Depakin
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEPAKINEÒ (DEPAKINEÒ)
Composition:
Active substance: sodium valproate;
1 ml of syrup contains sodium valproate 57.64 mg;
Excipients: methyl paraben (E 218), propyl paraben (E 216), sucrose, sorbitol solution crystallizing (E 420), glycerol, artificial cherry flavoring, concentrated hydrochloric acid or sodium hydroxide, purified water.
Pharmaceutical form. Syrup.
Main physicochemical properties: clear syrupy liquid of pale yellow color with a cherry odor.
Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03A G01.
Pharmacological Properties
Pharmacodynamics
The pharmacological activity of valproate is primarily directed at the central nervous system. It has anticonvulsant properties against a broad spectrum of seizures in animals and epilepsy in humans.
Two mechanisms of the anticonvulsant action of valproate have been identified in experimental and clinical studies.
The first is a direct pharmacological effect dependent on the concentration of valproate in blood plasma and brain tissue.
The second is an indirect effect, possibly related to valproate metabolites remaining in the brain, or to modifications of neurotransmitters, or to a direct action on the membrane.
The most plausible hypothesis is that after administration, valproate increases the level of gamma-aminobutyric acid (GABA).
Valproate shortens the duration of intermediate sleep phase and simultaneously prolongs slow-wave sleep phase.
Pharmacokinetics
Various pharmacokinetic studies of valproate have shown that its bioavailability in blood after oral administration is close to 100%. The volume of distribution is mainly limited to blood and extracellular fluids undergoing rapid exchange. Valproate penetrates into cerebrospinal fluid and brain tissue. Valproate crosses the placental barrier in both animals and humans (see section "Use in pregnancy or breastfeeding"); in animals, valproate crosses the placental barrier in amounts similar to those in humans. Several publications have assessed the concentration of valproate in umbilical cord blood of newborns during delivery in women: the concentration of valproate in umbilical cord serum was equal to or slightly higher than that in maternal serum. The elimination half-life is 15–17 hours. The minimum serum concentration of valproate required for therapeutic effect is usually 40–50 mg/L; therapeutic efficacy is observed over a wide concentration range — from 40 to 100 mg/L. If higher concentrations are required, the expected benefit should be weighed against the likelihood of developing adverse effects, especially dose-dependent ones. However, serum concentrations persistently above 150 mg/L require dose reduction. Steady-state plasma concentration is achieved within 3–4 days. Valproate is highly protein-bound in plasma. Protein binding is dose-dependent and saturable. The main metabolic pathway of valproate is glucuronidation (approximately 40%), primarily mediated by UGT1A6, UGT1A9, and UGT2B7 enzymes. Valproate is excreted predominantly in urine, following metabolism via conjugation with glucuronic acid and beta-oxidation. The valproate molecule is dialyzable, but hemodialysis is effective only for the free fraction of valproate in blood (approximately 10%). Valproate does not induce enzymes of the cytochrome P450 metabolic system; therefore, unlike most other antiepileptic drugs, it does not accelerate either its own degradation or that of other substances such as estrogen-progestogen agents or vitamin K antagonists.
Children
In children from 10 years of age, valproate clearance is similar to that in adults. In patients under 10 years of age, systemic clearance of valproate varies with age. In neonates and infants up to 2 months of age, valproate clearance is reduced compared to adults and is lowest immediately after birth. According to scientific literature, the elimination half-life of valproate in infants up to 2 months of age shows significant variability, ranging from 1 to 67 hours.
In children aged 2 to 10 years, valproate clearance is 50% higher than in adults.
Preclinical Safety Data
Animal studies have shown that in utero exposure to valproate leads to morphological and functional disturbances in the auditory system of rats and mice.
In vitro, valproate showed no mutagenic effect on bacteria or mouse lymphoma cells and did not induce DNA repair activity in primary cultures of rat hepatocytes. However, in vivo results were conflicting at teratogenic doses depending on the route of administration. After oral administration—the common route in humans—valproate did not induce chromosomal aberrations in rat bone marrow or significant lethal effects in mice during preclinical studies. Intraperitoneal injection of valproate increased DNA strand breaks and chromosomal aberrations in rodents.
Furthermore, published studies have reported increased sister chromatid exchanges in patients with epilepsy receiving valproate compared to untreated healthy subjects. However, conflicting results were observed when comparing data from valproate-treated epilepsy patients with those from untreated epilepsy patients. The clinical significance of these findings regarding DNA/chromosome effects is unknown.
Preclinical data from traditional carcinogenicity studies do not indicate a specific risk for humans.
Reproductive Toxicity
Valproate caused teratogenic effects (malformations in several organ systems) in mice, rats, and rabbits.
Behavioral disturbances in offspring of mice and rats in the first generation after in utero exposure have been reported. In mice, certain behavioral changes were also observed in the second generation, less pronounced in the third generation, following acute in utero exposure of the first generation to teratogenic doses of valproate. The primary mechanisms and clinical significance of these findings are unknown.
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 400 mg/kg/day and 150 mg/kg/day, respectively. Administration of valproate at 270 mg/kg/day in adult rats and 90 mg/kg/day in adult dogs did not cause significant adverse effects on the testes. It is not possible to extrapolate AUC (area under the curve) data obtained from rat and dog studies to human safety levels.
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 sensitivity to valproate in young animals was not considered greater than in adults. The sensitivity of testes to valproate 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 breastfeeding. Pregnancy. Breastfeeding. Fertility" and "Adverse reactions").
Clinical Characteristics
Indications.
Adults and children. As monotherapy or in combination with other antiepileptic drugs for:
- Treatment of generalized epilepsy with the following seizure types: clonic, tonic, tonic-clonic, absence, myoclonic, atonic seizures, and Lennox-Gastaut syndrome;
- Treatment of focal epilepsy: focal seizures with or without secondary generalization.
Children. Prophylaxis of recurrent seizures following one or more complicated febrile convulsions when intermittent prophylaxis with benzodiazepines is ineffective.
Contraindications.
Pregnancy, except in cases where alternative treatments are ineffective (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Lactation").
Valproate is contraindicated in women of childbearing potential who do not meet the conditions of the Pregnancy Prevention Programme (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Lactation").
Hypersensitivity to valproate, divalproex, valpromide, or to any component of the medicinal product in the patient's history.
Acute hepatitis and chronic hepatitis. History of severe hepatitis in the patient or family members, particularly if drug-induced.
Hepatic porphyria.
Valproate is contraindicated in patients with known mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG), such as Alpers-Huttenlocher syndrome, and in children under two years of age suspected of having a POLG-related disorder (see section "Special Warnings and Precautions for Use").
Deficiency of enzymes of the urea cycle (see section "Special Warnings and Precautions for Use").
Valproate is contraindicated in patients with known systemic primary carnitine deficiency with uncorrected hypocarnitinaemia (see section "Special Warnings and Precautions for Use").
Concomitant use with St. John’s wort (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Interaction with Other Medicinal Products and Other Forms of Interaction.
Contraindicated Combinations
St. John’s wort (Hypericum perforatum). Risk of reduced plasma concentrations and decreased efficacy of the anticonvulsant.
Not Recommended Combinations
Lamotrigine. Increased risk of serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis).
Additionally, possible increase in lamotrigine plasma concentrations (due to inhibition of hepatic metabolism by sodium valproate).
If concomitant use cannot be avoided, careful clinical monitoring of the patient is required.
Penems (carbapenems). Risk of seizures due to rapid reduction in valproic acid plasma concentrations, which may fall below the limit of detection.
Concomitant administration of valproic acid and carbapenems has led to a 60–100% reduction in plasma valproic acid concentrations within approximately two days. Due to the rapid onset and extent of this reduction, concomitant use of carbapenems should be avoided in patients whose condition is stabilized on valproic acid and in whom close monitoring is not feasible (see section "Special Warnings and Precautions for Use").
Combinations Requiring Special Precautions
Acetazolamide. Increased risk of hyperammonaemia and subsequent encephalopathy. Regular clinical and laboratory monitoring is indicated.
Aztreonam. Risk of seizures due to reduced plasma concentrations of valproic acid. Clinical monitoring, measurement of plasma drug concentrations, and possible adjustment of the anticonvulsant dose during and after antibiotic therapy are required.
Carbamazepine. Increased plasma concentrations of the active metabolite of carbamazepine, with signs of carbamazepine toxicity. Additionally, reduced plasma concentrations of valproic acid due to enhanced hepatic metabolism induced by carbamazepine. Clinical monitoring, measurement of plasma concentrations, and dose adjustment of both anticonvulsants are indicated.
Felbamate. Increased serum concentrations of valproic acid with risk of overdose. Clinical and laboratory monitoring, and possible dose adjustment of valproate, are indicated during and after felbamate therapy.
Estrogen-containing medicinal products, including estrogen-containing hormonal contraceptives. Estrogens are inducers of UDP-glucuronosyltransferase (UGT) isoenzymes involved in the glucuronidation of valproate and may increase valproate clearance, potentially reducing serum valproate concentrations and possibly compromising efficacy (see section "Special Warnings and Precautions for Use"). Monitoring of serum valproate levels should be considered. Conversely, valproate does not induce enzymes and therefore does not reduce the efficacy of estrogen-progestogen hormonal contraceptives in women.
Metamizole. Metamizole may reduce serum valproate concentrations when used concomitantly with other medicinal products, potentially reducing the clinical efficacy of valproate.
Clinical response (seizure control or mood) should be monitored, and serum valproate concentration monitoring should be considered if necessary.
Methotrexate. Several reports describe a marked decrease in serum valproate levels following methotrexate administration, leading to seizures. Physicians should monitor clinical response (seizure or mood control) and consider monitoring serum valproate levels if required.
Nimodipine (oral and, by extrapolation, parenteral). Risk of a 50% increase in nimodipine plasma concentrations. Dose reduction of nimodipine is recommended, particularly in patients with arterial hypotension.
Clozapine. Concomitant treatment with valproate and clozapine may increase the risk of clozapine-induced neutropenia and myocarditis. If concomitant use is necessary, careful monitoring for both adverse reactions is required.
Phenobarbital and, by extrapolation, primidone. Increased risk of hyperammonaemia and encephalopathy. Regular clinical and laboratory monitoring is indicated.
Phenytoin and, by extrapolation, fosphenytoin. Increased risk of hyperammonaemia and encephalopathy. Regular clinical and laboratory monitoring is indicated.
Propofol. Possible increase in blood propofol levels. Dose reduction of propofol should be considered when used concomitantly with valproate.
Rifampicin. Risk of seizures due to enhanced hepatic metabolism of valproate. Clinical and laboratory monitoring, and possible dose adjustment of the anticonvulsant, are indicated during and after rifampicin therapy.
Rufinamide. Possible increase in rufinamide concentrations, especially in children weighing less than 30 kg. For children weighing less than 30 kg, the total daily dose should not exceed 600 mg after titration.
Topiramate. Increased risk of hyperammonaemia and encephalopathy. Regular clinical and laboratory monitoring is indicated.
Zidovudine. Increased risk of zidovudine adverse reactions, particularly haematological toxicity, due to reduced zidovudine metabolism by valproic acid. Regular clinical and laboratory monitoring is indicated. Complete blood counts should be performed monthly during the first two months of combination therapy to monitor for anaemia.
Zonisamide. Increased risk of hyperammonaemia and encephalopathy. Regular clinical and laboratory monitoring is indicated.
Other Interactions
Pivalate-conjugated medicinal products. Concomitant use of valproate with pivalate-conjugated drugs (e.g., cefditoren pivoxil, adefovir dipivoxil, pivmecillinam, pivampicillin) should be avoided due to increased risk of hypocarnitinaemia (see section "Special Warnings and Precautions for Use": Patients at Risk of Hypocarnitinaemia). Patients who cannot avoid concomitant use of these drugs should be closely monitored for signs and symptoms of hypocarnitinaemia.
Lithium. Depakine® does not affect serum lithium levels.
Risk of Hepatic Injury
Concomitant use with salicylates should be avoided in children under 3 years of age due to the risk of hepatotoxicity (see section "Special Warnings and Precautions for Use").
Concomitant use of valproate with other antiepileptic drugs increases the risk of hepatic injury, particularly in younger children (see section "Special Warnings and Precautions for Use").
Combination with cannabidiol increases the frequency of transaminase elevations. In clinical trials involving patients of various ages receiving cannabidiol at doses of 10–25 mg/kg and valproate concomitantly, 19% of patients experienced ALT elevations greater than three times the upper limit of normal. Appropriate hepatic monitoring is required when valproate is used with other antiepileptic drugs with potential hepatotoxicity, including cannabidiol, and consideration should be given to dose reduction or discontinuation in case of significant abnormalities in liver function tests (see section "Special Warnings and Precautions for Use").
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 (see section "Use in pregnancy or breastfeeding"), the medicine Depakine® should not be used in female children and women of childbearing potential, except when other treatments are ineffective or not tolerated. If treatment with other medicines is not possible, valproate should be prescribed in accordance with the requirements of the Pregnancy Prevention Programme outlined below. Depakine® is contraindicated:
Conditions of the Pregnancy Prevention Programme The prescribing physician must:
These conditions also apply to women who are currently not sexually active, unless the physician has compelling reasons to consider pregnancy risk absent. Female children
Pregnancy testing. Pregnancy must be excluded prior to initiating valproate therapy. Valproate treatment should not be started in women of childbearing potential unless a negative pregnancy test result has been obtained using plasma with a sensitivity of at least 25 mIU/mL, as approved by a healthcare professional, to prevent unintended exposure during pregnancy. This pregnancy test should be repeated at regular intervals during treatment. Contraception. Women of childbearing potential prescribed valproate must use effective contraception continuously throughout the entire treatment period. 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 form such as an intrauterine device or implant) or two complementary methods, one of which must be barrier, should be used. The choice of contraceptive method must be individualised, with patient involvement in the discussion to ensure active participation and adherence to the chosen preventive measures. Even in patients experiencing amenorrhea, all recommendations for effective contraception must be followed. Estrogen-containing medicines. Concomitant use of valproate with estrogen-containing medicines, 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 medicine should monitor clinical response (seizure control) when initiating or discontinuing estrogen-containing agents. Conversely, valproate does not reduce the effectiveness of hormonal contraceptives. Annual specialist review of treatment. A specialist must reassess at least annually whether valproate remains the most appropriate treatment for the patient. The specialist must discuss the Annual Risk Information Form at the beginning of treatment and during each annual review, ensuring 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. If a woman plans to become pregnant, a specialist experienced in managing epilepsy should reassess valproate treatment and consider alternative treatment options. All possible measures should be taken to transition the patient to acceptable alternative treatments before conception and before discontinuing contraception (see section "Use in pregnancy or breastfeeding"). If such transition is not possible, additional counselling regarding risks associated with valproate to the unborn child should be provided to ensure the woman receives adequate information for making 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 therapies. Pregnant patients who received valproate during pregnancy and their partners should be referred to a specialist experienced in teratology for evaluation and counselling regarding treatment during pregnancy (see section "Use in pregnancy or breastfeeding"). The pharmacist must ensure that:
Educational materials. To assist healthcare professionals and patients in avoiding valproate use during pregnancy, the marketing authorisation holder provides educational materials to further highlight the warnings regarding teratogenicity (the ability to cause congenital malformations) and fetotoxicity (the ability to cause neurodevelopmental disorders) of valproate, and to inform about instructions for using valproate in women of childbearing potential, including 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 by both the specialist and the patient (or her legal representative) at the initiation of treatment and during each annual specialist review of valproate treatment. |
| Use in male children and men of reproductive age Data from a retrospective observational study indicate an increased risk of neurodevelopmental disorders in children fathered by men who received valproate treatment during the 3 months prior to conception, compared to children fathered by men who received treatment with lamotrigine or levetiracetam (see section "Use during pregnancy or breastfeeding"). To prevent these risks, the physician prescribing valproate therapy must inform male patients about the risks and discuss with them:
Valproate treatment in male children and men of reproductive age should be regularly reviewed by the prescribing physician to determine whether valproate remains the most appropriate treatment. Male patients planning to father a child should consider and discuss appropriate alternative treatment options with their physician. Individual circumstances should be evaluated separately in each specific case. It is recommended to seek advice from a physician experienced in treating epilepsy with valproate. Educational materials on risk reduction are available for healthcare professionals and male patients of reproductive age. Male patients of reproductive age taking valproate should be provided with a patient guide. |
Exacerbation of seizures. As with any antiepileptic agent, administration of valproate may, instead of improving the condition, lead to a reversible increase in the frequency and severity of seizures (including epileptic status) or to the emergence of a new type of seizure. Patients should be advised to seek immediate medical attention if seizures worsen (see section "Adverse reactions").
These seizures must be differentiated from those that may occur due to pharmacokinetic interactions (see section "Interaction with other medicinal products and other forms of interaction"), toxicity (liver damage or encephalopathy, see sections "Special precautions for use" and "Adverse reactions") or overdose.
Since this medicinal product is metabolized to valproic acid, it must not be combined with other medicinal products undergoing the same transformation to avoid valproic acid overdose (e.g., divalproex, valpromide).
Severe liver damage
Conditions of occurrence. Rare cases of liver damage with severe, and sometimes fatal, clinical outcomes have been reported. The highest risk occurs in infants and children under 3 years of age with severe epilepsy, including children with epilepsy associated with brain damage, mental retardation, and/or congenital metabolic disorders, including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations (see sections "Contraindications" and "Special precautions for use") or degenerative genetic diseases.
In children aged 3 years and older, this risk significantly decreases and gradually diminishes with age.
In most cases, such liver damage occurred within the first 6 months of treatment, most frequently between weeks 2 and 12, usually during combination antiepileptic therapy.
Signs to watch for. Early diagnosis is based on clinical presentation. In particular, symptoms that may precede jaundice, especially in patients at risk (see above "Conditions of occurrence"), should be considered:
- non-specific symptoms, which typically appear suddenly, such as asthenia, anorexia, depression, drowsiness, sometimes associated with recurrent vomiting and abdominal pain;
- recurrence of epileptic seizures despite adequate adherence to therapy.
The patient (or their caregivers, if the patient is a child) should be informed of the need to seek immediate medical attention if these symptoms occur. The patient should be promptly evaluated, including clinical examination and laboratory tests of liver function.
Detection. Liver function tests should be performed before initiating therapy and then regularly during the first 6 months of treatment, especially in patients at increased risk. If there is a change (dose increase or new treatment) in concomitant therapy known for its hepatotoxicity, 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. If pathologically low prothrombin time is confirmed, especially in conjunction with other abnormal biological parameters (marked decrease in fibrinogen and coagulation factors, increased bilirubin and liver enzymes), treatment with Depakine® must be discontinued immediately. As a precaution, concomitant salicylate therapy should also be discontinued, as they share the same metabolic pathway.
Pancreatitis. Cases of pancreatitis, sometimes fatal, have been reported very rarely. It may occur regardless of patient age and duration of treatment, with particularly high risk in young children. Pancreatitis with unfavorable clinical outcomes is generally observed in younger children or in patients with severe epilepsy, brain damage, or those receiving combination antiepileptic therapy.
If pancreatitis develops on the background of liver failure, the risk of fatal outcomes increases significantly.
In the event of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting, and/or loss of appetite, pancreatitis should be considered in the differential diagnosis, and the medicinal product should be discontinued in patients with elevated pancreatic enzymes, and appropriate alternative therapy measures should be initiated.
Children. Depakine® should be administered to children under 3 years of age only as monotherapy. For this age group, therapy should be initiated only after weighing the clinical benefits against the risk of liver damage or pancreatitis (see sections "Special precautions for use. Severe liver damage" and "Interaction with other medicinal products and other forms of interaction").
Concomitant administration of salicylate derivatives should be avoided in children under 3 years of age due to the risk of hepatotoxicity and bleeding (see subsection "Severe liver damage").
Children with a history of unexplained liver and gastrointestinal disorders (loss of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, mental retardation, or a family history of neonatal or infant death should undergo metabolic testing before initiating any valproate therapy, including measurement of blood ammonia levels in fasting state and after food intake.
Suicidal thoughts and behavior. Cases of suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of data from randomized placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this effect is unknown, and currently available data do not allow exclusion of an increased risk with valproate use.
Therefore, patients should be monitored for early detection of suicidal thoughts and behavior, and appropriate therapy should be prescribed. Patients (and caregivers) should be warned that if signs of suicidal thoughts or behavior occur, they should seek immediate medical attention.
Severe skin reactions and angioedema. Severe skin adverse reactions (SSARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and angioedema, have been reported with valproate use. Patients should be informed about the signs and symptoms of serious skin reactions and closely monitored. If signs of SSAR or angioedema appear, immediate evaluation is required, and treatment should be discontinued if SSAR or angioedema is confirmed.
Patients with known or suspected mitochondrial disease. Valproate may trigger or worsen clinical manifestations of existing mitochondrial disorders caused by mutations in mitochondrial DNA or in the nuclear gene encoding mitochondrial polymerase gamma (POLG).
In particular, cases of valproate-induced acute liver failure and associated fatalities have been reported in patients with hereditary neurometabolic syndromes caused by POLG mutations (e.g., Alpers-Huttenlocher syndrome). POLG-related disorders should be suspected in patients with a family history of POLG-related disorders or those exhibiting symptoms suggestive of POLG-related disorders, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status at presentation, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Diagnostic evaluation for such disorders should include POLG mutation testing according to current clinical practice (see section "Contraindications").
Urea cycle disorders and risk of hyperammonemia. This medicinal product is contraindicated in patients with deficiencies of enzymes of the urea cycle. Due to the risk of hyperammonemia with valproate use, metabolic investigations should be performed before initiating treatment if a urea cycle enzyme deficiency is suspected.
Several cases of hyperammonemia associated with stupor or coma have been reported in such patients (see sections "Contraindications" and subsections "Severe liver damage", "Risk of developing hypocarnitinemia").
Risk of developing hypocarnitinemia
Administration of valproate may cause or worsen hypocarnitinemia, which may lead to hyperammonemia (potentially resulting in hyperammonemic encephalopathy). Other symptoms such as hepatotoxicity, hypoketotic hypoglycemia, myopathy including cardiomyopathy, rhabdomyolysis, and Fanconi syndrome have been observed predominantly in patients with risk factors for hypocarnitinemia or pre-existing hypocarnitinemia. Patients at increased risk of symptomatic hypocarnitinemia during valproate treatment include those with metabolic disorders, particularly mitochondrial disorders related to carnitine (see "Patients with known or suspected mitochondrial disease", "Urea cycle disorders and risk of hyperammonemia"), impaired dietary carnitine intake, patients under 10 years of age, and patients concurrently using pivolate-conjugated medicinal products or other antiepileptic drugs.
Patients should be warned to report immediately any signs of hyperammonemia, such as ataxia, impaired consciousness, vomiting. If symptoms of hypocarnitinemia occur, carnitine supplementation should be considered.
Valproate should be used in patients with primary systemic carnitine deficiency and corrected hypocarnitinemia only if the benefits of valproate treatment outweigh the risks and no suitable therapeutic alternative is available. In these patients, carnitine levels should be closely monitored.
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".
Interaction with other medicinal products. This medicinal product is not recommended for concomitant use with lamotrigine and penems (carbapenems) (see section "Interaction with other medicinal products and other forms of interaction").
Information related to sodium content. This medicinal product contains less than 1 mmol (23 mg) of sodium per 100 mg of sodium valproate; therefore, it can be considered essentially sodium-free.
Information on excipients with known effect
This medicinal product is not recommended for patients with fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency (rare hereditary conditions).
Since this medicinal product contains 105 mg of sorbitol per 1 ml, it is not recommended for patients with hereditary fructose intolerance.
This medicinal product contains parahydroxybenzoates and may cause allergic reactions (possibly delayed type).
This medicinal product contains 0.00014 mg of ethanol per 30 mg dose, equivalent to 0.00027 mg ethanol per 1 ml of syrup (0.000027% w/v). The amount of ethanol in 1 ml of this medicinal product is equivalent to less than 1 ml of beer or less than 1 ml of wine. It is unlikely that the small amount of ethanol in this medicinal product will cause any noticeable effects.
Cognitive or extrapyramidal disorders. Cognitive or extrapyramidal disorders may be accompanied by signs of brain atrophy on imaging studies. Therefore, this type of clinical presentation may be misinterpreted as dementia or Parkinson's disease. These disorders are reversible after discontinuation of the drug (see section "Adverse reactions").
Alcohol. Alcoholic beverages should not be consumed during valproate treatment.
Effect on diagnostic methods. Valproate is primarily excreted in urine, partially in the form of ketone bodies. Urine ketone testing may yield false-positive results in patients with diabetes mellitus.
Precautions for use
Liver function tests should be performed before starting treatment (see section "Contraindications") and periodically thereafter during the first 6 months, especially in patients at risk (see section "Severe liver damage. Detection").
As with most antiepileptic medicinal products, a mild, isolated, and transient increase in transaminase levels may occur, particularly at the beginning of treatment, in the absence of any clinical signs. In such cases, a more comprehensive evaluation (including prothrombin time) is recommended; if necessary, dosage adjustment should be considered and tests repeated according to parameter changes.
Blood tests (complete blood count including platelet count, bleeding time, and coagulation parameters) are recommended before initiating treatment, then after 15 days and at the end of treatment, as well as before any surgical procedures and in case of bruising or spontaneous bleeding (see section "Adverse reactions").
In patients with renal impairment, elevated valproic acid concentrations in circulation should be considered and the dose adjusted accordingly.
Although immunological disorders due to this medicinal product are known to occur only rarely, the benefit-risk ratio should be carefully considered in patients with systemic lupus erythematosus.
At the beginning of treatment, patients should be informed about the risk of weight gain, and appropriate measures, primarily related to diet, should be taken to minimize this effect.
Use during pregnancy or breastfeeding.
| Valproate is contraindicated (see sections "Contraindications" and "Special precautions"):
|
| Use in male children and adult males of reproductive age See sections "Special instructions" and subsection "Male children and adult males of reproductive age" below. |
Pregnant women and women of reproductive age
Teratogenicity and effects on neurodevelopment following in utero exposure
| In women, the use of valproate as monotherapy or in combination therapy, including with other antiepileptic drugs, is frequently associated with adverse clinical outcomes of pregnancy. Available data indicate an increased risk of major congenital malformations and neurodevelopmental disorders with valproate monotherapy and combination therapy compared to those in the population not exposed to valproate. Valproate has been shown 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 safety data"). |
- Congenital malformations following in utero exposure
A meta-analysis including registry studies and cohort studies showed that approximately 11% of children born to women with epilepsy who received valproate monotherapy during pregnancy had major congenital malformations. This risk of the most common congenital malformations is higher than in the general population, where the risk is approximately 2–3%.
The risk of major congenital malformations in children exposed in utero to combination antiepileptic therapy including valproate is higher than with combination antiepileptic therapy without valproate. This risk is dose-dependent with valproate monotherapy, and available data indicate that it is also dose-dependent with combination therapy including valproate. However, a threshold dose below which there is no risk has not been established.
Available data indicate an increased frequency of minor and major developmental abnormalities. The most common malformations include neural tube defects (approximately 2–3%), facial dysmorphisms, cleft lip and palate, craniosynostosis, cardiac, renal, and urogenital malformations (particularly hypospadias), limb malformations (including bilateral radial aplasia), and multiple anomalies affecting various organ systems.
In utero exposure to valproate may also lead to hearing impairment or loss due to malformations of the ear and/or nose (secondary effect) and/or direct toxic effects on auditory function. Cases of unilateral and bilateral deafness or hearing disorders have been reported. Outcomes were not reported in all cases. When outcomes were reported, in most cases the impairment was not resolved.
In utero exposure to valproate may lead to ocular malformations (including coloboma, microphthalmia), which have been reported in association with other congenital malformations. These ocular malformations may affect vision.
- Neurodevelopmental disorders following in utero exposure
Available data indicate that in utero exposure to valproate increases the risk of neurodevelopmental disorders in exposed children. This risk of neurodevelopmental disorders (including autism) is likely dose-dependent when valproate is used as monotherapy, but based on available data, a threshold dose below which there is no risk cannot be established.
When valproate is used in combination with other antiepileptic drugs during pregnancy, the risk of neurodevelopmental disorders in children is also significantly increased compared to children in the general population or children whose mothers had epilepsy but did not receive treatment.
The exact period of pregnancy during which there is a risk of such effects has not been determined, but the possibility that the risk exists throughout the entire pregnancy cannot be excluded.
Studies involving preschool-aged children exposed in utero to valproate used as monotherapy showed that developmental delays occurred in approximately 30–40% of cases, including delays in speech and walking, reduced cognitive function, poor language skills (both expressive and receptive language), and memory impairments.
The intelligence quotient (IQ) measured in school-aged children (aged 6 years) exposed in utero to valproate was on average 7–10 points lower than in children exposed to other antiepileptic drugs. Although the role of other factors cannot be excluded, there is evidence that the risk of reduced cognitive function in children exposed to valproate in utero may not depend on maternal IQ.
Data on long-term outcomes are limited.
Available data from population-based studies indicate that children exposed in utero to valproate have an increased risk of autism spectrum disorders (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed study population.
Available data from another population-based study show that children exposed in utero to valproate have an increased risk of attention deficit hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed study population.
Women of childbearing potential
Depakine® should not be used in women of childbearing potential, except when other treatments are ineffective or poorly tolerated by the patient. If alternative treatments cannot be used, Depakine® may be prescribed only if the requirements of the Pregnancy Prevention Programme are met (see section «Special precautions»), including:
- the patient is not pregnant (negative pregnancy test results using blood plasma with a sensitivity of at least 25 mIU/mL at the start of treatment and periodically during treatment);
- the patient uses at least one effective method of contraception;
- the patient has been informed of the risks of valproate use during pregnancy.
Women of childbearing potential must undergo regular reassessment of the benefit-risk balance at regular intervals during treatment (at least annually).
Estrogen-containing medications. Medications containing estrogens, including estrogen-containing hormonal contraceptives, may increase the clearance of valproate, which is believed to lead in turn to decreased serum valproate concentrations and potentially reduce the efficacy of valproate (see sections «Special precautions» and «Interaction with other medicinal products and other forms of interaction»).
If a woman is planning pregnancy
Treatment with valproate in women planning pregnancy should be re-evaluated by a specialist experienced in the treatment of epilepsy. Where possible, all measures should be taken to switch women planning pregnancy to an appropriate alternative treatment before conception and before discontinuing contraception (see section «Special precautions»). If such a switch is not possible, additional counseling regarding the risks of valproate use for the unborn child should be provided to ensure the woman is adequately informed to make an informed decision regarding family planning.
Folic acid supplementation before and during early pregnancy may reduce the risk of neural tube defects, which are common in all pregnancies. However, available data do not confirm that this prevents congenital malformations or developmental abnormalities due to valproate exposure.
Pregnant women
The use of valproate for the treatment of epilepsy is contraindicated during pregnancy, except when no suitable alternative treatment is available (see sections «Contraindications» and «Special precautions»).
If a woman taking valproate becomes pregnant, she should be referred immediately to a specialist to consider alternative treatment options.
During pregnancy, tonic-clonic seizures and epileptic status with hypoxia in the woman may be associated with a particular risk of serious consequences or death for both the pregnant woman and the fetus.
If, despite the known risks of valproate use during pregnancy, after careful consideration of alternative treatment options, a pregnant woman must receive valproate for the treatment of epilepsy in exceptional circumstances, the following is recommended:
- use the lowest effective dose;
- it is recommended to divide the daily dose of valproate into several doses taken 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 counseling regarding treatment during pregnancy.
- specialized prenatal monitoring should be performed to detect possible fetal neural tube defects or other developmental abnormalities.
Before delivery
Prior to delivery, coagulation parameters should be assessed in the pregnant woman, including platelet count, fibrinogen levels, and coagulation time (activated partial thromboplastin time (aPTT)).
Risk in the neonatal period
- Hemorrhagic syndrome has been very rarely reported in newborns whose mothers took valproate during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or reduced levels of other coagulation factors. Afibrinogenemia has also been reported, which may lead to fatal outcomes. However, this syndrome should be differentiated from vitamin K deficiency caused by phenobarbital and enzyme inducers. Normal coagulation test results in the mother do not exclude coagulation disorders in her newborn. Therefore, platelet count, plasma fibrinogen levels, coagulation tests, and coagulation factors should be determined in newborns immediately after birth.
- 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.
- Neonates whose mothers took valproate during the last trimester of pregnancy may develop withdrawal syndrome (manifested, in particular, as nervous excitability, irritability, increased excitability, increased neuromuscular reflex excitability, hyperkinesia, tonic disorders, tremor, seizures, and sucking disorders).
Monitoring of newborns/older children
Children exposed to valproate during their in utero development should undergo careful monitoring of neurodevelopmental milestones, and appropriate treatment should be initiated as early as possible if necessary.
Male children and men of reproductive age
Potential risk of neurodevelopmental disorders in a child whose father received valproate within 3 months before conception
Data from a retrospective observational study conducted in three Scandinavian countries indicate an increased risk of neurodevelopmental disorders in a child (aged 0 to 11 years) whose father received valproate as monotherapy within 3 months before conception, compared to a child whose father received lamotrigine or levetiracetam as monotherapy, with an adjusted risk ratio (RR) of 1.50 (95% CI 1.09–2.07). The adjusted cumulative risk of neurodevelopmental disorders was 4.0% to 5.6% in the valproate group compared to 2.3% to 3.2% in the lamotrigine/levetiracetam group. The number of patients included in the study was insufficient to investigate associations with specific subtypes of neurodevelopmental disorders. Study limitations included potential confounding by indication and differences in observation duration between patient groups. The mean observation duration for children in the valproate group was 5.0 to 9.2 years compared to 4.8 and 6.6 years in the lamotrigine/levetiracetam group. There is an increased risk of neurodevelopmental disorders in a child whose father took valproate within 3 months before conception, although a causal relationship with valproate has not been confirmed. Furthermore, the study did not assess the risk of neurodevelopmental disorders in a child whose father discontinued valproate more than 3 months before conception (i.e., allowing for new spermatogenesis without valproate exposure).
To prevent these risks, the physician prescribing valproate therapy should inform male patients about the risks and discuss:
- the need for effective contraception, including for their partners, during valproate treatment and for at least 3 months after discontinuation of treatment (see section «Special precautions»);
- not donating sperm during valproate treatment and for at least three months after stopping valproate.
Valproate treatment in male children and men of reproductive age should be regularly reviewed by the prescribing physician to determine whether valproate remains the most appropriate treatment for the patient. Male patients planning to father a child should consider and discuss appropriate alternative treatment options with their physician. Individual circumstances should be evaluated on a case-by-case basis. It is recommended to seek advice from a physician experienced in the treatment of epilepsy.
Breastfeeding
Valproate is excreted in human breast milk at concentrations of 1 to 10% of the mother's serum level. 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 to discontinue/abstain from Depakine® treatment should be made considering the benefits of breastfeeding for the child and the benefits of treatment for the woman.
Fertility
Cases of amenorrhea, polycystic ovary syndrome, and elevated testosterone levels have been reported in women taking valproate (see section «Adverse reactions»). Valproate use may also lead to impaired fertility in men (including reduced sperm motility) (see section «Adverse reactions»). In some cases, fertility impairment was reversible and resolved at least 3 months after discontinuation of the drug. Limited case reports suggest that a significant dose reduction may improve fertility. However, reversibility of male infertility has not been reported in some other cases.
Ability to affect reaction speed when driving or operating machinery. Patients, especially those who drive or operate machinery, should be warned of the risk of drowsiness, particularly when receiving combination antiepileptic therapy or when valproate is combined with other medications that cause drowsiness.
Dosage and administration.
| Girls and women of childbearing potential Treatment with valproate should be initiated and monitored by a specialist experienced in the treatment of epilepsy. Valproate should not be used in girls and women of childbearing potential unless other treatments are ineffective or not tolerated. In such cases, valproate should be prescribed in accordance with the requirements of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special warnings and precautions for use"). |
| Male children, men of reproductive age Treatment with valproate should be initiated and supervised by a specialist physician experienced in the treatment of epilepsy (see sections "Contraindications" and "Use in pregnancy or breastfeeding"). |
An oral dosage form as a syrup is particularly suitable for use in children under 11 years of age.
The medicinal product is intended for oral administration. To open the bottle, press down on the cap and twist it. After using the medicinal product, the bottle must be tightly closed. The dosing device supplied in the pack is intended exclusively for administering the medicinal product Depakine® syrup, 57.64 mg/mL. The syrup should be taken only with the oral syringe (with a white plunger) supplied in the package. The single dose is indicated on the syringe plunger (dosing device). The dose can be read directly from the scale marked on the dosing device, graduated every 20 mg from 10 mg to 260 mg, with intermediate graduations of 10 mg. For intermediate doses, the prescribed dose in milligrams should be calculated and then rounded to the nearest corresponding graduation mark, considering half-way between graduation marks.
The medicinal product should preferably be taken during meals, dividing the daily dose:
- into 2 doses – for children under 1 year of age,
- into 3 doses – for children from 1 year of age.
The average daily dose is:
- infants and children: 30 mg/kg body weight (preferably use syrup, oral solution, or prolonged-release granules);
- adults: 20–30 mg/kg body weight (preferably use tablets, prolonged-release tablets, or prolonged-release granules).
This medicinal product must be prescribed in milligrams.
Initiation of treatment. In patients already receiving antiepileptic drugs that are to be replaced by Depakine®, the optimal dose should be reached gradually over approximately 2 weeks. Then, depending on the efficacy of treatment, the dose of the other antiepileptic drug should be gradually reduced.
For patients not receiving other antiepileptic drugs, the dose should be increased gradually every 2–3 days to achieve the optimal dose within approximately one week.
If combination therapy with other antiepileptic drugs is required, they should be introduced gradually (see "Interaction with other medicinal products and other forms of interaction").
Patients with renal insufficiency may require dose reduction or dose adjustment in patients undergoing hemodialysis. Sodium valproate is dialyzable (see section "Overdose"). The dose should be adjusted according to clinical monitoring of the patient (see section "Special precautions for use").
Children.
The medicinal product can be used in pediatric practice (see sections "Indications", "Dosage and administration").
The oral dosage form as a syrup is particularly suitable for use in children under 11 years of age.
Overdose.
The clinical picture of severe acute overdose typically includes more or less profound coma without agitation, accompanied by muscle hypotonia, hyporeflexia, miosis, impaired spontaneous respiration, metabolic acidosis, arterial hypotension, and vascular collapse/shock.
Several cases of increased intracranial pressure associated with cerebral edema have been reported.
Emergency treatment in hospital 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 should be performed if necessary.
Overall, the prognosis in such overdose cases is favorable. However, several cases with fatal outcome have been reported.
The presence of sodium in valproate may lead to hypernatremia in overdose.
In cases of valproate overdose leading to hyperammonemia, intravenous carnitine may be administered to normalize ammonia levels.
Adverse Reactions
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 disorders of neuro-psychological development (see section "Special precautions for use" and "Use during pregnancy or breastfeeding").
Disorders of the blood and lymphatic system
Common: anaemia, thrombocytopenia.
Cases of dose-dependent thrombocytopenia have been reported, which typically occurred in a systematic manner and had no clinical consequences.
In patients with symptomatic thrombocytopenia, simple dose reduction of the medicinal product, if possible, taking into account platelet levels and disease control, usually leads to resolution of thrombocytopenia.
Uncommon: leukopenia, pancytopenia.
Rare: generalized bone marrow aplasia or erythroid aplasia, agranulocytosis, macrocytic anaemia, macrocytosis.
Investigations
Common: weight gain*.
Rare: decreased levels of coagulation factors (at least one), pathological coagulation test results (e.g. prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased international normalized ratio (INR)) (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding"), vitamin B8 (biotin) deficiency / biotinidase deficiency.
Frequency not known: acquired Pelger-Huët anomaly**.
* Since weight gain is a risk factor for polycystic ovary syndrome, body weight should be carefully monitored in female patients (see section "Special precautions for use").
** Acquired Pelger-Huët anomaly has been reported (with and without myelodysplastic syndrome).
Nervous system disorders
Very common: tremor.
Common: extrapyramidal disorders**, stupor*, sedation, convulsions*, memory impairment, headache, nystagmus, nausea or dizziness.
Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism**, ataxia, paraesthesia.
Rare: diplopia, cognitive disorders with gradual onset and progressive development (which may progress to full dementia), which were reversible within several weeks or months after discontinuation of the drug**.
* Cases of stupor and lethargy, sometimes leading to transient coma (encephalopathy), have been reported during valproate use. Symptoms improved after discontinuation or dose reduction of valproate. This most commonly occurs during combination therapy (especially with phenobarbital or topiramate) or after a rapid increase in the dose of sodium valproate.
** These symptoms may be accompanied by signs of brain atrophy on imaging studies.
Ear and labyrinth disorders
Common: hearing loss.
Respiratory, thoracic and mediastinal disorders
Uncommon: pleural effusion (eosinophilic).
Gastrointestinal disorders
Very common: nausea.
Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, upper abdominal pain, diarrhoea, which may occur at the beginning of treatment and usually resolve within a few days without the need to discontinue the drug.
Uncommon: pancreatitis, sometimes fatal, requiring immediate discontinuation of the drug (see section "Special precautions for use").
Renal and urinary disorders
Common: urinary incontinence.
Uncommon: renal failure.
Rare: enuresis, tubulointerstitial nephritis, Fanconi syndrome.
Skin and subcutaneous tissue disorders
Common: transient and/or dose-dependent alopecia, nail and nail bed abnormalities.
Uncommon: angioneurotic oedema, skin reactions, hair disorders (such as unusual hair texture, hair colour changes, abnormal hair growth).
Rare: Lyell's syndrome (toxic epidermal necrolysis), Stevens-Johnson syndrome, erythema multiforme, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) or drug hypersensitivity syndrome.
Frequency not known: hyperpigmentation.
Endocrine disorders
Uncommon: syndrome of inappropriate antidiuretic hormone secretion, hyperandrogenism (hirsutism, virilization, acne, androgenic alopecia and/or increased levels of androgenic hormones).
Rare: hypothyroidism (see section "Use during pregnancy or breastfeeding").
Metabolic and nutritional disorders
Common: hyponatremia.
Rare: hyperammonaemia* (see section "Special precautions for use"), obesity.
* Isolated cases of mild hyperammonaemia without changes in liver function tests may occur, particularly during combination therapy, and do not require discontinuation of treatment. However, cases of hyperammonaemia associated with neurological symptoms (which may progress to coma) have also been reported and require further investigation (see also section "Special precautions for use": Urea cycle disorders and risk of hyperammonaemia. Risk of developing carnitine deficiency).
Frequency not known: carnitine deficiency (see sections "Contraindications" and "Special precautions for use").
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Rare: myelodysplastic syndromes.
Vascular disorders
Common: haemorrhages (see section "Special precautions for use").
Uncommon: cutaneous vasculitis, predominantly leukocytoclastic vasculitis.
General disorders
Uncommon: hypothermia, mild peripheral oedema.
Hepatobiliary disorders
Common: liver damage (see section "Special precautions for use").
Reproductive system and breast disorders
Common: menstrual disorders.
Uncommon: amenorrhoea.
Rare: male infertility (see section "Use during pregnancy or breastfeeding"), polycystic ovaries.
Musculoskeletal and connective tissue and bone disorders
Uncommon: decreased bone mineral density, osteopenia, osteoporosis, fractures in patients receiving long-term valproate treatment. The mechanism by which valproate affects bone metabolism is not established.
Rare: acute systemic lupus erythematosus (see section "Special precautions for use"), 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 observed predominantly 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 developing pancreatitis. These risks decrease with age (see section "Special precautions for use"). Psychiatric disorders such as aggression, agitation, attention disturbances, abnormal behaviour, psychomotor hyperactivity and learning difficulties are observed predominantly in children.
Reporting of suspected adverse reactions
Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Shelf life after opening the bottle – 1 month.
Storage conditions. Keep out of the reach of children. Store in the original packaging at a temperature not exceeding 25 °C.
Packaging. No. 1: 150 ml in a bottle; 1 bottle with a dosing device in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Unither Liquid Manufacturing.
Sanofi Winthrop Industrie.
Manufacturer's address and site of operations.
Zone Industrielle D'En Cigal, Entree 1, 3 Allee De La Neste, Bp 70319, Colomiers, 31770, France.
30-36 Avenue Gustave Eiffel, Tours, 37100, France.
Marketing Authorization Holder. LLC "Sanofi-Aventis Ukraine".
Address of the Marketing Authorization Holder. 48-50A Zhylianska St., Kyiv, 01033, Ukraine.