Depakin® enteric 300

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPAKINE® ENTERIC 300

Composition:

Active substance: sodium valproate;

One tablet contains sodium valproate 300 mg;

Excipients: povidone (K 90), calcium silicate, talc, magnesium stearate; coating: methacrylate copolymer (type A), talc, Opaspray white type K1-7000 (containing titanium dioxide (E 171) and hydroxypropylcellulose), diethyl phthalate, cellulose acetate phthalate.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: white, biconvex, coated tablets.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code: N03AG01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Sodium valproate is a non-nitrogenous antiepileptic agent exerting anticonvulsant effects in various types of seizures. The mechanism of action is most likely related to increased GABA-ergic activity in the brain. The active form of sodium valproate administered intravenously or orally is valproic acid.

Clinical efficacy and safety.

Although no randomized double-blind studies have been conducted, published results from prospective and retrospective open-label studies demonstrate that intravenous valproate effectively terminates epileptic status in patients in whom prior conventional therapy with agents such as benzodiazepines and phenytoin has failed.

According to published clinical data, satisfactory effect was achieved with a bolus dose of 15 mg/kg in adults and 20 mg/kg in children administered over no more than 10 minutes, followed by continuous infusion at 1 mg/kg/hour if necessary.

Pharmacokinetics.

Absorption. After oral administration, the bioavailability of valproic acid in blood is close to 100%, regardless of the dosage form used.

Distribution.

Crossing of the placental barrier (see section "Use in pregnancy or breast-feeding").

Valproate crosses the placental barrier in both animals and humans.

• In animals, valproate crosses the placental barrier similarly to humans.
• In humans, several publications have assessed valproate concentrations in umbilical cord blood at delivery. Serum valproate concentrations in the umbilical cord were equal to or slightly higher than those in the mother.

Protein binding, primarily to albumin, is dose-dependent and saturable. At total plasma concentrations of valproic acid between 40–100 mg/L, the unbound fraction typically ranges from 5% to 15%. In patients with renal insufficiency, there is a tendency toward increased unbound fraction due to reduced albumin levels and, consequently, fewer available binding sites.

Maximum plasma concentration is reached on average 1 hour after administration of oral forms (oral solution and syrup), 3–4 hours after administration of enteric-coated forms, and 5–7 hours after administration of extended-release formulations. These time intervals may increase by 2–4 hours if the drug is taken with food. During prolonged treatment, approximately two days are required to achieve steady-state plasma concentrations when using Depakine® Enteric 300.

Valproic acid penetrates into cerebrospinal fluid, the central nervous system, and placenta, where its concentrations reach approximately one-tenth of the total blood concentration.

Metabolism. Valproic acid is extensively metabolized in the liver (via conjugation with glucuronic acid and beta- and omega-oxidation). More than 10 metabolites are known, some of which have demonstrated anticonvulsant properties in animal studies. The main metabolic pathway is glucuronidation (~40%), primarily mediated by UGT1A6, UGT1A9, and UGT2B7 enzymes. Enterohepatic circulation occurs.

Elimination. The drug is primarily excreted by the kidneys: 70% as glucuronide conjugates and approximately 7% as unchanged valproic acid. Residual amounts are excreted via the respiratory tract and feces. Elimination half-life is significantly prolonged in preterm neonates, reaching 30–70 hours depending on the degree of prematurity, compared to 20–30 hours in full-term neonates and infants during the first month of life, gradually approaching values typical for children and adults, which range from 8 to 22 hours, with a mean of 12 hours.

Pharmacokinetic/pharmacodynamic relationship. Sodium valproate does not induce enzymes present in the endoplasmic reticulum of hepatocytes and therefore does not accelerate its own metabolism or the metabolism of other substances such as estrogens/progestogens and vitamin K antagonists.

Interaction with estrogen-containing drugs. Concomitant use of the drug with estrogen-containing agents, including estrogen-containing hormonal contraceptives, may potentially reduce the efficacy of valproate (see section "Interaction with other medicinal products and other forms of interaction").

Preclinical data.

In vitro, valproate showed no mutagenic effects on bacteria or mouse lymphoma cells and did not induce DNA repair activity in primary rat hepatocyte cultures. However, in vivo results at teratogenic doses were conflicting depending on the route of administration. After oral administration—the preferred 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 epileptic patients exposed to valproate compared to healthy subjects not receiving this treatment. However, conflicting results were observed when comparing data from epileptic patients treated with valproate versus untreated epileptic patients. The clinical significance of these DNA/chromosomal findings is unknown.

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

Reproductive toxicity

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

Behavioral disturbances in offspring of mice and rats in the first generation after intrauterine exposure have been reported. In mice, certain behavioral changes were also observed in the 2nd and 3rd generations, although less pronounced in the 3rd generation, following acute intrauterine exposure of the first generation to teratogenic doses of valproate. The primary mechanisms and clinical relevance of these findings are unknown.

In repeat-dose toxicity studies, testicular degeneration/atrophy, spermatogenesis abnormalities, and reduced testicular weight were reported in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.

In young rats, 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. No effects on male reproductive organs were observed at tolerated doses (up to 90 mg/kg/day). Based on these data, testicular effects in young animals were not considered more pronounced than in adults. The significance of testicular sensitivity to valproate exposure in the pediatric population is unknown.

In a rat fertility study, valproate at doses up to 350 mg/kg/day did not affect male reproductive function. However, male infertility has been identified as an adverse reaction in humans (see sections "Use in pregnancy or breast-feeding. Pregnancy. Breast-feeding. Fertility" and "Adverse reactions").

Clinical characteristics.

Indications.

As monotherapy:

• primary generalized epilepsy: clonic-tonic seizures (grand mal seizures) with or without myoclonic seizures, absences (petit mal seizures), myoclonic seizures, combined tonic-clonic seizures and absences;
• benign partial epilepsy, particularly rolandic epilepsy.

As monotherapy or in combination with other antiepileptic drugs in:

• secondary generalized epilepsy;
• simple or complex partial epileptic seizures.

If monotherapy is not sufficiently effective, combination therapy with Depakine® Enteric 300 and another anticonvulsant is indicated.

Contraindications.

Pregnancy, except in cases where other treatment options are ineffective (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

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

Hypersensitivity to the active substance or to any of the excipients in the patient's history.

Acute hepatitis.

Chronic hepatitis.

History of severe hepatitis, particularly drug-induced, in the patient or family.

Hepatic porphyria.

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

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, and in children under 2 years of age suspected of having a polymerase gamma-related disorder, as well as in patients with a history of urea cycle disorders (see section "Special precautions").

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

Known systemic primary carnitine deficiency with uncorrected hypocarnitinaemia (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of drugs that may provoke seizures or lower the seizure threshold should be considered, not recommended, or contraindicated depending on the potential risk. Such drugs include most antidepressants (imipramines, selective serotonin reuptake inhibitors), neuroleptics (phenothiazines and butyrophenones), mefloquine, chloroquine, bupropion, tramadol.

Effect of valproate on other medicinal products.

Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines. Depakine® Enteric 300 may potentiate the effects of other psychotropic drugs such as neuroleptics, MAO inhibitors, tricyclic antidepressants and benzodiazepines; therefore, clinical monitoring is required and dosage adjustment may be necessary.

Lithium. Depakine® Enteric 300 does not affect serum lithium levels.

Phenobarbital. Depakine® Enteric 300 may increase plasma phenobarbital concentrations (due to inhibition of hepatic catabolism), resulting in signs of sedative effects, particularly observed in children. Clinical monitoring is recommended during the first 15 days of combination therapy, and immediate reduction of phenobarbital dose is required if any signs of sedation occur. Whenever possible, regular monitoring of plasma phenobarbital concentrations is advised.

Primidone. Depakine® Enteric 300 increases plasma primidone concentrations and enhances its adverse effects (sedative effect). This interaction diminishes with prolonged use. Clinical monitoring and possible dose adjustment of primidone are required, especially at the beginning of combination therapy.

Phenytoin. Depakine® Enteric 300 decreases total plasma phenytoin concentration. It particularly increases the concentration of free phenytoin fraction, potentially leading to signs of overdose (valproic acid displaces phenytoin from its plasma protein binding sites and slows its hepatic catabolism). Therefore, careful clinical monitoring is recommended. When measuring phenytoin plasma levels, the concentration of its free fraction should also be considered.

Carbamazepine. Cases of clinical toxicity have been reported with concomitant use of valproate and carbamazepine, as valproate may potentiate the toxic effects of carbamazepine. Clinical monitoring is recommended, especially at the beginning of combination therapy, and dosage adjustment may be necessary.

Lamotrigine. Valproate inhibits lamotrigine metabolism and nearly doubles its elimination half-life. This interaction may increase lamotrigine toxicity, particularly causing serious rashes. Clinical monitoring is recommended, and dosage adjustments (reduction) may be required.

Zidovudine. Valproate may increase zidovudine plasma concentrations, increasing the risk of zidovudine toxicity.

Olanzapine. Valproic acid may reduce olanzapine plasma concentrations.

Rufinamide. Valproic acid may increase rufinamide plasma concentrations. This increase is dependent on valproic acid concentrations. Caution is advised, especially in children, as this effect is more pronounced in this patient population.

Felbamate. Valproic acid may reduce the average clearance of felbamate by 16%.

Propofol. Valproic acid may increase propofol plasma concentrations. When used concomitantly with valproate, consideration should be given to reducing the propofol dose.

Nimodipine. In patients receiving concomitant sodium valproate and nimodipine, nimodipine levels may increase by 50%. Therefore, in case of arterial hypotension, the nimodipine dose should be reduced.

Effect of other medicinal products on Depakine® Enteric 300.

Antiepileptic drugs with enzyme-inducing effects (especially phenytoin, phenobarbital, carbamazepine) reduce valproate plasma concentrations. In case of combination therapy, treatment should be adjusted based on clinical response and blood drug levels.

Concomitant use of phenytoin or phenobarbital may increase plasma levels of valproic acid metabolites. Therefore, patients receiving either of these two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.

Combination of felbamate and valproate reduces the clearance of valproic acid by 22–50%, leading to increased serum valproic acid concentrations. Monitoring of valproate plasma concentrations is required.

Mefloquine enhances valproate metabolism and has a seizure-stimulating effect, increasing the risk of epileptic seizures with this combination.

Concomitant use of valproate and drugs with high plasma protein binding (salicylates, phenylbutazone, fatty acids) may lead to increased circulating valproate concentrations in plasma.

When treating with vitamin K antagonist anticoagulants, prothrombin time should be closely monitored.

Concomitant use with cimetidine or erythromycin may increase valproate plasma levels (due to reduced hepatic metabolism). There are insufficient data to determine whether the interaction characteristic of erythromycin also occurs with other macrolides.

There is a theoretical possibility of interaction between clonazepam and valproate. However, such interaction has not been demonstrated, and its mechanism is unclear. Nevertheless, caution is advised when combining these drugs.

Carbapenems. Concomitant use with carbapenem antibiotics has been associated with a rapid and significant decrease in valproic acid blood concentrations, reducing levels by 60–100% within approximately 2 days. Due to the magnitude and speed of this reduction, the use of carbapenems in patients stabilized on valproic acid is not recommended and should be avoided (see section "Special precautions"). If treatment with these antibiotics cannot be avoided, targeted monitoring of valproic acid blood levels is necessary.

Rifampicin may reduce valproate blood levels, leading to loss of therapeutic efficacy. Therefore, dose adjustment of valproate may be required when used concomitantly with rifampicin.

Protease inhibitors. When used concomitantly, protease inhibitors such as lopinavir and ritonavir reduce valproate plasma concentrations.

Cholestyramine. Concomitant use may reduce valproate plasma concentrations.

Estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives. Estrogens are inducers of UDP-glucuronosyltransferase (UGT) isoenzymes involved in valproate glucuronidation and may increase valproate clearance, which is believed to lead to decreased serum valproate concentrations and potentially reduce valproate efficacy (see section "Special precautions"). Monitoring of serum valproate levels should be considered. Conversely, valproate has no enzyme-inducing effect; therefore, valproate does not reduce the efficacy of estrogen-progestogen preparations in women using hormonal contraceptives.

Metamizole. Concomitant use may reduce valproate serum concentrations, potentially leading to reduced clinical efficacy of valproate. Prescribing physicians should monitor clinical response (seizure control or mood disorders) and consider monitoring serum valproate levels if necessary.

Methotrexate. Some reports describe a significant decrease in serum valproate levels following methotrexate administration, accompanied by seizures. Prescribing physicians should monitor clinical response (seizure control or mood disorders) and consider monitoring serum valproate levels if necessary.

Other interactions.

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

Risk of liver injury.

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

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

Patients of various ages receiving concomitant cannabidiol at doses of 10 to 25 mg/kg and valproate reported elevated ALT levels more than 3 times above the upper limit of normal in 19% of patients in clinical trials. Adequate liver monitoring is required when valproate is used concomitantly with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and consideration should be given to dose reduction or discontinuation in case of significant liver function test abnormalities (see section "Special precautions").

Concomitant use of valproate with topiramate/acetazolamide is associated with encephalopathy and/or hyperammonaemia. Patients taking these two drugs require careful monitoring for possible signs and symptoms of hyperammonaemia-induced encephalopathy.

Concomitant use with protease inhibitors, such as lopinavir and ritonavir, increases valproate plasma concentrations.

Concomitant use with cholestyramine may lead to decreased valproate plasma concentrations.

Quetiapine. Concomitant use of valproate and quetiapine may increase the risk of neutropenia/leukopenia.

Valproate enhances the sedative effect of alcohol.

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

Special precautions for use.

Pregnancy prevention programme.

Due to the high teratogenic potential and high risk of congenital malformations and neurodevelopmental disorders in infants exposed to valproate in utero, the medicinal product Depakine® Enteric 300 mg is contraindicated:

• during pregnancy, except in cases where other treatment options are ineffective (see sections "Contraindications" and "Use in pregnancy or lactation");
• in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Contraindications" 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 the discussion, ensure her engagement, discuss treatment options, and ensure understanding of the risks and measures necessary to minimise risks;
• assess the possibility of pregnancy in all female patients;
• ensure that 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 that the patient understands the necessity of a pregnancy test prior to initiating treatment and, if necessary, during treatment;
• advise the patient to use contraception and verify the patient’s ability to comply with continuous use of effective contraceptive methods (additional information is provided in the subsection "Contraception" within this boxed warning) throughout the entire course of valproate treatment;
• ensure that the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in epilepsy management;
• ensure that the patient understands the need to consult her physician if she plans a pregnancy, to allow timely discussion and transition to alternative treatments before conception and before discontinuation of contraceptive methods;
• ensure that the patient understands the need to seek immediate medical advice if pregnancy occurs;
• provide the Patient Information Leaflet;
• ensure that the patient understands the dangers and necessary precautionary measures associated with the use of valproate (Annual Risk Information Form).

These conditions also apply to girls who are not currently sexually active, except in cases where, in the physician’s opinion, there are compelling reasons to believe that there is no risk of pregnancy.

Female children.

• The prescribing physician must ensure that parents/guardians of female children understand the necessity of consulting a specialist immediately after the onset of menstruation in a female child receiving valproate.
• The prescribing physician must ensure that parents/guardians of female children receive comprehensive information about the risks of congenital malformations and neurodevelopmental disorders, including the extent of these risks for children exposed to valproate during their intrauterine 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, 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 prior to 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 use of the drug 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 must be provided with comprehensive information on pregnancy prevention and 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 individualised, involving the patient in the discussion to ensure her active participation and adherence to the chosen preventive measures. Even if the patient experiences amenorrhoea, she must follow all recommendations for effective contraception.

Annual review by a specialist. The specialist must reassess at least annually whether valproate remains the most appropriate treatment for the patient. The specialist must discuss the Annual Risk Information Form at the beginning of treatment and during each annual review, ensuring that 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. When the drug is indicated for "epilepsy", if a woman plans to become pregnant, a specialist experienced in managing epilepsy must reassess valproate treatment and consider the possibility of switching to alternative treatments. All possible measures should be taken to transition the patient to acceptable alternative treatments before conception and before discontinuation of contraceptive methods (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 to make an informed decision about family planning.

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 treatment with the drug during pregnancy (see section "Use in pregnancy or lactation").

The pharmacist must ensure that:

• at each dispensing of valproate, the patient is provided with the patient card and understands the information contained therein;
• patients are advised not to discontinue valproate and to seek immediate medical advice in case of planned or suspected pregnancy.

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

The Annual Risk Information Form must be used, properly completed, and signed at the initiation of treatment and during each annual review of valproate treatment by the specialist and the patient (or her legal representative).

• Caution should be exercised in patients prone to bleeding.
• Sodium valproate has demonstrated in vitro stimulatory effects on HIV replication in various infected cell lines. Although the clinical significance of these data is not established, caution should be exercised when prescribing this substance to patients with AIDS.

Severe liver damage.

Occurrence conditions. Rare cases of severe liver damage, sometimes leading to fatal outcomes, have been reported. Experience with the use of the drug in epilepsy indicates that the highest risk, particularly when co-administered with other antiepileptic drugs, occurs in infants and children up to 3 years of age with severe epilepsy, especially in children with brain damage, intellectual disability, and/or genetically determined metabolic disorders, including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see section "Special precautions for use"), or degenerative diseases.

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

In the vast majority of cases, such liver damage occurred within the first 6 months of treatment.

Signs to watch for. Early diagnosis is based on clinical presentation. Particular attention should be paid to symptoms that may precede jaundice, especially in patients at risk (see above "Occurrence conditions"):

• non-specific systemic symptoms, which typically appear suddenly, such as asthenia, anorexia, lethargy, somnolence, sometimes associated with recurrent vomiting and abdominal pain.
• in patients with epilepsy – recurrence of epileptic 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 must be immediately examined, including clinical assessments and laboratory tests of liver function.

Detection. Liver function tests should be performed prior to initiating therapy and then regularly during the first 6 months of treatment. If concomitant medication known to be hepatotoxic is changed (dose increase or new treatment), liver function tests should be repeated (see also section "Interaction with other medicinal products and other forms of interaction" regarding the risk of liver damage with salicylates, other anticonvulsants, including cannabidiol).

In addition to routine tests, the most informative are those reflecting protein synthesis, particularly prothrombin time (PT) levels. If pathologically low PT levels are confirmed, especially in conjunction with other abnormal biological parameters (marked decrease in fibrinogen and coagulation factors, increased bilirubin and liver enzymes), valproate therapy must be immediately discontinued. As a precautionary measure and in cases of concomitant therapy with salicylates, their use should also be discontinued, as they share the same metabolic pathway.

Pancreatitis. Very rare cases of severe pancreatitis, sometimes with fatal outcomes, have been reported. The risk is particularly high in younger children, especially those with a history of hypersensitivity to the drug. This risk decreases with age.

Risk factors may include severe seizures, neurological disorders, or polytherapy with anticonvulsants.

If pancreatitis develops on the background of liver failure, the risk of fatal outcomes increases.

In case of acute abdominal pain, patients must immediately undergo medical evaluation. If pancreatitis develops, valproate administration should be discontinued.

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 randomized 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 current data do not allow exclusion of an increased risk with valproate use.

Therefore, patients should be monitored for timely 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 attention should be sought.

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

In particular, cases of valproate-induced acute liver failure and deaths due to liver dysfunction have been reported in patients with hereditary neurometabolic syndromes caused by POLG gene mutations (e.g., Alpers-Huttenlocher syndrome). POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or those with symptoms indicating such a disorder, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, 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").

Urea cycle disorders and risk of hyperammonaemia. Metabolic investigations should be performed before initiating treatment if there is suspicion of an enzymatic deficiency in the urea cycle due to the risk of hyperammonaemia with valproate use (see section "Special precautions for use": Patients at risk of developing hypocarnitinaemia. Risk of liver damage).

Patients at risk of developing hypocarnitinaemia.

Administration of valproate may cause or worsen hypocarnitinaemia, which may lead to hyperammonaemia (potentially resulting in hyperammonaemic encephalopathy). Other symptoms such as hepatotoxicity, hypoketotic hypoglycaemia, myopathy including cardiomyopathy, rhabdomyolysis, and Fanconi syndrome have been observed predominantly in patients with risk factors for hypocarnitinaemia or with pre-existing hypocarnitinaemia. Valproate may reduce carnitine levels in blood and tissues and thus impair mitochondrial metabolism, including the mitochondrial urea cycle. Risk factors for symptomatic hypocarnitinaemia during valproate treatment include metabolic disorders, particularly mitochondrial disorders related to carnitine (see also section "Special precautions for use": Patients with known or suspected mitochondrial disorders. Urea cycle disorders and risk of hyperammonaemia), impaired carnitine uptake, patient age under 10 years, concomitant use of pivaloyl-conjugated medicinal products or other antiepileptic drugs.

Patients should be warned to immediately report any signs of hyperammonaemia, such as ataxia, impaired consciousness, vomiting, for further investigation. If symptoms of hypocarnitinaemia occur, consideration should be given to carnitine supplementation.

Valproate should be prescribed to patients with known systemic primary carnitine deficiency and corrected hypocarnitinaemia only if the benefits of valproate treatment outweigh the risks and there is no suitable therapeutic alternative. These patients should be carefully monitored for recurrence of hypocarnitinaemia.

Patients with primary carnitine-palmitoyltransferase (CPT) type II deficiency should be warned of the increased risk of rhabdomyolysis during valproate use. Carnitine supplementation should be considered for these patients (see also sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

Exacerbation of seizures. As with any antiepileptic drug, valproate administration may instead of improving the condition lead to reversible exacerbation of seizure frequency and severity (including status epilepticus) or the emergence of a new seizure type. Patients should be advised to seek immediate medical advice if seizures worsen.

Precautions for use.

Initiation and discontinuation of treatment

Liver function tests should be performed prior to initiating treatment (see section "Contraindications") and then periodically during the first 6 months, especially in patients with risk factors (see section "Special precautions for use"). It should be emphasized that, as with most antiepileptic drugs, mild, isolated, and transient elevation of transaminase levels without clinical signs may occur, particularly at the beginning of treatment. If this occurs, more laboratory tests (including prothrombin time) are recommended; dose adjustment may be necessary, and tests should be repeated based on parameter changes. Treatment is generally recommended to be discontinued if transaminase levels exceed three times the upper limit of normal.

Treatment may be resumed at the lowest effective dose after transaminase levels return to normal. If levels rise again under these conditions and reach values equal to or greater than three times normal, complete discontinuation of treatment is recommended. Discontinuation due to elevated transaminase levels should be gradual, with dose reduction over approximately 1 week, depending on the daily dose. The choice of an alternative antiepileptic drug remains at the physician’s discretion and depends on the type of epilepsy.

Children under 3 years of age.

Valproate is recommended for children under 3 years of age only as monotherapy and only after weighing the clinical benefits against the risk of liver damage or pancreatitis for this age group (see section "Special precautions for use. Severe liver damage" and "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of salicylate derivatives to children under 3 years of age should be avoided due to the risk of hepatotoxicity (see section "Interaction with other medicinal products and other forms of interaction").

Assessment of bleeding time and coagulation parameters.

Blood tests (complete blood count including platelet count, assessment of bleeding time and coagulation parameters) are recommended prior to drug administration, before any surgical procedures, and in case of bruising or spontaneous bleeding (see section "Adverse reactions").

Renal impairment. Dose reduction may be necessary in patients with renal impairment. Since plasma concentration data interpretation can sometimes be difficult, the dose should be adjusted according to the clinical response obtained.

Pancreatitis.

Pancreatitis has been reported in rare cases; therefore, patients with acute abdominal pain should undergo immediate medical evaluation. If pancreatitis occurs, valproate intake must be discontinued.

Immunological disorders.

Although sodium valproate is known to cause immunological disorders only in rare cases, the benefit-risk balance of using this drug should be considered in patients with systemic lupus erythematosus.

Deficiency of urea cycle enzymes. Metabolic investigations should be performed prior to initiating treatment if there is suspicion of deficiency of urea cycle enzymes due to the risk of hyperammonaemia with valproate use.

Diabetes mellitus.

In patients with diabetes mellitus receiving valproate treatment, some metabolites of valproic acid may distort the interpretation of ketonuria tests due to false positive results.

Weight gain.

At the beginning of treatment, the patient should be informed about the risk of weight gain and appropriate measures to mitigate this effect.

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

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

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

Estrogen-containing medicinal products. Concomitant use of the drug with medicinal products containing estrogens, including estrogen-containing hormonal contraceptives, may potentially reduce the effectiveness of valproate (see section "Interaction with other medicinal products and other forms of interaction"). Physicians prescribing this drug should monitor clinical response (epilepsy control) when initiating or discontinuing estrogen-containing agents. Conversely, valproate does not reduce the effectiveness of hormonal contraceptives.

Excipients.

This medicinal product contains 41 mg of sodium per tablet, equivalent to 2.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Use in pregnancy or lactation.

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

• during pregnancy, except in cases where other treatment options are ineffective for the treatment of epilepsy;
• in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Contraindications", "Special precautions for use").

Women of childbearing potential should use effective contraception during treatment.

For women planning pregnancy, all possible efforts should be made to replace valproate with an acceptable alternative treatment before conception.

Women of childbearing potential.

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

Teratogenicity and impact on intrauterine development.

If a woman plans pregnancy. Treatment with valproate in women planning pregnancy or who are pregnant should be reassessed by a specialist experienced in epilepsy management. All possible measures should be taken to replace the drug in women planning pregnancy with an appropriate alternative treatment before conception and before discontinuation of contraceptive methods (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 to make an informed decision about family planning.

Pregnant women. The use of valproate for the treatment of epilepsy is contraindicated during pregnancy, except in cases where other treatment options are ineffective (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 treatments.

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

If, after careful assessment of risks and benefits, it is decided to continue valproate treatment during pregnancy, the following is recommended.

The lowest effective dose should be used, and the daily dose of valproate should be divided into several doses throughout the day. The use of a 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 specialist experienced in teratology for evaluation and counselling regarding the case of drug treatment during pregnancy.

Specialized prenatal monitoring should be performed to detect possible neural tube defects or other developmental abnormalities in the fetus.

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 developmental abnormalities due to valproate exposure.

Risk of valproate use during pregnancy. The use of valproate as monotherapy or in combination therapy, including with other antiepileptics, is frequently associated with deviations from normal pregnancy outcomes. Available data indicate an increased risk of severe congenital malformations and central nervous system developmental disorders with both monotherapy and combination therapy with valproate compared to the general population not exposed to valproate.

Valproate has demonstrated the ability to cross the placental barrier in both animals and humans (see section "Pharmacokinetics"). In animals, teratogenic effects have been demonstrated in mice, rats, and rabbits (see section "Preclinical data").

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

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

In utero exposure to valproate may also harm hearing or lead to deafness due to deformities of the ear and/or nose (side effect) and/or direct toxic effect on hearing function. Cases of unilateral and bilateral hearing loss or impairment have been described. However, outcomes were not reported for all cases. In most reported cases, hearing recovery did not occur.

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

Neurodevelopmental disorders. Available data indicate that in utero exposure to valproate may cause adverse effects on the intellectual 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, it is not possible to establish a threshold dose below which the risk is absent. When valproate is used in combination with other antiepileptic drugs during pregnancy, the risks of neurodevelopmental disorders in children are also significantly increased compared to risks in children in the general population or in children whose mothers had epilepsy but did not receive treatment. The exact period of pregnancy during which these effects are at risk is not defined, and the possibility of risk throughout the entire pregnancy cannot be excluded.

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

The intelligence quotient (IQ) measured in school-aged children (aged 6 years) exposed to valproate in utero was on average 7-10 points lower than in children exposed to other antiepileptic drugs. Although the role of other factors cannot be excluded, there is evidence that the risk of reduced intellectual 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 to valproate in utero have an increased risk of autistic spectrum disorders (approximately 3 times) and childhood autism (approximately 5 times) compared to the general studied population.

Available data from another population study show that children exposed to valproate in utero have an increased risk of attention deficit hyperactivity disorder (ADHD) (approximately 1.5 times) compared to the study population not exposed to valproate.

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

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

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

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

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

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

Lactation. Valproate is excreted in human breast milk at concentrations of 1 to 10% of its plasma levels in the mother. Blood disorders have been observed in newborns/infants whose mothers received treatment with this drug (see section "Adverse reactions").

The decision whether to discontinue breastfeeding or discontinue/abstain from taking Depakine® Enteric 300 should be made considering the benefit of breastfeeding for the child and the benefit of treatment for the woman.

Fertility. Cases of amenorrhoea, 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"). In some cases, it is noted that fertility impairment is reversible and resolves at least 3 months after discontinuation of the drug. A limited number of reported cases suggest that significant dose reduction may improve fertility. However, in some other cases, the reversibility of male infertility was unknown.

Ability to affect reaction speed when driving vehicles or operating machinery.

Patients should be warned of the risks associated with driving vehicles or operating machinery, particularly in the event of neurological adverse effects (such as somnolence, etc.) (see section "Adverse reactions"). Patients should also be warned of the risk of somnolence, especially if they are receiving combined anticonvulsant therapy or concomitant therapy with benzodiazepines (see section "Interaction with other medicinal products and other forms of interaction").

Dosage and Administration.

The recommended average daily dose of sodium valproate is 20–30 mg/kg for both children and adults. Daily doses exceeding 35 mg/kg in children and 30 mg/kg in adults are very rarely required during monotherapy with the drug.

Therapeutic effect is generally observed when the plasma concentration of the drug reaches 40–100 mg/L (278–694 µmol/L).

The dose should be reduced if plasma concentrations exceed 200 mg/L (1388 mmol/L). Monitoring of plasma drug levels is recommended when doses of 50 mg/kg/day or higher are used.

Blood samples for determination of valproic acid concentration should preferably be taken in the morning before administration of the first dose of the drug.

First-line monotherapy. Regardless of patient age, treatment with sodium valproate should be initiated gradually: the initial daily dose should be approximately 10 mg/kg, followed by increments of 5 mg/kg every 2–3 days, to achieve the optimal dose within approximately 1 week. Treatment with this drug requires gradual titration.

Combination with other antiepileptic drugs. The dose of valproate should be titrated gradually over approximately 2 weeks to reach the optimal dose, which is generally similar to that used in monotherapy or sometimes slightly higher. Therefore, an initial dose of 10 mg/kg should be used, gradually increased by 5 mg/kg every 2–3 days.

When adding valproate to combination therapy with other antiepileptic drugs, the doses of the latter should be reduced by at least one-quarter for two reasons: due to enzyme induction, these drugs increase the metabolism rate and thus the clearance of valproic acid; in addition, valproic acid slows the metabolism of other antiepileptic drugs.

Switching from other antiepileptic drugs to sodium valproate or switching from sodium valproate to other antiepileptic drugs. If switching from a previously used antiepileptic drug to valproate, the prior drug should be withdrawn gradually. Such a switch should be performed over 2–4 weeks. However, the transition period may be prolonged if the patient has had long-standing epilepsy, if seizures are not adequately controlled, if prior therapy was long-term, or if the treatment regimen included phenobarbital, primidone, and/or phenytoin.

The initial dose of sodium valproate is 5 mg/kg, with subsequent increments of 5 mg/kg every 4–5 days to achieve the optimal dose within approximately 2–3 weeks.

If switching from sodium valproate to another antiepileptic drug, the transition should be performed by gradually reducing the dose of one drug while gradually increasing the dose of the other. Daily doses should be reduced gradually by 5–10 mg/kg/day every 2–3 days.

The daily dose of the drug should be divided into 3–4 administrations.

Patients with well-controlled epilepsy may take the drug once daily at a dose of 20–30 mg/kg.

The drug should preferably be taken with food, and tablets must be swallowed whole.

If treatment with sodium valproate needs to be discontinued completely, the daily dose should be gradually reduced by 5–10 mg/kg/day every 2–3 days.

Due to the prolonged release mechanism of the active ingredient and the nature of the excipients in the formulation, the inert matrix is not absorbed in the gastrointestinal tract but is excreted in feces after release of the active substance.

Patients with renal impairment. Dose reduction may be required due to increased blood concentrations of valproic acid. This increase is caused by decreased plasma albumin concentration and reduced renal excretion of unbound metabolites, which must be taken into account, and doses should be correspondingly reduced.

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

Patients with hepatic impairment. Cases of liver dysfunction, including severe hepatic failure, have been reported in patients treated with valproate (see sections "Contraindications" and "Special Instructions").

Elderly patients. Age-related changes in pharmacokinetic parameters (increased volume of distribution and decreased plasma albumin binding, leading to higher blood concentrations of valproic acid) may occur. However, these changes are generally of limited clinical significance. Dose selection should be based on clinical response (seizure control) and drug plasma concentration.

Girls and female adolescents, women of childbearing potential, and pregnant women. Treatment should be initiated and managed under the supervision of a specialist experienced in epilepsy management. This drug should be prescribed only when other therapies are ineffective or not tolerated. Valproate should be prescribed and dispensed in accordance with the Pregnancy Prevention Programme (see sections "Contraindications" and "Special Instructions"); the benefit-risk balance of using this drug should be carefully reviewed during regular treatment evaluations. Generally, Depakine® Chrono 300 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 should be divided into at least two administrations (see section "Use during pregnancy or breastfeeding").

Children. For children under 11 years of age, syrup and oral drops are the most appropriate dosage forms.

Overdose.

A range of clinical manifestations may occur, from mild symptoms (drowsiness, sedation, etc.) to severe poisoning with coma, muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, arterial hypotension, and circulatory collapse/shock.

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

In children, drowsiness is the most commonly observed symptom in cases of moderate overdose.

However, symptoms may vary, and seizures have been reported in association with very high plasma levels of the drug. Cases of intracranial hypertension associated with cerebral edema have been described.

Overall, the prognosis in cases of overdose is generally favorable. However, several fatal cases have been reported.

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

Plasma or serum drug levels do not necessarily correlate with signs of intoxication.

Treatment of overdose in a hospital setting should be symptomatic: gastric lavage may be beneficial within 10–12 hours after oral ingestion; cardiovascular and respiratory functions must be monitored.

In cases of massive overdose, exchange blood transfusion and hemodialysis have been successfully used, but it should be noted that only the free fraction of the drug (approximately 10% of total drug content) is dialyzable.

In some individual cases, naloxone has been successfully used.

After resolution of the acute phase of intoxication, valproate therapy should be resumed at the lowest effective dose to avoid the risk of epileptic status.

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

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Congenital, familial and genetic disorders. Congenital malformations and disorders of nervous system development (see section "Use during pregnancy or breastfeeding").

Disorders of the blood and lymphatic system.

Common: anaemia, frequent thrombocytopenia (see section "Special precautions for use").

Uncommon: pancytopenia, leucopenia.

Rare: bone marrow aplasia, including pure red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis.

Metabolic and nutritional disorders.

Common: hyponatraemia. Weight gain. Since weight gain may lead to worsening of clinical symptoms of polycystic ovary syndrome, body weight should be carefully monitored.

Rare: hyperammonaemia (see section "Special precautions for use"). Isolated cases of mild hyperammonaemia have been reported without significant changes in standard liver function tests, particularly in the context of polytherapy. In the absence of clinical symptoms, discontinuation of treatment is not required. However, if hyperammonaemia is accompanied by neurological symptoms, additional investigations are necessary (see also section "Special precautions for use": Urea cycle disorders and risk of hyperammonaemia. Patients at risk of developing carnitine deficiency).

Frequency not known: hypokarnitinaemia (see sections "Contraindications" and "Special precautions for use"); obesity.

Cases of decreased bone mineral density, osteopenia, osteoporosis and fractures have been reported in patients receiving long-term treatment with sodium valproate. The mechanism by which sodium valproate affects bone metabolism is not established.

Cases of carnitine deficiency have been reported following administration of valproic acid. This deficiency is mainly manifested as increased fatigue, general weakness and myalgia. If such symptoms occur, valproic acid-induced carnitine deficiency should be considered.

Disorders of the nervous system.

Very common: tremor.

Common: extrapyramidal disorders, which may be irreversible, stupor*, somnolence, convulsions*, memory impairment, headache, nystagmus or dizziness may occur within minutes after intravenous injection and spontaneously resolve within minutes.

Uncommon: coma*, encephalopathy, lethargy (see below), reversible parkinsonism, ataxia, paraesthesia, seizure exacerbation, dizziness (with intravenous injection, dizziness may occur within minutes; this effect usually resolves within minutes).

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

* Cases of stupor or lethargy have been reported, sometimes leading to transient coma (encephalopathy). These events were isolated or associated with an increased frequency of seizures during treatment. They improved after discontinuation or dose reduction of the drug. Such effects most commonly occur during combination therapy (especially with phenobarbital or topiramate) or after a rapid increase in the dose of sodium valproate.

Disorders of the ear and labyrinth.

Common: hearing loss.

Disorders of the respiratory system, thoracic organs and mediastinum.

Uncommon: pleural effusion.

Gastrointestinal disorders.

Very common: nausea*.

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

* May also occur within minutes after intravenous injection and spontaneously resolves within minutes.

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

Disorders of the renal and urinary system.

Common: urinary incontinence.

Uncommon: renal failure.

Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome. However, the mechanism of these drug effects is currently unclear.

Disorders of the skin and subcutaneous tissue.

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

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

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

Endocrine disorders.

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

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

Vascular disorders.

Common: haemorrhage.

Uncommon: vasculitis.

General disorders and administration site conditions.

Uncommon: hypothermia, mild peripheral oedema.

Hepatobiliary disorders.

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

Disorders of the reproductive system and breast.

Common: dysmenorrhoea.

Uncommon: amenorrhoea.

Rare: male infertility (see section "Use during pregnancy or breastfeeding"), polycystic ovary.

Musculoskeletal and connective tissue disorders, bone disorders.

Uncommon: decreased bone mineral density, osteopenia, osteoporosis, fractures in patients receiving long-term treatment with valproate. The mechanism by which valproate affects bone metabolism is not established. Rare: systemic lupus erythematosus (see section "Special precautions for use"), rhabdomyolysis (see section "Special precautions for use").

Psychiatric disorders.

Common: confusion, hallucinations, aggression*, agitation*, attention deficit syndrome*.

Rare: behavioural disorders*, psychomotor hyperactivity*, learning difficulties*.

* These effects are predominantly observed in children.

Investigations.

Common: weight gain*

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

* Since weight gain may lead to worsening of clinical symptoms of polycystic ovary syndrome, body weight should be carefully monitored (see section "Special precautions for use").

Other laboratory test abnormalities have been observed, suggesting elevated levels of certain enzymes: AST, ALT, LDH, alkaline phosphatase, amylase. Since these changes may be dose-dependent and transient, they should be monitored and treatment adjusted (dose reduction or discontinuation) based on the course and degree of changes (e.g., treatment interruption if liver transaminases exceed three times the upper limit of normal).

Children.

The safety profile of valproate in children is similar to that in adults, but certain 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 disorders, abnormal behaviour, psychomotor hyperactivity and learning disorders are mainly observed in children.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients and 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 (10x10): 10 tablets in a blister, 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Sanofi Winthrop Industrie.
2. SANOFI-AVENTIS S.A.

Manufacturer's address and place of business.

1. 1, rue de la Vierge, AMBARE ET LAGRAVE 33565 – CARBON BLANC Sedex, France.
2. Ctra. C-35 (La Batlloria-Ostalric, km 63.09) 17404 Riells i Viabrea, (Girona), Spain.