been reported, particularly during polytherapy, which do not require discontinuation of treatment. In the absence of clinical symptoms, discontinuation of treatment is not necessary. However, cases of hyperammonaemia associated with neurological symptoms (which may progress to coma) have also been reported; additional investigations should be performed (see also section "Special precautions for use. Urea cycle disorders and risk of hyperammonaemia. Patients at risk of developing carnitine deficiency").

Unknown: carnitine deficiency (see sections "Contraindications" and "Special precautions for use").

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Rare: myelodysplastic syndromes.

Vascular disorders

Common: haemorrhage (see section "Special precautions for use").

Uncommon: cutaneous vasculitis, predominantly leukocytoclastic vasculitis.

General disorders

Uncommon: mild peripheral oedema, hypothermia.

Hepatobiliary disorders

Common: liver injury (see section "Special precautions for use").

Disorders of the reproductive system

Common: dysmenorrhoea.

Uncommon: amenorrhoea.

Rare: male infertility (particularly decreased sperm motility) (see section "Use in pregnancy or breastfeeding"), polycystic ovaries.

Musculoskeletal, connective tissue and bone disorders

Uncommon: decreased bone mineral density, osteopenia, osteoporosis, fractures in patients receiving long-term valproate treatment. The mechanism by which valproate affects bone metabolism is not established.

Rare: acute systemic lupus erythematosus, rhabdomyolysis (see section "Special precautions for use").

Psychiatric disorders

Common: psychosis, hallucinations, aggression*, agitation*, attention disturbances*.

Rare: abnormal behaviour*, psychomotor hyperactivity*, learning difficulties*.

* These adverse reactions are mainly observed in children.

Children

The safety profile of valproate in children is similar to that in adults, but some adverse reactions are more severe or predominantly observed in children. There is a particular risk of severe liver injury in infants and children under 3 years of age. Younger children are also at particular risk of pancreatitis. These risks decrease with age (see section "Special precautions for use"). Psychiatric disorders such as aggression, agitation, attention disturbances, abnormal behaviour, psychomotor hyperactivity and learning disorders are predominantly observed in children.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of the reach and sight of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

No. 30: 30 tablets in a container closed with a cap containing a desiccant, in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sanofi Winthrop Industrie.

Manufacturer's address and place of business.

1, rue de la Vierge AMBARE ET LAGRAVE 33565 – CARBON BLANC Sédex, France.