Depakin chrono® 300 mg

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPAKINE® CHRONO 300 mg (DEPAKINE® CHRONO 300 mg)

Composition:

Active substances: sodium valproate and valproic acid;

One tablet contains sodium valproate 199.8 mg, valproic acid 87.0 mg (equivalent to 300 mg of sodium valproate);

Excipients: hypromellose 4000 (3000 mPa·s), ethylcellulose 20 mPa·s, colloidal anhydrous silica, sodium saccharin;

Coating: hypromellose (6 mPa·s), polyethylene glycol 6000, talc, titanium dioxide (E 171), polyacrylate dispersion or dry extract.

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties: elongated, almost white tablets with a break line, coated with a film coating.

Pharmacotherapeutic group. Antiepileptic agents. Fatty acid derivatives.

ATC code N03AG01.

Pharmacological Properties

Pharmacodynamics

In pharmacological studies in animals, valproate inhibited various experimentally induced seizures (generalized and focal). Similarly, in humans, the antiepileptic effect of valproate may also be observed in different types of epilepsy. Valproate most likely acts by enhancing GABA-ergic activity and by inhibiting or suppressing the spread of electrical discharge.

In some in vitro studies, a stimulatory effect of valproate on HIV-1 replication was observed. However, this effect is not very pronounced and is not reproducible in all experiments. The clinical implications of this observation in HIV-1-infected patients are unknown. These data should be taken into account when evaluating viral load in HIV-1-infected patients receiving sodium valproate.

Pharmacokinetics

Absorption. The bioavailability of valproate in blood plasma after oral administration is approximately 100%.

The drug Depakine Chrono® 300 mg is present in the blood plasma as valproic acid. Depakine Chrono® 300 mg is rapidly absorbed in the gastrointestinal tract. Its absorption is consistent and prolonged. Therefore, there are no peak concentrations of the drug in plasma, and therapeutic concentrations of valproic acid are better maintained over time.

Distribution. The volume of distribution of valproic acid is primarily limited to blood and extracellular fluid undergoing rapid exchange. Valproic acid is predominantly bound to plasma albumin. Protein binding is dose-dependent and saturable. At total drug levels in plasma of 40–100 mg/L, approximately 6–15% of valproic acid is unbound.

The level of valproic acid in cerebrospinal fluid is close to the concentration of the unbound substance in plasma (approximately 10%).

Valproic acid is subject to dialysis, but the hemodialyzable fraction is very limited (approximately 10%) due to binding of the active substance to albumin.

Valproic acid crosses the placental barrier (see section "Use during pregnancy or breastfeeding") in both animals and humans:

• In animals, valproate crosses the placental barrier in amounts approximately similar to those in humans.
• Several publications have evaluated the concentration of valproate in the umbilical cord of newborns during delivery in humans. The concentration of valproate in umbilical serum, corresponding to fetal concentration, was similar to or slightly higher than maternal concentration.

When Depakine Chrono® 300 mg is administered to breastfeeding women, valproic acid is excreted in breast milk (1–10% of the total concentration in blood serum).

It takes approximately 3–4 days, and sometimes longer, to achieve steady-state concentrations of valproic acid in blood serum when initiating chronic treatment with Depakine Chrono® 300 mg.

The effective therapeutic range for valproic acid levels in plasma is generally considered to be 40–100 mg/L (278–694 µmol/L). If total plasma valproic acid levels exceed 150 mg/L (1040 µmol/L), the daily dose should be reduced.

Metabolism. Metabolism of Depakine Chrono® 300 mg occurs primarily in the liver. The main metabolic pathways are conjugation with glucuronic acid and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate its own degradation or the degradation of other substances such as estrogen-progestogens. This property indicates that it does not induce enzymes of the cytochrome P450 metabolic system.

Elimination. During long-term treatment, the mean elimination half-life of valproic acid from plasma in adults is 10.6 hours (but may range from 5 to 20 hours), forming the basis for a twice-daily dosing regimen. In full-term infants, the half-life is 20–30 hours. However, it rapidly approaches adult values as the infant matures. Valproic acid is primarily excreted by the kidneys. A small fraction remains unchanged, but most is found in urine as metabolites.

Pharmacokinetics in specific patient populations

In patients with renal impairment, albumin binding is reduced. Therefore, increased free fraction of valproic acid in plasma should be considered, and the dose should be adjusted accordingly. Pharmacokinetic parameter changes have been observed in elderly patients, but they were not clinically significant. Thus, clinical response (seizure control) is decisive for dose adjustment.

Preclinical data. Teratogenic effects of the drug were observed in studies in animals (mice, rats, and rabbits).

Mutagenicity. Genotoxicity studies on gene mutation induction and chromosomal aberrations did not indicate genotoxic effects of valproate in vitro (in the Ames test), in mouse lymphoma L5178Y cells at the thymidine kinase locus (mouse lymphoma assay), or induction of DNA repair activity in primary rat hepatocyte cultures. In vivo, after oral administration, valproate did not induce chromosomal aberrations in rat bone marrow or dominant lethal effects in mice.

However, publications have reported increased incidence of DNA and chromosomal damage (DNA strand breaks, chromosomal or micronucleus aberrations) in rodents after intraperitoneal administration of valproate. The significance of these results obtained via intraperitoneal administration is unknown.

A statistically significant increase in sister chromatid exchange (SCE) frequency was observed in patients receiving valproate compared to healthy individuals not taking valproate. However, these data may have been influenced by confounding factors. Two published studies on SCE frequency in epileptic patients treated with valproate versus untreated patients yielded conflicting results. The biological significance of increased SCE frequency is unknown.

Carcinogenicity. Two-year carcinogenicity studies were conducted in mice and rats receiving oral doses of valproate of approximately 80 and 160 mg/kg/day (the maximum tolerated doses for these species, but lower than the maximum recommended human dose based on body surface area). Subcutaneous sarcomas were observed in male rats, and hepatocellular carcinomas and bronchioloalveolar adenomas occurred at a slightly higher frequency in male mice compared to concurrent controls, but were comparable to historical control data. Therefore, sodium valproate is not considered carcinogenic.

Reproductive toxicity

Embryo-fetal and postnatal development

Teratogenic (affecting multiple organ systems) and embryotoxic effects have been demonstrated in mice, rats, rabbits, and monkeys.

Publications have reported behavioral deviations in the first generation of mice and rats following in utero exposure to clinically relevant doses/amounts of valproate. In mice, behavioral changes were also observed in the second and third generations, although less pronounced in the third generation, following acute in utero exposure in the first generation. The relevance of these findings to humans is unknown.

Fertility. In subchronic and chronic toxicity studies with repeated dosing, testicular degeneration/atrophy, spermatogenesis abnormalities, 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 effects 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 clinically relevant doses (up to 90 mg/kg/day). Reduced testicular weight was observed only at doses exceeding the maximum tolerated dose (from 240 mg/kg/day intraperitoneally or intravenously) without associated histopathological changes. The sensitivity of testes to valproate effects in the pediatric population is unknown.

Clinical characteristics.

Indications.

The primary indication for the use of Depakine Chrono® 300 mg, preferably as monotherapy, is primary generalized epilepsy: absence seizures/absence epilepsy, generalized myoclonic seizures, generalized tonic-clonic seizures with or without myoclonia, and photosensitive forms of epilepsy.

Depakine Chrono® 300 mg 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);
• Epilepsy with secondary generalization;
• Mixed forms of epilepsy (generalized and partial).

Treatment of manic episodes associated with bipolar affective disorders when contraindications to or intolerance of lithium exist. Prophylaxis of relapse 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

Pregnancy, except in cases where alternative treatment options are unavailable and after thorough counseling of the patient regarding risks (see sections "Special precautions" and "Use in pregnancy or lactation").

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

Treatment and prophylaxis of bipolar disorders

Contraindicated in pregnant women (see sections "Special precautions" and "Use in pregnancy or lactation").

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

All indications

Acute hepatitis or chronic hepatitis (see section "Special precautions").

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

Pancreatitis (see section "Special precautions").

Hypersensitivity to valproate, divalproex, valpromide, or to any component of the medicinal product in medical history.

Hepatic porphyria.

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

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

Combination with St. John’s wort (see section "Interaction with other medicinal products and other forms of interaction").

Patients with known systemic primary carnitine deficiency with uncorrected hypocarnitinemia (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

St. John’s wort. Risk of reduced plasma concentrations and decreased efficacy of the anticonvulsant.

Effect of valproate on other medicinal products. Valproic acid inhibits cytochrome P450 isoenzymes CYP2C9 and CYP3A. Therefore, metabolic effects can be predicted based on relevant data. Particularly significant interactions include:

• Neuroleptics, MAO inhibitors, antidepressants, and benzodiazepines. Depakine Chrono® 300 mg may potentiate the effects of other neuro-psychotropic agents such as neuroleptics, MAO inhibitors, antidepressants, and benzodiazepines. Therefore, clinical monitoring and possibly dose adjustment are required.
• Lithium. Depakine Chrono® 300 mg does not affect serum lithium levels.
• Phenobarbital. Depakine Chrono® 300 mg increases plasma concentrations of phenobarbital (due to inhibition of hepatic catabolism) and may lead to sedative effects, especially in children. Clinical monitoring during the first 15 days of combined treatment is recommended, and immediate reduction of phenobarbital dose is advised if sedation occurs; plasma levels of phenobarbital should be measured if necessary.
• Primidone. Depakine Chrono® 300 mg increases plasma levels of primidone, exacerbating its side effects (sedative effect). This interaction diminishes with prolonged use. Clinical monitoring, especially at the beginning of combination therapy, is recommended, with dose adjustment as needed.
• Phenytoin. During treatment with Depakine Chrono® 300 mg, total plasma concentrations of phenytoin decrease. This leads to an increase in the free fraction of phenytoin, potentially causing signs of overdose (valproic acid displaces phenytoin from its plasma protein binding sites and slows its hepatic catabolism). Clinical monitoring is recommended. When measuring phenytoin plasma levels, the unbound fraction should be particularly considered.
• Carbamazepine. Cases of clinical toxicity have been reported when sodium valproate/valproic acid is used in combination with carbamazepine, as sodium valproate/valproic acid may enhance the toxic effects of carbamazepine. Clinical monitoring, measurement of plasma concentrations, and dose adjustment of both anticonvulsants are indicated.
• Lamotrigine. Depakine Chrono® 300 mg reduces the metabolism of lamotrigine and nearly doubles its average elimination half-life. This interaction may increase lamotrigine toxicity, including severe skin reactions. Several serious skin reactions have been reported during the first 6 weeks of combination therapy, partially resolving upon discontinuation of therapy, and sometimes only after appropriate treatment. Careful clinical monitoring is required, and dose adjustment (reduction of lamotrigine dose) should be considered as needed.
• Penems. Risk of seizures due to rapid decrease in plasma concentrations of valproic acid, which may fall below detectable levels.
• Zidovudine. Plasma concentrations of zidovudine may increase during concomitant use of sodium valproate/valproic acid, increasing the risk of zidovudine toxicity.
• Felbamate. During treatment with Depakine Chrono® 300 mg, the average clearance of felbamate may decrease by nearly 16%.
• Olanzapine. Valproic acid may reduce plasma concentrations of olanzapine.
• Rufinamide. Plasma concentrations of rufinamide may increase depending on valproic acid concentrations. Caution is advised, especially in pediatric patients, as this effect is more pronounced in this patient population.
• Quetiapine. Increased risk of neutropenia/leukopenia may occur.
• Propofol. Increased blood levels of propofol are possible. When used concomitantly with valproate, consideration should be given to reducing the propofol dose.
• Nimodipine. Concomitant therapy with nimodipine and valproic acid may increase plasma concentrations of nimodipine by 50%.

Effect of other medicinal products on valproic acid

• Antiepileptic drugs. During concomitant use of enzyme-inducing antiepileptic drugs (including phenytoin, phenobarbital, primidone, carbamazepine), serum concentrations of valproic acid decrease. When used in combination therapy, doses should be adjusted according to clinical response and blood levels of the drug.

Concomitant use of felbamate and valproic acid may reduce the clearance of valproic acid by 22–50%, leading to dose-dependent increases in serum concentrations of valproic acid. Monitoring of plasma levels of the drug is necessary.

When administered together with phenytoin or phenobarbital, the concentration of valproic acid metabolite in serum may increase. Therefore, careful monitoring for symptoms of hyperammonemia is required in patients receiving both drugs.

• Mefloquine. During use of mefloquine, metabolism of valproic acid is enhanced, and a seizure-inducing effect may occur. Thus, there is a risk of epileptic seizures during combined use of these drugs.
• Highly protein-bound drugs. Concomitant use of Depakine Chrono® 300 mg with substances highly bound to plasma proteins (e.g., acetylsalicylic acid) may lead to increased concentrations of unbound valproic acid in serum.
• Cimetidine or erythromycin. Concomitant use with cimetidine or erythromycin may increase serum levels of valproic acid (due to inhibition of hepatic metabolism).
• Carbapenems. Decreased blood levels of valproic acid have been reported when used concomitantly with carbapenems (e.g., panipenem, meropenem, imipenem): valproic acid levels may decrease by 60–100% within two days, sometimes accompanied by seizures. Due to the rapid onset and extent of valproic acid concentration reduction, the consequences of possible interaction between valproic acid and carbapenems in patients whose condition was stable on valproic acid are considered uncontrolled. Concomitant use of valproic acid with carbapenems should be avoided in patients whose condition has been stabilized on valproic acid (see section "Special precautions"). If use of these antibiotics cannot be avoided, intensified monitoring of plasma valproic acid levels is necessary.
• Rifampicin. Serum levels of valproic acid may decrease during concomitant use of rifampicin, leading to insufficient therapeutic effect. Therefore, dose adjustment of valproate may be required when used concomitantly with rifampicin.
• Protease inhibitors. Concomitant use with protease inhibitors such as lopinavir and ritonavir increases plasma concentrations of valproate.
• Cholestyramine. Concomitant use with cholestyramine may reduce plasma concentrations of valproate.
• Estrogen-containing drugs. Valproate does not reduce the efficacy of hormonal contraceptives, as it does not induce enzymes. However, it has been shown that estrogens and estrogen-containing drugs induce UGT enzyme activity in vitro and in vivo. Enzymes UGT1A6, UGT1A9, and UGT2B7 are responsible for 40% of the biotransformation of valproic acid.

Pharmacokinetic studies, scientific publications, and post-marketing data have shown that estrogen-containing hormonal contraceptives can increase valproate clearance, potentially leading to decreased serum valproate concentrations and reduced efficacy of valproate (see sections "Method of administration and dosage", "Special precautions", and "Use in pregnancy or lactation").

• Metamizole. Metamizole is an inducer of certain cytochrome P450 isoenzymes and a potential inducer of uridine diphosphate-glucuronosyltransferases (UGT) involved in valproate biotransformation. Thus, metamizole may reduce serum concentrations of valproate, potentially reducing its therapeutic efficacy. During combined therapy with valproate and metamizole, prescribers should monitor clinical response (seizure or manic episode control) and initiate regular monitoring of serum valproate levels. If serum valproate levels decrease, or if seizures or manic episodes recur, the dose should be adjusted according to clinical response and blood levels.
• Methotrexate. Cases of significant reduction in serum valproate levels and clinical symptoms such as seizures have been reported within hours after methotrexate administration. During combined therapy with valproate and methotrexate, prescribers should monitor clinical response (seizure or manic episode control) and initiate regular monitoring of serum valproate levels.

Other types of interaction

Risk of liver injury

Concomitant use of salicylates in children should be avoided due to the risk of hepatotoxicity (see section "Special precautions").

Concomitant use of valproate with multiple anticonvulsant therapies increases the risk of liver injury, especially in younger children (see section "Special precautions"). During combination therapy with valproate and other potentially hepatotoxic anticonvulsants, physicians should monitor liver function through clinical and laboratory evaluations. If significant liver function abnormalities occur, valproate and/or concomitant potentially hepatotoxic drugs should be reduced or discontinued.

Potentially hepatotoxic drugs and alcohol may increase the hepatotoxicity of valproic acid (see section "Special precautions").

Cannabidiol

In clinical studies and literature, increased levels of ALT and AST exceeding the upper normal limit by three times have been reported in patients of various ages receiving cannabidiol at doses of 10 to 25 mg/kg and valproate simultaneously. The risk of elevated transaminases depends on patient age (younger children are more vulnerable), cannabidiol dose, and baseline transaminase levels. Additionally, concomitant use of clobazam is an additional risk factor for elevated transaminases. Furthermore, concomitant use of valproate and cannabidiol has been associated with increased frequency of thrombocytopenia, diarrhea, and appetite loss.

During combination therapy with valproate and cannabidiol, physicians must monitor liver function (especially when used concomitantly with clobazam) and platelet count (see section "Special precautions") via clinical and/or laboratory tests. If significant abnormalities occur, treatment with valproate and/or cannabidiol should be reduced or discontinued (see sections "Special precautions. Severe liver function disorders", "Special precautions. Children").

Vitamin K antagonists

Since valproic acid generally does not induce enzymes, its use does not reduce total plasma concentrations of estrogen and progestogen in women using hormonal contraceptives.

For the same reason, valproic acid use does not reduce total plasma levels of vitamin K antagonists.

However, during treatment with Depakine Chrono® 300 mg, an increase in the free fraction of warfarin may occur, as warfarin is competitively displaced from its albumin binding sites. Therefore, intensified monitoring of prothrombin levels is required during treatment with vitamin K antagonists.

Topiramate and acetazolamide

Concomitant use of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs should be closely monitored for symptoms of hyperammonemic encephalopathy.

Pivalate-conjugated medicinal products

Concomitant use of valproate with pivalate-conjugated medicinal products that reduce carnitine levels (e.g., cefditoren pivoxil, adefovir dipivoxil, pivmecillinam) is not recommended, as this may lead to hypocarnitinemia (see section "Special precautions. Patients at risk of carnitine deficiency"). Patients in whom concomitant use cannot be avoided should be closely monitored for signs and symptoms of hypocarnitinemia.

Special precautions for use.

Pregnancy prevention programme

Due to the high teratogenic potential of valproate, children exposed to the drug in utero have a high risk of congenital malformations and neurological disorders (see section "Use in pregnancy or lactation").

Depakine Chrono® 300 mg is contraindicated in the following cases:

Treatment of epilepsy

• Depakine Chrono® 300 mg is contraindicated in pregnant women, except when no alternative treatment options are available and after thorough patient counselling regarding the risks (see sections "Special precautions for use" and "Use in pregnancy or lactation").
• Depakine Chrono® 300 mg is 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 in pregnancy or lactation").

Treatment and prevention of bipolar disorders

• Depakine Chrono® 300 mg is contraindicated in pregnant women (see sections "Special precautions for use" and "Use in pregnancy or lactation").
• Depakine Chrono® 300 mg is 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 in pregnancy or lactation").

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 necessary measures to minimize risks;
• assess the possibility of pregnancy in all female patients;
• ensure the patient understands and appreciates 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 before starting treatment and, if necessary, during treatment;
• advise the patient to use contraception and verify her ability to adhere to continuous use of effective contraceptive methods (further 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 of treatment by a specialist experienced in treating epilepsy or bipolar disorders;
• ensure the patient understands the necessity of consulting her physician if she plans pregnancy, to timely discuss this issue and switch to alternative treatments before conception and before discontinuing 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 precautionary measures associated with valproate use (Annual Risk Information 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 assert the absence of pregnancy risk.

The pharmacist must ensure that:

• at each dispensing of valproate, the patient receives the patient card and understands the information provided in it;
• patients are advised not to discontinue valproate and to immediately contact a specialist in case of planned or suspected pregnancy.

Female children

• The prescribing physician must ensure that parents/guardians of female children understand the necessity of immediately consulting a specialist when menstruation begins 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 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 must take all possible measures to transition female children to alternative treatments before they reach sexual maturity or adulthood.

Pregnancy test. Pregnancy must be excluded before initiating valproate therapy. Valproate treatment must not be initiated in women of childbearing potential unless a negative pregnancy test result, using plasma blood testing approved by a healthcare professional, has been obtained to exclude unintended drug use during pregnancy. This pregnancy test must 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 must be provided with comprehensive information on pregnancy prevention and referred for contraception counselling if they are not using effective contraceptive methods.

At least one effective contraceptive method (preferably user-independent forms such as intrauterine device or implant) or two complementary contraceptive methods, one of which must be a barrier method, should be used. The choice of contraceptive method must be evaluated individually in each case, involving the patient in the discussion to ensure her active participation and adherence to the selected preventive measures. Even if the patient experiences amenorrhea, she must follow all recommendations for effective contraception.

Annual specialist review of treatment. The specialist must 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).

Pregnancy planning. Regarding use in epilepsy, if a woman plans to become pregnant, a specialist experienced in managing epilepsy patients should reassess valproate treatment and consider alternative treatment options. All possible measures must be taken to transition the patient to acceptable alternative treatments before conception and before discontinuing contraception (see section "Use in pregnancy or lactation"). 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 for making 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 required, and valproate therapy should be discontinued and, if necessary, replaced with alternative treatment (using medicinal products not containing valproic acid or non-pharmacological options) before conception, prior to 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 treatment options. Pregnant patients who received valproate during pregnancy and their partners should be referred to a teratology specialist for evaluation and counselling regarding drug use during pregnancy (see section "Use in pregnancy or lactation").

Educational materials. To assist healthcare professionals and patients in avoiding valproate use during pregnancy, the marketing authorization holder provides educational materials to draw additional attention to the warnings regarding teratogenicity (ability to cause congenital malformations) and fetotoxicity (ability to cause neurodevelopmental disorders) of valproate and to provide instructions on valproate use 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 Annual Risk Information Form must be used, properly completed, and signed at the initiation of treatment and during each annual specialist review of valproate treatment by both the specialist and the woman planning pregnancy or who is pregnant.

Hepatic injury risk

Conditions of occurrence. Cases of severe hepatic 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, particularly 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 combination antiepileptic therapy, including the use of cannabidiol.

The risk significantly decreases in children aged 3 years and older and gradually diminishes with age (see section "Special precautions for use. Children").

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

Clinical features and diagnosis. Early diagnosis primarily depends on clinical and biological monitoring. In particular, the following symptoms (which usually occur suddenly) should be considered, especially in high-risk patients (see above "Conditions of occurrence"), as they may precede jaundice:

• non-specific general symptoms, e.g.,
• somnolence, depression, indifference, impaired consciousness, confusion, agitation, abnormal movements, malaise, asthenia;
• anorexia, nausea, sometimes accompanied by recurrent vomiting and abdominal pain;
• bruising, epistaxis;
• local or generalized edema;
• in patients with epilepsy – recurrence, increased frequency, or worsening severity of epileptic seizures.

The patient (or their caregivers, if the patient is a child) should be informed about the necessity of immediate medical consultation if such symptoms occur. The patient must be immediately examined, including clinical assessments and laboratory liver function tests. Fatal cases have been reported with normal liver function test results shortly after the onset of clinical symptoms. Therefore, normal laboratory results do not exclude hepatic injury in a patient with clinical signs of liver dysfunction.

Before initiating valproate therapy, a detailed medical history should be obtained, particularly regarding the presence of metabolic disorders, liver, pancreatic diseases, and coagulation disorders. Metabolic disorders, liver, pancreatic diseases, and coagulation disorders in the patient and family members (see section "Contraindications"). Liver function should be assessed in all patients, with periodic monitoring recommended for the first 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. Hepatic injury risk").

It should be emphasized that isolated and transient increases in transaminase levels without clinical signs are frequently observed, especially at the beginning of therapy. In such cases, more comprehensive laboratory testing is recommended (see below), dosage adjustment should be reviewed as necessary, and tests should be repeated to monitor trends.

In addition to routine tests, the most informative assessments are those reflecting protein synthesis, particularly prothrombin levels. If a pathologically low prothrombin level is confirmed, especially in conjunction with other abnormal biological parameters (significant 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.

Congenital malformations and neurodevelopmental disorders in children exposed to the drug Depakine Chrono® 300 mg (see sections "Use in pregnancy or lactation" and "Adverse reactions"). Clinical study data show that valproate use leads to a high risk of congenital malformations (incidence 11% in children exposed to valproate in utero).

Furthermore, children exposed to valproate in utero as monotherapy have a high risk of neurodevelopmental disorders (with an incidence of up to 30–40%) (see sections "Use in pregnancy or lactation" and "Adverse reactions").

Use in male patients of reproductive potential

Data from a retrospective observational study conducted in two countries indicate a trend toward 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 lactation"). The risk for children conceived by male patients who discontinued valproate at least three months before conception (for a complete new spermatogenesis cycle without valproate exposure) is unknown.

Despite the study limitations, as a precautionary measure, the prescribing physician should inform the male patient about this potential risk and necessary preventive measures. 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 should 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 father a child, before discontinuing contraception, to discuss alternative treatment options;
• the necessity of urgent consultation with appropriate physicians together with the partner 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 annually verify 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 necessary precautions associated with valproate use. 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 Information Form, confirming 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.

Patients with systemic lupus erythematosus

Although sodium valproate rarely causes immunological disorders, the benefit-risk ratio should be carefully considered before initiating therapy in patients with systemic lupus erythematosus.

Pancreatitis

Very rare cases of severe pancreatitis, sometimes with fatal outcomes, have been reported. This risk is particularly high in young children and decreases with increasing patient age. Risk factors may include severe epileptic seizures, neurological deficit, or concomitant anticonvulsant combination therapy (see sections "Special precautions for use. Children", "Special precautions for use. Hepatic injury risk"). Cases of pancreatitis have been reported shortly after initiation of treatment and after several years of valproate therapy. Hepatic failure caused by pancreatitis increases the risk of fatal outcome (see sections "Special precautions for use" and "Children").

Patients and family members (if the patient is a child) must be informed about the necessity of immediate medical examination (including pancreatic enzyme assays and appropriate additional tests) in patients with acute abdominal pain and non-specific symptoms such as nausea, loss of appetite, anorexia, and/or vomiting.

If pancreatitis is diagnosed, valproate treatment must be permanently discontinued and alternative treatment for the underlying condition initiated depending on the clinical picture.

Children

Valproate should be used in children under 3 years of age only as monotherapy. For this age group, therapy should be initiated only after comparing clinical benefits against the risk of hepatic injury or pancreatitis development (see sections "Special precautions for use. Hepatic injury risk" and "Special precautions for use. Pancreatitis"). As a precautionary measure, concomitant use of salicylates should be avoided in all patients due to the risk of hepatotoxicity (see section "Interaction with other medicinal products and other forms of interaction").

Fasting during intercurrent illness increases the risk of hepatic injury in children receiving valproate.

Renal impairment

In patients with renal impairment, increased circulating valproic acid concentrations should be considered and dosage adjusted accordingly.

Blood tests

Blood tests (complete blood count with platelet count, assessment of bleeding time and coagulation parameters including fibrinogen, activated partial thromboplastin time (APTT), assay of 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 "Adverse reactions. Blood and lymphatic system disorders", "Adverse reactions. Laboratory test results").

Urea cycle enzyme deficiency and hyperammonemia risk

If urea cycle enzyme deficiency is suspected, metabolic investigations should be performed before initiating treatment due to the risk of hyperammonemia with valproate use (see sections "Contraindications", "Special precautions for use. Patients at risk of carnitine deficiency" and "Special precautions for use. Hepatic injury risk").

Patients at risk of carnitine deficiency

Valproate may reduce carnitine concentrations in tissues and plasma, consequently altering mitochondrial metabolism with impaired fatty acid beta-oxidation and urea cycle function.

Carnitine deficiency may develop or worsen during valproate treatment. This deficiency may cause hyperammonemia (which may lead to hyperammonemic encephalopathy) (see sections "Adverse reactions" and "Overdose"). Other reported symptoms include hepatic toxicity, hypoketotic hypoglycemia, 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 mitochondrial disorders related to carnitine (see sections "Special precautions for use. Patients with known or suspected mitochondrial disorders" and "Special precautions for use. Urea cycle disorders and hyperammonemia risk"), patients with carnitine deficiency due to inadequate dietary intake, patients under 10 years of age, patients concomitantly 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 advised to immediately report any signs of hyperammonemia (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. In such cases, blood carnitine levels may not necessarily be decreased. Additional investigations may be required to detect 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 prescribed the drug after correction of this deficiency and with particular caution. Such patients should be under close monitoring for recurrence of carnitine deficiency.

Carnitine palmitoyltransferase (CPT) type II deficiency. Patients with concomitant carnitine palmitoyltransferase (CPT) type II deficiency should be warned about the increased risk of rhabdomyolysis with valproate use. Carnitine supplementation may be considered for such patients.

Weight gain

At the beginning of treatment, the patient should be informed about the risk of weight gain, and appropriate measures should be taken to minimize this effect, primarily through dietary adjustments (see section "Adverse reactions").

Estrogen-containing medicinal products

Valproate does not reduce the effectiveness of hormonal contraceptives. However, estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives, may increase valproate clearance, potentially leading to decreased serum valproate concentrations and potential reduction in valproate efficacy.

Prescribing physicians should monitor clinical response (seizure control or mood control) at the initiation or discontinuation of estrogen-containing medicinal products. 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 randomized placebo-controlled antiepileptic drug trials 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 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 occur, immediate medical help should be sought.

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 valproic acid treatment. The mechanism of valproic acid action on bone metabolism is not yet fully understood (see section "Adverse reactions").

Carbapenems. Concomitant use of Depakine Chrono® 300 mg and carbapenems is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Patients with known or suspected mitochondrial disorders. Valproate may trigger or worsen clinical signs of existing mitochondrial disorders caused by mitochondrial DNA mutations and nuclear genes 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 deaths due to liver function impairment have been reported. POLG-related disorders should be suspected in patients with family history of POLG-related disorders or those with symptoms indicating such disorders, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status, 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").

Exacerbation of seizures

As with any antiepileptic drug, valproate use may, instead of improving the condition, lead to reversible exacerbation of seizure frequency and severity (including epileptic status) or emergence of new seizure types. Patients should be advised to immediately consult their physician if seizures worsen (see section "Adverse reactions").

Cognitive or extrapyramidal disorders. Cognitive or extrapyramidal disorders may be accompanied by signs of brain atrophy on imaging studies. Therefore, this clinical picture may be misinterpreted as dementia or Parkinson's disease. These disorders are reversible after drug discontinuation (see section "Adverse reactions").

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

This medicinal product contains 28.3 mg of sodium per tablet. This should be taken into account for patients on a strict low-sodium diet.

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.

Use in pregnancy or lactation.

Treatment of epilepsy

Valproate is contraindicated for epilepsy treatment during pregnancy, except when no alternative treatment options are available and the patient has been fully informed about the associated risks.

Valproate is contraindicated for use in female children and women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special precautions for use").

Treatment and prevention of bipolar disorders

Valproate is contraindicated for bipolar disorder treatment during pregnancy.

Valproate is contraindicated for use in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special precautions for use").

Teratogenicity and effect on fetal development after exposure in male and female patients. Risk of valproate-related effects during pregnancy. Valproate has demonstrated the ability to cross the placental barrier in both animals and humans (see section "Pharmacokinetics").

In women, both valproate monotherapy and valproate polytherapy with other antiepileptic drugs are frequently associated with deviations from normal pregnancy. Available data indicate an increased risk of severe congenital malformations and central nervous system disorders with valproate monotherapy and combination therapy compared to the general population not receiving valproate.

Animals: teratogenic effect has been demonstrated (see section "Preclinical safety data").

Risk for children born to male patients who received valproate. Data from a retrospective observational study of electronic medical records conducted in three Nordic countries indicate a trend toward 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 who received valproate and from 2.3% to 3.2% in the group of fathers who received monotherapy with lamotrigine or levetiracetam. The adjusted risk ratio, combined from data on neurodevelopmental disorders in three countries (including all subtypes), obtained in meta-analysis, was 1.50 (95% CI: 1.09–2.07).

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 of neurodevelopmental disorders.

Physicians should inform male patients of reproductive potential about this potential risk and necessary preventive measures, including the necessity of effective contraceptive methods 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 after 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 for the most common 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, and available data indicate it is dose-dependent also with combination therapy including valproate. However, establishing a threshold dose below which the risk is absent is not possible.

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

Valproate exposure in utero may also lead to hearing impairment or loss due to ear and/or nose malformations (adverse effect) and/or direct ototoxicity. Cases describe both unilateral and bilateral deafness or hearing loss. Outcomes are not known for all cases. When outcomes were reported, most cases were not detected. Monitoring for signs and symptoms of ototoxicity is recommended.

In utero exposure to valproate may lead to eye malformations (including coloboma, microphthalmia), reported in combination with other congenital malformations. These eye malformations may affect vision (see also sections "Adverse reactions" and "Special precautions for use").

Neurodevelopmental disorders due to in utero exposure to Depakine Chrono® 300 mg (see sections "Special precautions for use" and "Adverse reactions"). Available data indicate that in utero exposure to valproate may cause adverse effects on mental and physical development of exposed children. This risk of neurodevelopmental disorders (including autism) is likely dose-dependent with valproate monotherapy, but based on available data, establishing a threshold dose below which the risk is absent is not possible. With valproate use in combination with other antiepileptic drugs during pregnancy, the risk of neurodevelopmental disorders in children 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 such effects are possible is not defined, and the possibility of risk throughout the entire pregnancy cannot be excluded.

Studies involving preschool-aged children exposed in utero to valproate used as monotherapy showed that developmental delays, such as speech and walking delays, decreased intellectual functions, inadequate language skills (speech and language comprehension), and memory disorders, occurred in approximately 30–40% of cases.

The intelligence quotient (IQ) measured in school-aged children (6 years old) 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, there is evidence that the risk of decreased intellectual functions in children exposed to valproate may not depend on maternal IQ.

Data on long-term outcomes are limited.

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

Available data from a second study based on the Danish National Prescription Registry show that children exposed in utero to valproate have an increased risk (approximately 1.5 times higher) of developing symptoms of attention deficit hyperactivity disorder (ADHD) compared to the untreated population in the study.

Estrogen-containing medicinal products

Valproate does not reduce the effectiveness of hormonal contraceptives. However, estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives, may increase valproate clearance, potentially leading to decreased serum valproate concentrations and potential reduction in valproate efficacy.

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

If a woman plans pregnancy. In epilepsy, if a woman plans to become pregnant, a specialist experienced in managing epilepsy patients should reassess valproate treatment and consider alternative treatment options. All possible measures should be taken to replace the drug in women planning pregnancy with an appropriate alternative treatment before conception, prior to discontinuing contraception (see section "Special precautions for use"). If such transition is not possible, the woman should receive additional counselling regarding the risks of valproate use for the unborn child to ensure she is adequately informed for making an informed decision about family planning.

Regarding the indication for bipolar disorders, if a woman plans to become pregnant, consultation with a specialist experienced in treating bipolar disorder is required, and valproate treatment should be discontinued and, if necessary, replaced with alternative treatment (using medicinal products not containing valproic acid or non-pharmacological options) before conception, prior to discontinuing contraception.

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

Pregnant women. Valproate use is contraindicated for bipolar disorder treatment during pregnancy. Valproate use for epilepsy treatment is contraindicated during pregnancy, except when no alternative treatment options are available (see sections "Contraindications" and "Special precautions for use").

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 epileptic status with hypoxia in the woman may be associated with a particular risk of death for both the pregnant woman and the unborn child.

If, based on careful risk-benefit assessment, the decision is made to continue valproate treatment during pregnancy, 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. Use of the prolonged-release formulation is more appropriate compared to other formulations to avoid high peak plasma concentrations (see section "Dosage and administration").

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

Specialized prenatal monitoring should be performed to detect possible fetal neural tube defects or other malformations (see sections "Use in pregnancy or lactation", "Special precautions for use" and "Adverse reactions").

Risk in the neonatal period. Very rare cases of hemorrhagic syndrome have been reported in newborns whose mothers took valproate during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and/or decreased levels of other coagulation factors. Cases of afibrinogenemia, which may lead to fatal outcomes, have also been reported. However, this syndrome should be differentiated from vitamin K deficiency caused by phenobarbital and enzyme inducers. Therefore, newborns should have platelet count, plasma fibrinogen level, coagulation tests, and coagulation factors determined.

Cases of hypoglycemia 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 excitation, irritability, increased excitability, increased neuromuscular reflex excitability, hyperkinesia, tonic disorders, tremor, seizures, and sucking disorders).

Lactation. Sodium valproate is excreted in human breast milk at concentrations ranging from 1 to 10% of its plasma level in the mother. This medicinal product may have a pharmacological effect on breastfed infants. Breastfeeding is not recommended.

Fertility. Cases of amenorrhea, polycystic ovary syndrome, and increased testosterone levels have been reported in women taking valproate (see section "Adverse reactions"). Valproate use may also lead to impaired fertility in men (see section "Adverse reactions"). Several cases of changes in spermograms, reversible at least 3 months after discontinuation of valproate treatment, have been reported. Cases of pregnancy have also been reported. A limited number of reported cases indicate that spermogram abnormalities were not reversible even after several months. In other cases, the consequences of such abnormalities are unknown (see sections "Adverse reactions" and "Pharmacological properties. Fertility").

Ability to influence reaction speed when driving vehicles or operating other machinery.

Due to possible adverse effects, Depakine Chrono® 300 mg may negatively affect the ability to drive vehicles and operate other machinery.

Patients should also be warned about the risk of somnolence, particularly if they are receiving combination anticonvulsant therapy or concomitant benzodiazepine therapy (see section "Interaction with other medicinal products and other forms of interaction").

Method of Administration and Dosage

Girls, women of childbearing potential, and pregnant women. Treatment with this medicinal product should be initiated and conducted under the supervision of a specialist experienced in the treatment of epilepsy or bipolar disorders. Valproate therapy should be prescribed to girls and women of childbearing potential only when alternative treatments are unavailable or not tolerated by the patient (see sections "Special Warnings" and "Use in Pregnancy or Breastfeeding"). In such cases, valproate must be prescribed in accordance with the requirements of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special Warnings"). The benefit and risk of using this medicinal product must be carefully reassessed during regular treatment evaluations. In individual cases where valproate is the only treatment option during pregnancy in women with epilepsy, it should be prescribed as monotherapy at the lowest effective dose, and, if possible, in a prolonged-release formulation to avoid high peak plasma concentrations. The daily dose of immediate-release formulations should be divided into at least two administrations (see section "Use in Pregnancy or Breastfeeding").

Estrogen-containing medicinal products

Valproate does not reduce the efficacy of hormonal contraceptives. However, estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, potentially leading to reduced serum valproate concentrations and a possible decrease in its efficacy.

Physicians prescribing valproate should monitor the clinical response (seizure control or mood stabilization) when initiating or discontinuing estrogen-containing medicinal products. Monitoring of serum valproate levels is recommended (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Epilepsy

Standard dosage. 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. The optimal dose should be established based on the clinical response achieved. In cases of inadequate seizure control or suspicion of possible adverse reactions, in addition to clinical observation, measurement of plasma drug concentrations may be necessary.

As first-line monotherapy

Due to the prolonged-release formulation of Depakine Chrono®, the daily dose can be administered once daily. Ideally, the medication should be taken at the beginning of a meal. 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.

If possible, treatment with Depakine Chrono® 300 mg should be initiated gradually. The initial daily dose is 10–15 mg/kg, which should then be increased at intervals of 2–3 days, reaching the recommended daily dose within approximately one week. After achieving the required dose used as monotherapy—e.g., 15 mg/kg/day for elderly patients, 20 mg/kg/day for adults or adolescents, 25 mg/kg/day for children—continued observation for a certain period may be necessary. If clinical efficacy at this stage is satisfactory, this dose should be maintained.

In rare cases, particularly during monotherapy, daily doses higher than 25 mg/kg for elderly patients, 30 mg/kg for adults or adolescents, or 35 mg/kg for children may be required.

If seizure control is still not achieved with these doses, further dose escalation may be considered. If the daily dose exceeds 50 mg/kg, it is recommended to divide it into three doses, with additional clinical monitoring and biochemical blood tests (see section "Special Warnings").

Use of Depakine Chrono® 300 mg in combination with other antiepileptic drugs. Initiation of sodium valproate should follow the same approach as for first-line monotherapy. The average daily dose is usually identical to that recommended for monotherapy. However, in some cases, the dose may be increased by 5–10 mg/kg.

The effect of Depakine Chrono® 300 mg on other antiepileptic drugs should also be considered (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Switching from another antiepileptic drug to Depakine Chrono® 300 mg. If a gradual and complete substitution of a previous antiepileptic drug with Depakine Chrono® 300 mg is planned, the latter should be administered according to the recommendations for first-line monotherapy. The dose of certain previous medications, especially barbiturates, should be reduced immediately, followed by a gradual tapering over 2–8 weeks until complete discontinuation.

Manic episodes in patients with bipolar disorders. 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 ranging from 45 to 125 µg/mL.

The recommended maintenance dose for 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 the individual clinical response.

Children and adolescents: The efficacy and safety of Depakine Chrono® 300 mg for the treatment of manic episodes associated with bipolar disorders have not been studied. For information on the safety profile of valproate in children, see section "Adverse Reactions".

Prevention of relapses of manic episodes associated with 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.

Special dosage instructions. Depakine Chrono® 300 mg tablets should be taken with half a glass of water, milk, or another non-alcoholic beverage.

Due to the prolonged-release mechanism and the type of excipients in the formulation, the inert matrix is not absorbed in the gastrointestinal tract—it is excreted intact during defecation after the active substance has been released.

Patients with renal impairment. Patients with renal impairment may require dose reduction, or dose adjustment may be necessary for patients undergoing hemodialysis. Sodium valproate is dialyzable (see section "Overdose"). Dose adjustments should be based on clinical monitoring of the patient (see section "Special Warnings").

Children. For information on epilepsy treatment in children, see sections "Indications", "Special Warnings", and "Method of Administration and Dosage".

In patients under 18 years of age, the efficacy and safety of Depakine Chrono® 300 mg for the treatment of manic episodes associated with bipolar disorders have not been evaluated.

Overdose.

Clinical manifestations of acute massive overdose include coma of varying depth, accompanied by muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, myocardial depression leading to hypotension, circulatory collapse, or shock.

The prognosis following overdose is generally favorable. However, several fatal cases have been reported.

Symptoms may vary; epileptic seizures have been reported at high plasma levels of the drug. Cases of increased intracranial pressure associated with cerebral edema have also been described.

Hypernatremia may occur in overdose due to the sodium content of valproate.

Emergency management in a hospital setting should include gastric lavage, which is indicated within 10–12 hours after ingestion, and careful monitoring of cardiovascular and respiratory functions.

In cases of valproate overdose causing hyperammonemia, intravenous carnitine may be administered to normalize ammonia levels.

Naloxone has been successfully used in individual cases. Hemodialysis and hemoperfusion have proven effective in massive overdoses.

Side effects

Adverse effects are classified according to frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (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 during pregnancy or breastfeeding").

Blood and lymphatic system disorders

Common: anaemia, thrombocytopenia.

Valproate administration may lead to decreased platelet count, which is often dose-dependent and transient (see section "Special precautions for use. Blood tests").

Uncommon: pancytopenia, leukopenia.

Rare: bone marrow aplasia, erythroblastopenia, agranulocytosis, macrocytic anaemia, macrocytosis (see section "Special precautions for use. Blood tests").

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

Investigations

Rare: decreased levels of coagulation factors (at least one), pathological results in coagulation tests (e.g. prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio (INR)). Published reports have described coagulation disorders resembling von Willebrand disease type I (see "Special precautions for use. Blood tests").

Rare: biotin deficiency / biotinidase deficiency.

Nervous system disorders

Very common: tremor.

Common: extrapyramidal disorders (sometimes irreversible), stupor, somnolence, seizures, memory impairment, headache, nystagmus, nausea or dizziness (with intravenous injection, dizziness occurs several minutes after injection and usually resolves spontaneously within several more minutes).

Uncommon: coma, encephalopathy, lethargy, reversible parkinsonism, ataxia, paraesthesia, exacerbation of seizures (see section "Special precautions for use").

Rare: diplopia, reversible dementia with cerebral atrophy, cognitive disorders.

Several cases of hyperactivity and irritability at the beginning of treatment have been reported, predominantly in children.

Very rare cases of neurological effects such as confusion (usually mild and transient) have been reported in patients receiving sodium valproate in combination with other antiepileptic drugs, particularly phenobarbital, without gradual initiation of treatment.

Stupor or lethargy have been observed during valproate therapy, sometimes leading to transient coma/encephalopathy. These events occurred either in isolation or accompanied by recurrence of the seizures being treated, and resolved after discontinuation or dose reduction of the drug. Such effects most frequently occur during combination therapy (especially with phenobarbital or topiramate) or after a rapid increase in the dose of sodium valproate.

Ear and labyrinth disorders

Common: deafness (sometimes irreversible).

Frequency not known: tinnitus.

Respiratory, thoracic and mediastinal disorders

Uncommon: pleural effusion.

Gastrointestinal disorders

Very common: nausea.

Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhoea, which usually resolve within a few days without the need to discontinue the drug. The incidence of these disorders can be significantly reduced by very gradual initiation of treatment with Depakine Chrono® 300 mg (film-coated tablets) and administration at the beginning of a meal. Symptomatic treatment is recommended for such patients.

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

Prompt medical evaluation (measurement of pancreatic enzymes, other appropriate examinations) is recommended for all patients receiving sodium valproate/valproic acid who present with acute abdominal pain.

Hepatobiliary disorders

Cases of severe liver damage, sometimes fatal, have been reported in patients receiving valproate therapy (see "Special precautions for use. Risk of liver damage" and "Interaction with other medicinal products and other forms of interaction. Risk of liver damage").

Renal and urinary disorders

Common: urinary incontinence.

Uncommon: renal failure.

Rare: enuresis, tubulointerstitial nephritis, Fanconi syndrome, although the pathophysiological mechanism remains unclear.

Skin and subcutaneous tissue disorders

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

Uncommon: angioneurotic oedema, rash.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) or drug hypersensitivity syndrome. Hair growth disturbances (such as unusual hair texture, change in hair colour, abnormal hair growth).

Endocrine disorders

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

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

Frequency not known: alterations in sex hormone levels (e.g. testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin) (see also sections "Side effects. Disorders of the reproductive system and breast" and "Pharmacological properties. Preclinical data").

Metabolism and nutrition disorders

Common: weight gain (in 5–10% of patients), particularly in adolescents and young women. 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 significant abnormalities in standard liver function tests have been reported. In the absence of clinical symptoms, discontinuation of treatment is not necessary. However, if hyperammonaemia is accompanied by neurological symptoms, further investigations are required (see also sections "Special precautions for use. Urea cycle disorders and risk of hyperammonaemia" and "Special precautions for use. Patients at risk of carnitine deficiency").

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

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

Rare: myelodysplastic syndrome.

Vascular disorders

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

Uncommon: vasculitis.

General disorders

Uncommon: mild peripheral oedema, hypothermia.

Hepatobiliary disorders

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

Reproductive system and breast disorders

Common: dysmenorrhoea.

Uncommon: amenorrhoea (see section "Use during pregnancy or breastfeeding. Fertility", "Side effects. Endocrine disorders" and "Pharmacological properties. Preclinical data").

Frequency not known: infertility in men, polycystic ovaries, abnormalities in sperm analysis. Cases of testicular volume reduction have been observed, although a clear association with valproate has not been established (see section "Use during pregnancy or breastfeeding. Fertility", "Side effects. Endocrine disorders" and "Pharmacological properties. Preclinical data").

Musculoskeletal and connective tissue 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: systemic lupus erythematosus, rhabdomyolysis (see section "Special precautions for use").

Psychiatric disorders

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

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

*These effects are predominantly 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 damage in infants and young children, especially under 3 years of age. Young 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 mainly observed in children.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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 reach of children. Store in the original packaging in a dry place at a temperature not exceeding 25 °C.

Packaging.

No. 100 (50 × 2): 50 tablets in a container closed with a lid containing a desiccant, 2 containers in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

SANOFI WINTHROP INDUSTRIE.

Manufacturer's address and place of business.

1 rue de la Recherche, 33565 CARBON BLANC CEDEX, France.