Valprocom 500 chrono

INSTRUCTIONS for medical use of the medicinal product VALPROCOM 500 chrono (VALPROCOM 500 chrono)

Composition:

Active substances: sodium valproate/valproic acid;

One tablet of Valprocom 500 Chrono contains 333 mg of sodium valproate and 145 mg of valproic acid (equivalent to 500 mg of sodium valproate per tablet);

Excipients: ethylcellulose, ammonio-methacrylate copolymer (type B), silicon dioxide colloidal anhydrous, coating for film coating (hypromellose, glycerin, ammonio-methacrylate copolymer (type A), polyacrylate dispersion, polyethylene glycol 1500, talc).

Pharmaceutical form. Film-coated prolonged-release tablets.

Main physicochemical properties: white, round, biconvex tablets with a score line on one side, film-coated.

Pharmacotherapeutic group. Antiepileptic agents. Fatty acid derivatives.

ATC code N03A G01.

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 the 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 blood 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 valproate administration 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 an antiepileptic effect 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 HIV-1 replication; 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 considered for the correct 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 yielded the following results.

After oral administration, the bioavailability of the drug in plasma approaches 100%. The active ingredient of Valprocom 500 Chrono in plasma is valproic acid.

The absorption of the prolonged-release formulation Valprocom 500 Chrono in the gastrointestinal tract begins immediately and continues with a uniform and prolonged profile. This results in the absence of plasma concentration peaks 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 fluid. Valproate penetrates into cerebrospinal fluid and brain tissue.

Valproate crosses the placental barrier in both animals and humans (see section "Use in pregnancy or breastfeeding").

In animals, valproate crosses the placental barrier to the same extent as in humans.

Several publications have assessed valproate concentrations in umbilical cord blood of newborns during delivery in humans: the concentration of valproate in umbilical cord serum 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 total plasma concentrations of valproic acid of 40–100 mg/L, the free fraction typically constitutes 6–15%. In patients with renal insufficiency, there is a tendency toward increased free fraction due to reduced albumin levels and, consequently, reduced number of available binding sites.

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

Valproic acid is removed during dialysis, but the amount eliminated 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 the total serum concentration) in women who received Valprocom 500 Chrono 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 valproate therapy, steady-state serum concentrations of valproic acid are reached 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 typically ranges from 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.

Metabolism of Valprocom 500 Chrono occurs primarily 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 degradation or that of other substances such as estrogens and progestogens. This property indicates that it does not induce enzymes of the cytochrome P450 metabolic system.

There are more than 10 known metabolites, some of which have demonstrated anticonvulsant properties in animal studies. The primary metabolic pathway is glucuronidation (approximately 40%), which occurs mainly via UGT1A6, UGT1A9, and UGT2B7 enzymes. Enterohepatic recirculation is present.

Elimination.

With continuous administration of valproic acid, the 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 (while in full-term neonates and infants during the first month of life it is 20–30 hours), but later gradually approaches values typical for children and adults, i.e., 8–22 hours with an average 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 either its own degradation or that of other substances such as estrogen-progestogen agents and oral anticoagulants.

Valproic acid is primarily excreted 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 insufficiency. Reduced binding to albumin occurs. The possibility of increased serum concentration of the free fraction of valproic acid should be considered. In such cases, the drug 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 formulation at equivalent doses demonstrates the following characteristics:

• no absorption delay;
• prolonged absorption;
• identical bioavailability;
• lower total maximum plasma concentration (Cmax) and free fraction plasma concentration (Cmax approximately 25% lower with a relatively stable plateau from 4–14 hours after administration); this "peak smoothing" effect provides more stable and 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 10 years of age, valproate clearance is similar to that in adults. In patients under 10 years of age, systemic valproate clearance varies with age.

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

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

Non-clinical safety data.

Animal studies have shown that in utero exposure to valproate leads to 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 induce DNA repair activity in primary rat hepatocyte cultures. However, in vivo results with teratogenic doses were conflicting, depending on the route of administration. After oral administration—the primary route 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. Additionally, published studies reported increased sister chromatid exchanges in patients with epilepsy exposed to valproate compared to healthy subjects not receiving this treatment. However, when comparing data from patients with epilepsy treated with valproate to those not treated, results were conflicting. The clinical significance of these DNA/chromosome findings is unknown.

In traditional non-clinical carcinogenicity studies, no specific risk for humans was identified.

Reproductive toxicity

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

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

It is known that in repeat-dose toxicity studies, valproate caused testicular degeneration/atrophy or abnormalities in spermatogenesis and reduced testicular weight in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.

Fertility. In subchronic and chronic repeat-dose toxicity studies, 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. However, no adverse effects on testes were observed at doses of 270 mg/kg/day 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. After administration of maximum tolerated doses (up to 90 mg/kg/day), no effect on male reproductive organs was noted. Reduced testicular weight was observed only at highly toxic doses (≥240 mg/kg/day intraperitoneally or intravenously) without associated histopathological changes. The sensitivity of testes to valproate effects in the pediatric rat population is unknown.

Clinical characteristics.

Indications.

The primary indication for the medicinal product Valprocom 500 Chrono, preferably as monotherapy, is primary generalized epilepsy: minor epileptic seizures / absence epilepsy, generalized bilateral myoclonic seizures, major epileptic seizures with or without myoclonia, photosensitive forms of epilepsy.

The medicinal product Valprocom 500 Chrono is also effective, either as monotherapy or in combination with other antiepileptic agents, 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).

For the treatment of manic episodes associated with bipolar affective disorders in adult patients when contraindications to or intolerance of lithium exist.

For the prevention of relapses of dysthymic episodes in adult patients with bipolar disorders who have shown a therapeutic response to valproate during treatment of manic episodes.

Contraindications.

Treatment of epilepsy

Contraindicated during pregnancy, except when no alternative treatment options are available and the patient has been fully informed of the risks (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Contraindicated in female children and women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Treatment and prevention 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 unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

All indications

Hypersensitivity to valproate, valproate semisodium, divalproate, valpromide, or to any of the excipients of the medicinal product.

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 the mitochondrial enzyme polymerase gamma, e.g., Alpers–Huttenlocher syndrome, in children under two years of age suspected of having a polymerase gamma-related disorder, 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 hypocarnitinaemia (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 reduction in valproic acid plasma concentrations, which may fall below detectable levels.

Concomitant administration of valproic acid and carbapenems has led to a reduction in plasma valproic acid concentrations by approximately 60–100% within about two days. Due to the rapid onset of these changes and the extent of plasma concentration reduction, concomitant use with carbapenems should be avoided in patients whose condition is stabilized on valproic acid and in whom monitoring is not feasible (see section "Special precautions for use").

Combinations requiring special precautions during use.

Clozapine. Concomitant treatment with valproates and clozapine may increase the risk of clozapine-induced neutropenia and myocarditis. If concomitant use of valproate and clozapine is necessary, appropriate careful monitoring of the patient is required.

Acetazolamide. Possible enhancement of hyperammonaemia, increasing the risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

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

Carbamazepine. Possible increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose. Additionally, decreased plasma concentrations of valproic acid 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 monitoring, and possibly dose adjustment of valproate during and after felbamate therapy are indicated.

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

Metamizole. During antiepileptic therapy, concomitant use of metamizole may reduce serum valproate concentrations, potentially reducing the clinical efficacy of valproate.

Monitoring of clinical response (seizure control or mood control) is required, and monitoring of serum valproate concentrations should be considered if necessary when used concomitantly with metamizole.

Methotrexate. Some reports describe a significant decrease in serum valproate levels after methotrexate administration, leading to seizures. Physicians prescribing the drug should monitor clinical response (seizure control or mood control) and consider monitoring serum valproate levels if necessary.

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

Phenobarbital and, by extrapolation, primidone. Possible enhancement of hyperammonaemia, increasing the risk of encephalopathy. Regular monitoring of clinical and laboratory parameters is indicated.

Phenytoin and, by extrapolation, fosphenytoin. Possible enhancement of hyperammonaemia, increasing the 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 the propofol dose should be considered.

Rifampicin. Risk of seizures due to enhanced hepatic metabolism of valproate. Clinical monitoring, laboratory monitoring, and possibly 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 with body weight less than 30 kg, the total daily dose should not exceed 600 mg after titration.

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

Zidovudine. Risk of increased zidovudine adverse reactions, particularly haematological, due to reduced metabolism by valproic acid. Regular monitoring of clinical and laboratory parameters is indicated. During the first two months of combination therapy, a complete blood count should be performed to detect anaemia.

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

Other types of interactions.

Pivalate-conjugated medicinal products. Concomitant use of valproate and pivalate-conjugated medicinal products, which reduce carnitine levels (e.g., cefditoren pivoxil, adefovir dipivoxil, pivmecillinam, and pivampicillin), may lead to the development of hypocarnitinaemia (see section "Special precautions for use. Patients at risk of developing hypocarnitinaemia"). Concomitant use of these medicinal products with valproate is not recommended. In patients for whom concomitant use cannot be avoided, careful monitoring for signs and symptoms of hypocarnitinaemia is required.

Lithium. Valprocom 500 Chrono does not affect serum lithium levels.

Risk of liver injury.

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

Concomitant use of valproate with polytherapy antiepileptic treatment increases the risk of liver injury, particularly in younger children (see section "Special precautions for use").

Combination with cannabidiol increases the frequency of transaminase elevation.

In 19% of patients of various ages receiving cannabidiol at doses of 10 to 25 mg/kg and valproate simultaneously in clinical trials, an increase in ALT (alanine aminotransferase) levels more than 3 times above the upper limit of normal was observed. Appropriate monitoring of liver function is required when valproate is used concomitantly with other antiepileptic agents with potential hepatotoxicity, including cannabidiol, and consideration should be given to dose reduction or discontinuation of the drug in case of significant abnormalities in liver function tests (see section "Special precautions for use").

Special precautions for use.

Pregnancy prevention programme.

Valproate is a potent teratogen; therefore, infants exposed to valproate in utero have a high risk of congenital malformations and neurodevelopmental disorders (see section "Use during pregnancy or breastfeeding").

Valprocom 500 Chrono is contraindicated in the following cases:

Treatment of epilepsy

• During pregnancy, except when no alternative treatment options are available and the patient has been fully informed of the risks (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
• In female children and women of childbearing potential if the conditions of the Pregnancy Prevention Programme are not met (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Treatment and prophylaxis of bipolar disorders

• In pregnant women (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
• In women of childbearing potential if the conditions of the Pregnancy Prevention Programme are not met (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Conditions of the Pregnancy Prevention Programme.

The prescribing physician must:

• In each case, assess individual circumstances, involve the patient in discussions, ensure her engagement, discuss treatment options, and ensure understanding of risks and measures necessary to minimise risks;
• Assess the possibility of pregnancy in all female patients;
• Ensure the patient understands and is aware of 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 performing a pregnancy test before initiating treatment and, if necessary, during treatment;
• Advise the patient to use contraception and verify her ability to comply with recommendations for continuous use of effective contraceptive methods (additional information is provided in the subsection "Contraception" below) throughout the entire course of valproate treatment;
• Ensure the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in managing epilepsy or bipolar disorders;
• Ensure the patient understands the necessity of consulting her physician if she plans pregnancy, to discuss this issue in a timely manner and switch to alternative treatments before conception and before discontinuing contraceptive methods;
• Ensure the patient understands the necessity of urgent consultation with her physician if pregnancy occurs;
• Provide the patient with an Information Leaflet;
• Ensure the patient understands the dangers and necessary precautionary measures associated with the use of valproate (Annual Risk Information Form).

These conditions also apply to women who are currently not sexually active, except in cases where, in the physician’s opinion, there are compelling reasons to assume no risk of becoming pregnant.

Female children.

• The prescribing physician must ensure that parents/guardians of female children understand the necessity of immediately consulting a specialist once menstruation begins in a female child receiving valproate.
• The prescribing physician must ensure that parents/guardians of female children have received 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 menstruating, the prescribing physician must annually reassess the necessity of valproate treatment and consider the possibility of switching to alternative treatments. If valproate remains the only acceptable treatment option, the necessity of using effective contraceptive methods and all other conditions of the Pregnancy Prevention Programme should 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 should not be initiated in women of childbearing potential unless a negative result from a plasma pregnancy test with a sensitivity of at least 25 mIU/mL, approved by a healthcare professional, has been obtained to exclude unintended exposure during pregnancy. This pregnancy test should be repeated at regular intervals during treatment.

Contraception. Women of childbearing potential prescribed valproate must use effective contraceptive methods continuously throughout the entire period of valproate treatment. These patients should 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 a user-independent method 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 should be evaluated on an individual basis, involving the patient in discussions to ensure her active participation and adherence to selected preventive measures. Even if a patient experiences amenorrhea, she must follow all recommendations for effective contraception.

Estrogen-containing medicines. Concomitant use of Valprocom 500 Chrono with medicines containing estrogens, including estrogen-containing hormonal contraceptives, may reduce the efficacy of valproate (see section "Interaction with other medicinal products and other forms of interaction"). Physicians prescribing Valprocom 500 Chrono should 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. The specialist should reassess at least annually whether valproate remains the most appropriate treatment for this patient. The specialist must discuss the Annual Risk Information Form at the beginning of treatment and during each annual review and ensure the patient understands the information provided. The Annual Risk Information 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 should reassess valproate treatment and consider the possibility of using alternative treatments. All possible measures should be taken to transition the patient to acceptable alternative treatments before conception and before discontinuing contraception (see section "Use during pregnancy or breastfeeding"). If such transition is not possible, the woman should receive additional counselling regarding the risks associated with valproate for the unborn child to ensure she is adequately informed to make an informed decision about family planning.

Regarding use in bipolar disorders, if a woman plans to become pregnant, consultation with a specialist experienced in treating bipolar disorder is recommended, and valproate therapy should be discontinued and, if necessary, replaced with alternative treatment (pharmacological or non-pharmacological) before conception and before discontinuing 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 treatments. Pregnant patients who received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding valproate use during pregnancy (see section "Use during pregnancy or breastfeeding").

The pharmacist must ensure that:

• At each dispensing of valproate, the patient receives a patient card and understands the information provided;
• The patient is advised not to discontinue valproate and to immediately consult a specialist if planning pregnancy or suspecting pregnancy.

Educational materials. To assist healthcare professionals and patients in avoiding valproate use during pregnancy, the marketing authorisation holder provides educational materials to further highlight warnings regarding teratogenicity (ability to cause congenital malformations) and fetotoxicity (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 using valproate.

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

Congenital malformations and neurodevelopmental disorders following in utero exposure to Valprocom 500 Chrono (see sections "Use during pregnancy or breastfeeding" and "Undesirable effects"). Clinical data show that valproate use is associated with a high risk of congenital malformations [incidence of 11% in children exposed to valproate in utero].

Furthermore, children exposed to valproate in utero have a high risk of neurodevelopmental disorders (incidence up to 30–40%) (see sections "Use during pregnancy or breastfeeding" and "Undesirable effects").

Use in male patients of reproductive age.

Data from a retrospective observational study conducted in two countries indicate a trend towards increased risk of neurodevelopmental disorders (NDR) in children born to male patients who took valproates during the three months before and/or during conception, compared to those who took lamotrigine or levetiracetam (see section "Use during 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 should inform the male patient about this potential risk (see section "Use during pregnancy or breastfeeding") and necessary preventive measures. The physician should discuss with the patient the necessity of using effective contraceptive methods, including for his sexual partner, during valproate use and for at least three months after discontinuation. The physician should also inform the male patient that:

• Sperm donation should not be performed during valproate use and for at least three months after discontinuation;
• If the male patient plans to conceive a child, he should consult a specialist before discontinuing contraception to discuss alternative treatment options;
• If pregnancy occurs, the woman and her partner should seek prompt consultation with appropriate physicians if the child was conceived by a man during valproate use or within three months after discontinuation, to assess risks and receive recommendations.

Male patients should be informed of the necessity for regular (at least annual) review of treatment by a specialist experienced in managing epilepsy or bipolar disorder. The specialist should reassess at least annually whether valproate remains the most effective treatment for the patient. During such review, the specialist must ensure the patient fully understands the risks, comprehends the provided information, and the necessary precautionary measures when using valproate. An updated version of the valproate use instructions should be provided to all male patients of reproductive age. The patient must sign the Annual Risk Information Form, confirming receipt of instructions, 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 any antiepileptic drug, valproate administration may, instead of improving the condition, lead to reversible worsening of seizure frequency and severity (including status epilepticus) or the emergence of a new seizure type. Patients should be advised to consult their physician immediately if seizures worsen (see section "Undesirable 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 (liver injury or encephalopathy, see sections "Special precautions for use" and "Undesirable effects") or overdose.

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

Risk of 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, particularly with concomitant use of other antiepileptic drugs, occurs in infants and children under 3 years of age with severe epilepsy, especially in 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 use of cannabidiol.

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

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

Clinical features and diagnosis.

Early diagnosis primarily depends on clinical and biological monitoring. Symptoms (which usually appear suddenly) that may precede jaundice, especially in high-risk patients (see above "Conditions of occurrence"), should be considered:

• Non-specific symptoms, such as:
  • Drowsiness, 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 of the need to seek immediate medical attention if these symptoms occur.

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

Before initiating valproate therapy, a detailed medical history should be obtained, particularly regarding metabolic disorders, liver, pancreatic diseases, and coagulation disorders in the patient and family members (see section "Contraindications"). Liver function should be tested in all patients, followed by periodic monitoring for 6 months, especially in high-risk patients (see section "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 increases in transaminase levels without clinical signs are frequently observed, especially at the beginning of therapy. In such cases, further comprehensive laboratory testing (see below) is recommended, dose adjustment should be reviewed if necessary, and tests repeated to monitor trends.

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

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 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. Pancreatitis with unfavourable clinical outcomes is typically observed in younger children or patients with severe seizure episodes, neurological impairments, or those receiving polytherapy with anticonvulsants.

The risk of fatal outcome is significantly increased in cases of liver failure associated with pancreatitis.

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

Children under 3 years of age Valprocom 500 Chrono should be used only as monotherapy. Therapy in this age group should be initiated only after comparing clinical benefits against the risk of liver injury or pancreatitis development (see section "Special precautions for use. Risk of liver injury" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use of salicylate derivatives should be avoided in children 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 and particularly fasting and postprandial blood ammonia tests 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 reduced serum valproate concentrations and decreased efficacy of valproate.

Prescribing physicians should 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 have been received of suicidal thoughts and behaviour in patients receiving antiepileptic drugs for various indications. A meta-analysis of data from randomised placebo-controlled trials of antiepileptic drugs also showed a slight increase in the 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 prescribed. Patients (and caregivers) should be warned that if signs of suicidal thoughts or behaviour appear, immediate medical help should be sought.

Severe skin reactions and angioedema. Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema, have been reported during valproate treatment. Patients should be informed about signs and symptoms of serious skin manifestations and closely monitored. If symptoms suggestive of these severe skin reactions or angioedema occur, valproate use should be immediately discontinued and alternative treatment options considered.

Patients with known or suspected mitochondrial disorders. Valproate may trigger or worsen clinical symptoms of existing mitochondrial disorders caused by mutations in mitochondrial DNA or the nuclear gene encoding mitochondrial 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 exhibiting symptoms indicating 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 mutation should be performed according to current clinical practice for diagnostic evaluation of such disorders (see section "Contraindications").

Renal impairment. In patients with renal impairment, elevated blood concentrations of valproic acid should be considered, and the dose of the medicinal product should be appropriately reduced.

Blood tests. Blood tests (complete blood count with platelet count, assessment of bleeding time and coagulation parameters, including fibrinogen level, 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 section "Undesirable effects", subsections "Blood and lymphatic system disorders", "Investigations").

Urea cycle disorders and risk of hyperammonaemia. This medicinal product is contraindicated in patients with deficiencies of urea cycle enzymes. Several cases of hyperammonaemia with stupor or coma have been reported in such patients (see section "Contraindications" and subsections "Patients at risk of developing hypocarnitinaemia" below and "Risk of liver injury" above).

Patients at risk of developing hypocarnitinaemia. Valproate may reduce tissue and plasma carnitine concentrations and, consequently, alter mitochondrial metabolism, impairing beta-oxidation of fatty acids 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 "Undesirable effects" and "Overdose"). Other symptoms reported include hepatotoxicity, hypoketotic hypoglycaemia, myopathy, cardiomyopathy, rhabdomyolysis, and Fanconi syndrome, particularly in patients with risk factors for carnitine deficiency or pre-existing carnitine deficiency.

Patients at increased risk of symptomatic carnitine deficiency during valproate treatment include those with metabolic disorders, including mitochondrial disorders related to carnitine (see subsections "Patients with known or suspected mitochondrial disorders" and "Urea cycle disorders and risk of hyperammonaemia" above), patients with carnitine deficiency due to inadequate dietary intake, patients under 10 years of age, patients concurrently using pivalate-conjugated medicinal products, or those receiving combination therapy with other antiepileptic drugs (see sections "Interaction with other medicinal products and other forms of interaction" and "Overdose").

Patients should be warned 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 appear, the possibility of additional carnitine supplementation should be considered. Blood carnitine levels may not necessarily be reduced in such cases. Additional investigations may be required to identify carnitine deficiency.

Valproate may be used in patients with primary systemic carnitine deficiency that has been corrected only if the benefit of valproate treatment outweighs the risk and no alternative treatment options are available. In such patients, careful monitoring for recurrence of hypocarnitinaemia is required.

Carnitine palmitoyltransferase (CPT) type II deficiency. Patients with primary CPT type II deficiency should be warned of 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", "Undesirable effects", "Overdose".

Patients with systemic lupus erythematosus. Although immunological disorders have been reported only rarely during valproate use, the benefit-risk ratio of using this medicinal product should be carefully 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, indicating possible osteopenia or osteoporosis and even leading 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 "Undesirable effects").

Interaction with other medicinal products. This medicinal product is not recommended to be prescribed concomitantly 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 clinical picture may be misinterpreted as dementia or Parkinson's disease. These disorders are reversible after discontinuation of the drug (see section "Undesirable 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, partly as ketone bodies, urine ketone testing may yield false-positive results in patients with diabetes mellitus.

Sodium. This medicinal product contains 48.2 mg of sodium per tablet, equivalent to 2.4% of the WHO recommended maximum daily sodium intake of 2 g for adults. This should be considered by patients on a strict low-sodium diet.

Use during pregnancy or breastfeeding.

Treatment of epilepsy Valproate is contraindicated during pregnancy, except in cases where there are no alternative treatment methods and the patient has been fully informed about the associated risks. Valproate is contraindicated for use in female children and women of reproductive age unless the conditions of the Pregnancy Prevention Programme are met (see sections "Contraindications" and "Special warnings and precautions for use"). Treatment and prophylaxis of bipolar disorder Valproate is contraindicated during pregnancy. Valproate is contraindicated for use in women of reproductive age unless the conditions of the Pregnancy Prevention Programme are met (see sections "Contraindications" and "Special warnings and precautions for use").

Teratogenicity and effects on intrauterine development following administration to female and male patients. In women, the use of valproate as monotherapy or in combination therapy, including with other antiepileptic drugs, is frequently associated with adverse pregnancy outcomes. Available data indicate an increased risk of major congenital malformations and central nervous system disorders with valproate monotherapy and 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").

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

Available data indicate an increased frequency of rare and common malformations. The most common malformations include neural tube defects (approximately 2–3%), facial dysmorphism, cleft lip and palate, craniosynostosis, cardiac, renal, and urogenital 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 impairment or loss due to ear and/or nasal malformations (secondary effect) and/or direct toxic effects on auditory function. Cases of unilateral and bilateral deafness or hearing impairment have been reported. Not all cases reported outcomes; in most reports with available outcomes, such hearing impairments were irreversible.

Intrauterine exposure to valproate may result in congenital eye malformations (including coloboma, microphthalmia), which have been reported in combination with other congenital malformations. These eye malformations may affect vision.

Neurodevelopmental disorders due to intrauterine exposure.

Available data indicate that valproate increases the risk of neurodevelopmental disorders in children exposed in utero. The risk of neurodevelopmental disorders (including autism) is likely dose-dependent when valproate is used as monotherapy, although a threshold dose below which the risk disappears cannot be established based on current 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 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 has not been defined, and the possibility of risk throughout the entire pregnancy cannot be excluded.

Studies involving preschool-aged children exposed in utero to valproate monotherapy have shown that developmental delays in early childhood occur in approximately 30–40% of cases, including delays in speech and walking, reduced intellectual function, poor language skills (both expressive and receptive language), and memory impairment.

The intelligence quotient (IQ) measured in school-aged children (aged 6 years) exposed in utero to valproate was on average 7–10 points lower than in children exposed to other antiepileptic drugs.

Although the role of other factors cannot be excluded, evidence indicates that the risk of reduced intellectual function in children exposed to valproate may not depend on maternal IQ levels. Data on long-term outcomes are limited.

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

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

Women of childbearing potential. The medicinal product Valprocom 500 Chrono should not be used in women of childbearing potential and in pregnant women, except when other treatment options are ineffective or poorly tolerated by the patient. If alternative treatments cannot be used, Valprocom 500 Chrono may be prescribed only if the requirements of the Pregnancy Prevention Programme are met (see section "Special warnings and precautions for use"), including:

• the patient is not pregnant (negative pregnancy test results using plasma with a sensitivity of at least 25 mIU/mL at the start of treatment and periodically during treatment);
• the patient uses at least one effective method of contraception;
• the patient has been informed of the risks associated with valproate use during pregnancy.

Women of childbearing potential require regular benefit-risk assessment during treatment (at least annually).

Estrogen-containing medicinal products. Medicinal products containing estrogens, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which is believed to lead to reduced serum concentrations of valproate and may reduce its efficacy (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

If a woman is planning pregnancy.

Treatment with valproate in women planning pregnancy or who are pregnant should be re-evaluated by a specialist experienced in epilepsy management, and all alternative treatment options should be considered. Where possible, all measures should be taken to switch women planning pregnancy to an appropriate alternative treatment before conception and before discontinuing contraception (see section "Special warnings and precautions for use"). If such a switch is not possible, the woman should receive additional counseling regarding the risks of valproate use for the unborn child, enabling her to make an informed decision about family planning.

Regarding use of the medicinal product in bipolar disorder, if a woman is planning pregnancy, she should consult a specialist experienced in the treatment of bipolar disorder, and valproate treatment should be discontinued and, if necessary, replaced with alternative treatment (pharmacological or non-pharmacological) before conception, prior to discontinuation of contraception.

Pregnant women.

The use of valproate for the treatment of epilepsy is contraindicated during pregnancy, except when no suitable alternative treatment is available (see sections "Contraindications" and "Special warnings and precautions for use"). The use of valproate during pregnancy is contraindicated in the treatment of bipolar disorder.

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

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

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

The lowest effective dose should be used, and the daily dose of valproate should be divided into several doses taken 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 have received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for pregnancy evaluation and counseling during treatment.

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

Folic acid supplementation before and during early pregnancy may reduce the risk of neural tube defects, which are common in pregnancy. However, available data do not confirm that this prevents birth defects or malformations caused by valproate exposure.

Before delivery.

Prior to delivery, coagulation parameters should be assessed in the woman, including platelet count, fibrinogen levels, and coagulation time (activated partial thromboplastin time, aPTT).

Risk in the neonatal period.

Hemorrhagic syndrome in newborns whose mothers took valproate during pregnancy has been reported very rarely. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or reduced levels of other coagulation factors. Cases of afibrinogenemia, which may lead to fatal outcomes, have also been reported. However, this syndrome must be differentiated from vitamin K deficiency caused by phenobarbital and enzyme inducers. Normal coagulation parameters in the mother do not exclude coagulation disorders in her newborn. Therefore, in newborns, platelet count, plasma fibrinogen levels, coagulation tests, and coagulation factors should be assessed immediately after birth.

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

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

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

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

Risk for children born to male patients who received valproate within 3 months before conception.

Results from a retrospective observational study conducted in three Northern European countries indicate an increased risk of neurodevelopmental disorders (NDDs) in children (aged 0 to 11 years) born to men who received valproate monotherapy during the 3 months before and/or during conception, compared to those whose fathers received monotherapy with lamotrigine or levetiracetam. The cumulative risk of NDDs, adjusted for general risk factors and parental risk factors, ranged from 4.0% to 5.6% in the valproate group and from 2.3% to 3.2% in the lamotrigine/levetiracetam group, depending on the country. The adjusted risk ratio, combined across the three countries in a meta-analysis (accounting for all subtypes), was 1.50 (95% CI [confidence interval]: 1.09–2.07).

Due to study limitations, it is not possible to determine which of the investigated NDD subtypes (autism spectrum disorders, intellectual disability, speech disorders, attention deficit/hyperactivity, musculoskeletal disorders) contribute to the overall increased risk of NDDs. Study limitations also include potential confounding by indication and differences in observation duration between exposure groups. The average observation period for children in the valproate group ranged from 5.0 to 9.2 years, compared to 4.8 and 6.6 years in the lamotrigine/levetiracetam group. Overall, an increased risk of NDDs in children whose father took valproate within 3 months before and/or during conception is possible, although a causal relationship with valproate has not been confirmed. Additionally, the study did not assess the risk of NDDs in children born to men who discontinued valproate more than 3 months before conception (implying spermatogenesis occurred without valproate exposure).

Physicians prescribing the medicinal product should inform male patients of reproductive age about this potential risk and the preventive measures to be taken. The physician should discuss with the patient the need for effective contraception, particularly for his sexual partner, during valproate treatment and for at least three months after discontinuation of treatment (see section "Special warnings and precautions for use"). Male patients should not donate sperm during treatment and for at least 3 months after discontinuation of valproic acid-containing medications.

Male patients should also be informed about the necessity of regular (at least annual) review of treatment by a specialist experienced in the treatment of epilepsy or bipolar disorder. During such a review, the specialist should ensure that the patient fully understands the risks, comprehends the information provided, and is aware of the necessary preventive measures when using valproate. The specialist should review at least annually whether valproate remains the most effective treatment option for the patient. At the start of treatment and during each annual review of the medicinal product use, the physician should discuss with male patients planning to father a child alternative treatment options (see section "Special warnings and precautions for use"). Individual circumstances should be evaluated in each case.

Breast-feeding.

Valproate is excreted in human breast milk at concentrations ranging from 1 to 10% of maternal plasma levels. Blood disorders have been observed in newborns/infants whose mothers received treatment with this medicinal product (see section "Undesirable effects").

The decision whether to discontinue breast-feeding or to discontinue/abstain from Valprocom 500 Chrono treatment should be made considering the benefits of breast-feeding for the child and the benefits of treatment for the woman.

Fertility.

Cases of amenorrhea, polycystic ovary syndrome, and elevated testosterone levels have been reported in women taking valproate (see section "Undesirable effects"). Valproate use may also lead to impaired fertility in men (including reduced sperm motility) (see section "Undesirable effects"). In some cases, impaired fertility has been reported to be reversible and resolves at least 3 months after discontinuation of treatment. Limited case reports suggest that abnormalities in semen analysis were not reversible even several months later. In other cases, the outcomes of such abnormalities are unknown (see sections "Undesirable effects" and "Pharmacological properties. Fertility").

Ability to affect reaction speed when driving or operating machinery.

Due to possible adverse effects, Valprocom 500 Chrono may negatively affect the ability to drive or operate machinery.

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

Method of Administration and Dosage

The medicinal product should be taken orally, preferably with food. The daily dose should be taken once or divided into two doses. Single-dose administration may be considered in cases of well-controlled epilepsy. The tablet should be swallowed whole, without crushing or chewing, with half a glass of water, milk, or another non-alcoholic beverage. Due to the prolonged-release mechanism and the type of excipients used, the inert matrix of the medicinal product is not absorbed in the gastrointestinal tract—it is excreted during defecation after release of the active substance.

Treatment of Epilepsy

Girls and Women of Reproductive Age

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

Valproate should not be used in girls and female adolescents, women of reproductive age, or pregnant women, except when other treatment options 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").

Men

It is recommended that treatment with Valprocom 500 Chrono be initiated and supervised by a specialist experienced in the treatment of epilepsy or bipolar disorders (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy and Lactation").

Valprocom 500 Chrono is a prolonged-release formulation that provides lower peak plasma concentrations and ensures more stable plasma levels throughout the day.

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

This dosage form is not suitable 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.

Dosage

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

The average dose of the medicinal product is 20–30 mg/kg body weight per day. However, if seizures are not controlled at this dose, the dose may be increased with careful patient monitoring.

Recommended daily doses are as follows:

• 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 according to the patient’s age and body weight; however, it should be noted that the range of individual sensitivity to valproate is quite broad.

There is no clear correlation between the daily dose of the drug, its serum levels, and therapeutic effect: the dose should be determined primarily based on clinical response.

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

Initiation of Treatment

In patients who have achieved adequate disease control with immediate-release valproate formulations, it is recommended to maintain the equivalent total daily dose when switching to Valprocom 500 Chrono.

If the patient is already receiving treatment with other antiepileptic drugs, Valprocom 500 Chrono should be introduced 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 receiving other antiepileptic drugs, the dose should preferably be increased stepwise every 2 or 3 days to reach 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, and patients undergoing hemodialysis may require dose adjustment. Sodium valproate is dialyzable (see section "Overdose"). Dose adjustments should be 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 reproductive age 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 achieving 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 to the maximum level of 3000 mg/day. The dose should be adjusted according to individual clinical response.

Prevention of Recurrent Manic Episodes in Bipolar Disorders

The dose for prevention of recurrence corresponds to the lowest effective dose that adequately controls symptoms of acute mania in the patient. The maximum daily dose of 3000 mg should not be exceeded.

Children

The medicinal product is prescribed for 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, and circulatory collapse/shock.

Several cases of intracranial hypertension associated with cerebral edema have been reported. There have been cases in which massive overdose resulted in fatal outcomes. However, the prognosis in cases of overdose is generally favorable.

Emergency hospital care 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 required.

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

Symptoms of overdose may vary, and seizures may occur if plasma levels of the active substance are extremely high.

Cases of intracranial arterial hypertension caused by cerebral edema have been reported.

The presence of sodium in the valproate formulation may lead to hypernatremia in cases of overdose.

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

Side effects.

Side effects are classified by organ system and frequency of occurrence: 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); frequency not known (cannot be estimated from available data).

Congenital, familial and genetic disorders: congenital malformations and disorders of nervous system development (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Blood and lymphatic system disorders: common − anaemia, thrombocytopenia.

Cases of dose-dependent thrombocytopenia have been reported, which typically occurred in a systematic pattern and had no clinical consequences. In patients with asymptomatic thrombocytopenia, dose reduction, if possible, considering platelet levels and disease control, usually leads to resolution of thrombocytopenia.

Uncommon − pancytopenia, leukopenia; rare − macrocytosis, macrocytic anaemia, red bone marrow aplasia or erythrocyte aplasia, agranulocytosis.

Frequency not known — acquired Pelger-Huët anomaly (mainly observed in myelodysplastic syndrome).

Investigations: common – weight gain*; rare − decreased levels of coagulation factors (at least one), abnormal coagulation test results (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio [INR]) (see sections "Special precautions for use" and "Use during 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").

Nervous system disorders: very common − tremor; common − somnolence, headache, nystagmus, extrapyramidal disorders**, stupor*, sedation, convulsions*, memory impairment, nausea or dizziness; uncommon − coma*, encephalopathy*, paraesthesia, ataxia, reversible parkinsonism**, lethargy*; rare − diplopia, cognitive disorders with gradual onset and progressive development (which may progress to complete dementia), which were reversible within several weeks or months after discontinuation of the drug**.

*Cases of stupor or lethargy have been reported, sometimes leading to transient coma (encephalopathy) during valproate therapy. Symptoms decreased after discontinuation or dose reduction. These effects most commonly 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 brain atrophy on imaging studies.

Auditory disorders: common − hearing loss.

Respiratory, thoracic and mediastinal disorders: uncommon − pleural effusion (eosinophilic).

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").

Renal and urinary disorders: common – urinary incontinence; uncommon − renal failure; rare − enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome.

Skin and subcutaneous tissue disorders: common − transient and/or dose-dependent alopecia, nail and nail bed abnormalities; uncommon − angioneurotic oedema, skin reactions, abnormal hair growth (e.g., pathological hair texture, hair colour change, 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, frequency not known − hyperpigmentation.

Endocrine disorders: uncommon − syndrome of inappropriate antidiuretic hormone secretion, hyperandrogenism (hirsutism, virilization, acne, androgenic alopecia and/or increased androgen hormone levels); rare − hypothyroidism (see section "Use during pregnancy or breastfeeding").

Metabolism and nutrition disorders: common − weight gain (since weight gain may worsen clinical symptoms of polycystic ovary syndrome, body weight should be carefully monitored), hyponatraemia; rare − hyperammonaemia* (see also 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 and patients at risk of developing carnitine deficiency").

Frequency not known − carnitine deficiency (see sections "Contraindications" and "Special precautions for use").

Benign, malignant and unspecified neoplasms (including cysts and polyps): rare − myelodysplastic syndrome.

Vascular disorders: common − haemorrhage (see sections "Special precautions for use"); uncommon – skin vasculitis, predominantly leukocytoclastic vasculitis.

General disorders: uncommon − hypothermia, mild peripheral oedema.

Hepatobiliary disorders: common − liver damage (see section "Special precautions for use").

Reproductive system disorders: common − dysmenorrhoea; uncommon − amenorrhoea; rare − male infertility (particularly decreased sperm motility) (see section "Use during pregnancy or breastfeeding"), polycystic ovaries.

Musculoskeletal, connective tissue and bone disorders: uncommon − decreased bone mineral density, osteopenia, osteoporosis, fractures in patients during long-term valproate therapy. 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, aggression*, attention disturbances*, hallucinations, agitation*; rare − abnormal behaviour*, psychomotor hyperactivity*, learning difficulties*.

*These adverse reactions are mainly observed in children.

Children.

The safety profile of valproate in children is the same as in adults, but some adverse reactions are more severe or predominantly observed in children. There is an increased risk of severe liver damage in infants and young children, especially under 3 years of age. Younger children also have a higher risk of developing 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 mainly observed in children.

Reporting suspected adverse reactions.

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

Shelf life.

3 years. Do not use the medicinal product after the expiry date.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C. Do not refrigerate or freeze!

Packaging.

10 tablets in a blister; 1, 3 or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Pharma Start".

Manufacturer's location and address of its business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

Date of last review.

If adverse effects occur or if you have questions regarding the safety of using the medicinal product, please contact the pharmacovigilance department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.