Convulex

INSTRUCTIONS for medical use of the medicinal product CONVULEX (CONVULEX)

Composition:

Active substance: valproic acid;

1 ampoule (5 ml) contains sodium valproate 500 mg (equivalent to valproic acid 433.9 mg); 1 ml of solution contains sodium valproate 100 mg;

Excipients: sodium hydrogen phosphate dodecahydrate; sodium hydroxide; water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antiepileptic agents. Valproic acid. ATC code N03AG01.

Pharmacological Properties.

Pharmacodynamics.

The pharmacological effects of valproate are primarily directed at the central nervous system. The drug exerts anticonvulsant activity in various types of epilepsy in humans.

Data from experimental and clinical studies of valproate indicate the existence of two mechanisms of its anticonvulsant action.

The first mechanism is a direct pharmacological effect related to the concentration of valproate in plasma and brain tissue.

The second mechanism is likely indirect. It is probably associated with valproate metabolites retained in the brain, or with modifications of neurotransmitters, or with a direct effect on the membrane. The most likely hypothesis is that valproate administration increases the level of gamma-aminobutyric acid (GABA).

Valproate reduces the duration of intermediate sleep phase and simultaneously increases slow-wave sleep phase.

Pharmacokinetics.

Bioavailability of valproate in blood after oral or intravenous administration approaches 100%.

Absorption, distribution.

Various pharmacokinetic studies of valproate have demonstrated that valproate is distributed mainly in blood and rapidly exchanging extracellular fluid. Valproate penetrates into cerebrospinal fluid and brain tissue. The concentration of valproate in cerebrospinal fluid is close to the concentration of its free fraction in plasma.

The elimination half-life ranges from 15 to 17 hours.

The minimum plasma concentration of the drug required to achieve a therapeutic effect is 40–50 mg/L. This concentration may vary between 40 and 100 mg/L. If higher plasma concentrations are required, the expected benefit should be weighed against the risk of adverse effects, particularly dose-dependent ones. However, if plasma concentrations remain above 150 mg/L, the dose should be reduced.

Steady-state plasma concentration is achieved within minutes.

Plasma protein binding of valproate is substantial, dose-dependent, and saturable.

Biotransformation, elimination.

The drug is excreted predominantly in urine after its metabolism via conjugation with glucuronic acid and beta-oxidation.

Valproate molecules can be dialyzed, but during hemodialysis only the free fraction of valproate (approximately 10%) is removed.

Valproate does not induce enzymes of the cytochrome P450 metabolic system. In contrast to other antiepileptic drugs, valproate does not accelerate either its own biotransformation or the biotransformation of other substances such as estroprogestogens and oral anticoagulants.

When valproic acid is combined with other drugs (primidone, phenytoin, phenobarbital, carbamazepine), the elimination half-life decreases to 4–9 hours, depending on the degree of enzyme induction. The elimination half-life in newborns and infants up to 18 months of age ranges from 10 to 67 hours. The longest half-life was observed in a two-month-old newborn, approximately similar to that in adults.

The elimination half-life increases in patients with liver disease. In cases of overdose, the half-life was 30 hours.

During the third trimester of pregnancy, the distribution time of the drug increases, and hepatic and renal clearance also increase. Plasma concentration may decrease, even if the dose remains unchanged.

Children.

Clearance of valproate in children and adolescents starting from 10 years of age is similar to that in adults. In children under 10 years of age, systemic clearance of valproate varies with age. In newborns and infants up to 2 months of age, valproate clearance is reduced compared to adults, with the lowest clearance immediately after birth.

According to scientific literature, the elimination half-life of valproate in infants under two 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.

Safety preclinical data.

In repeated-dose toxicity studies, testicular degeneration/atrophy or abnormalities of spermatogenesis and reduced testicular weight were observed 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 occurred only at doses exceeding the maximum tolerated dose (from 240 mg/kg/day administered intraperitoneally or intravenously), without associated histopathological changes. No effects on male reproductive organs were observed at tolerated doses (up to 90 mg/kg/day). According to these data, the effect on testes in young animals was not considered more pronounced than in adult animals. The sensitivity of testes to valproate effects in the pediatric population is unknown.

In a fertility study in rats, 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 during pregnancy or breastfeeding" and "Adverse reactions").

Acute toxicity.

Acute toxicity studies of sodium valproate in various animal species showed LD50 values ranging from 750 to 950 mg/kg body weight after intravenous administration and from 1200 to 1600 mg/kg body weight after oral administration.

These data indicate that acute toxicity of sodium valproate in mice and rats is somewhat more pronounced after intravenous (i.v.) administration compared to oral administration. The i.v. LD50 in mice and rats is approximately 40 times higher than the recommended maximum therapeutic daily dose for humans (40 mg/kg body weight for adults).

Chronic toxicity.

A 4-week toxicity study with i.v. administration of sodium valproate to dogs did not cause toxic changes at doses of 50 mg/kg body weight/day (administered in two doses of 25 mg/kg each).

In chronic toxicity studies, testicular atrophy, ureter degeneration, impaired spermatogenesis, as well as changes in lungs and prostate gland were observed at doses exceeding 250 mg/kg in rats and 90 mg/kg in dogs (oral administration).

Mutagenic and oncogenic potential.

Mutagenicity tests in bacteria, as well as in rats and mice, were negative.

Long-term studies were conducted in rats and mice. Increased incidence of subcutaneous fibrosarcomas was observed in male rats when very high doses were administered.

Reproductive toxicity.

A causal relationship has been established between exposure to valproic acid during the first and early second trimesters of pregnancy and an increased risk of neural tube defects (e.g., spina bifida, meningomyelocele), other midline defects such as hypospadias in male offspring, skeletal defects, and congenital heart malformations. Similar developmental defects have also been observed with comparable frequency during the use of other antiepileptic drugs. Bilateral radial aplasia is a rare but specific consequence of medicinal products containing valproic acid. The use of valproic acid during pregnancy has also been associated with an increased frequency of such anomalies as facial dysmorphism, sometimes combined with intellectual disability, and anomalies of fingers and toes, including fingernails and toenails.

Local tolerance.

Sodium valproate injection solution showed relatively good tolerance after single administration in rabbits. Repeated administration of 50 mg/kg body weight twice daily into the same ear vein led to swelling, thrombosis, and venous necrosis. Dogs tolerated a dose of 20 mg/kg body weight twice daily for 5 days without any clinical signs of intolerance. In rabbits, perivenous administration of single doses caused erythema, swelling, and necrosis.

Clinical characteristics.

Indications.

For the temporary treatment of epilepsy in adults and children as a substitute for the oral formulation in cases of temporary inability to take the medicinal product orally.

Contraindications.

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

The medicinal product is contraindicated in women of reproductive age unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections "Special precautions" and "Use in pregnancy or breastfeeding").

Hypersensitivity to valproate, divalproate, valpromide, or to any of the components of the medicinal product in the patient's history.

Acute hepatitis.

Chronic hepatitis.

Cases of severe hepatitis in the patient’s personal or family history, particularly if induced by medicinal products.

Hepatic porphyria.

Family history of liver dysfunction leading to death of close relatives (e.g., sibling) who were treated with valproic acid.

Urea cycle disorders (see section "Special precautions").

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

Valproate is contraindicated in patients with mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial gamma-polymerase enzyme, e.g., patients with Alpers-Huttenlocher syndrome, children under 2 years of age suspected of having a polymerase gamma-related disorder, and patients with a history of ornithine cycle disorders (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

With mefloquine: increased risk of epileptic seizures in patients with epilepsy due to enhanced metabolism of valproic acid and the convulsant effect of mefloquine.

Dosage adjustment of Convulex may be required.

With St. John’s wort preparations: risk of reduced plasma concentration of the anticonvulsant and decreased efficacy.

Combinations not recommended

With lamotrigine: increased risk of lamotrigine toxicity, particularly the development of serious skin reactions (toxic epidermal necrolysis syndrome). In addition, increased plasma concentration of lamotrigine may occur (its hepatic metabolism is slowed by sodium valproate).

If such a combination is necessary, careful monitoring of the patient is required.

With carbapenem group agents: reduced blood levels of valproic acid have been reported when co-administered with carbapenem group agents (panipenem/meropenem/imipenem, etc.), resulting in 60–100% reduction in valproic acid levels within two days, sometimes associated with seizures. Due to the rapid decrease in valproic acid levels, concomitant use of carbapenem group agents should be avoided in patients receiving valproic acid (see "Adverse reactions"). If treatment with these antibiotics cannot be avoided, careful monitoring of valproic acid blood levels is required.

Combinations requiring precautions during use

With aztreonam: risk of seizures due to decreased plasma concentration of valproic acid. Clinical monitoring of the patient, measurement of plasma drug concentrations, and possibly dose adjustment of the anticonvulsant during and after antibacterial treatment are necessary.

With carbamazepine: increased plasma concentration of the active metabolite of carbamazepine, with signs of its overdose. Additionally, decreased plasma concentration of valproic acid due to enhanced hepatic metabolism induced by carbamazepine. When both anticonvulsants are used, clinical monitoring of the patient, measurement of plasma concentrations of valproic acid and carbamazepine, and dose adjustment are recommended.

With felbamate: increased plasma concentration of valproic acid due to 22–50% reduction in valproic acid clearance, with risk of overdose.

Clinical and laboratory monitoring is recommended, and possibly dose adjustment of valproate during and after felbamate treatment. Additionally, valproic acid may reduce the average clearance of felbamate by up to 16%.

With phenobarbital and by extrapolation – primidone: increased plasma concentration of phenobarbital or primidone with signs of overdose due to inhibition of hepatic metabolism, most commonly occurring in children. Additionally, decreased plasma concentration of valproic acid due to enhanced hepatic metabolism induced by phenobarbital.

Clinical monitoring of the patient during the first 15 days of combination therapy is recommended, with immediate reduction of phenobarbital dose upon any sign of sedative effect. Plasma concentrations of both anticonvulsants should be closely monitored.

With phenytoin and by extrapolation – fosphenytoin: altered plasma concentration of phenytoin. Additionally, there is a risk of decreased plasma concentration of valproic acid due to enhanced hepatic metabolism induced by phenytoin.

Clinical monitoring of the patient, measurement of plasma concentrations of both antiepileptic drugs, and possibly dose adjustment are recommended.

With cholestyramine: may reduce the absorption of Convulex.

With rifampicin: risk of seizures due to enhanced hepatic metabolism of valproate induced by rifampicin.

Clinical monitoring, laboratory tests, and possibly dose adjustment of the anticonvulsant during and after rifampicin treatment are recommended.

With topiramate: risk of hyperammonemia or encephalopathy, usually attributed to the effect of valproic acid, when used concomitantly with topiramate.

Enhanced clinical and laboratory monitoring is recommended at the beginning of treatment and if any symptoms suggesting these events occur.

With zidovudine: increased risk of zidovudine adverse reactions, particularly hematological, due to reduced metabolism of zidovudine induced by valproic acid.

Regular clinical monitoring and laboratory test evaluation are recommended. Blood tests to detect anemia should be performed during the first two months of concomitant use.

Combinations to be considered

With nimodipine (oral and by extrapolation – parenteral): risk of enhanced hypotensive effect of nimodipine due to increased plasma concentration (reduced metabolism induced by valproic acid).

Other types of interaction

Oral contraceptives. Valproate does not induce enzymes and therefore does not reduce the effectiveness of estrogen-progestogen in women using hormonal contraceptives.

Neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants, and benzodiazepines. Convulex may potentiate the effects of other neurotropic agents such as neuroleptics, MAOIs, antidepressants, and benzodiazepines. Therefore, clinical monitoring and possibly therapy adjustment are necessary.

Lithium. Valproate does not affect serum lithium levels.

Clinical study data showed that adding olanzapine to valproate or lithium therapy significantly increases the risk of olanzapine-related adverse reactions, namely: neutropenia, tremor, dry mouth, increased appetite, weight gain, speech disorders, and somnolence.

Cimetidine or erythromycin. Concomitant use with cimetidine or erythromycin is highly likely to increase serum concentrations of valproic acid (due to reduced hepatic metabolism of valproic acid).

Concomitant use of Convulex with medicinal products that have a high degree of plasma protein binding (such as acetylsalicylic acid) may lead to increased plasma concentration of the free fraction of valproic acid.

Convulex may increase the free fraction concentration of warfarin due to competition for albumin binding sites. Therefore, in patients receiving vitamin K antagonists, prothrombin time should be monitored more closely.

Temazolomide. Concomitant use of temazolomide and valproate may cause a slight decrease in temazolomide clearance, but there are no data on the clinical significance of this interaction.

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

Olanzapine. Valproic acid may reduce plasma concentrations of olanzapine.

Clozapine. Concomitant use of valproate and clozapine increases the risk of clozapine-induced neutropenia and myocarditis. If concomitant use of valproate with clozapine is necessary, careful monitoring for the development of these events is required.

Rufinamide. Valproic acid may cause increased plasma concentrations of rufinamide. This increase is dependent on valproic acid concentrations. Caution is required, especially in pediatric use, as this effect is more pronounced in this patient population.

Diazepam. In healthy volunteers, valproate displaced diazepam from its plasma binding sites and inhibited its metabolism. In concomitant therapy, the concentration of unbound diazepam may increase, while plasma clearance and volume of distribution of the unbound fraction of diazepam may decrease (by 25% and 20%, respectively). However, the half-life remains unchanged.

Lorazepam. In healthy individuals, concomitant use of valproate and lorazepam resulted in up to 40% reduction in lorazepam plasma clearance.

Propofol. Increased blood levels of propofol are possible. When used concomitantly with valproate, consideration should be given to reducing the dose of propofol.

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

Special precautions for use.

The initiation of antiepileptic drug therapy may sometimes be associated with a recurrence of epileptic seizures, the occurrence of more severe seizures, or the development of new types of seizures in patients, regardless of spontaneous fluctuations observed in certain epileptic conditions. When using valproate, this primarily relates to changes in the regimen of combined antiepileptic therapy or pharmacokinetic interactions (see section "Interaction with other medicinal products and other forms of interaction"), toxicity (liver disease or encephalopathy – see section "Undesirable effects"), or overdose.

The active substance of the drug is converted in the human body into valproic acid; therefore, other medicinal products undergoing the same transformation (e.g., divalproex, valpromide) should not be used concomitantly to avoid valproic acid overdose.

Female children / female adolescents / women of childbearing potential / pregnant women.

Use in male patients. A retrospective observational study indicates an increased risk of nervous system disorders (NSD) in children born to men who were treated with valproate during the 3 months prior to conception, compared to children born to men who received lamotrigine or levetiracetam (see section "Use during pregnancy or breastfeeding").

As a precaution, physicians prescribing this medicinal product should inform male patients about this risk (see section "Use during pregnancy or breastfeeding") and discuss the need for effective contraception, particularly for their female partners, during valproate treatment and for at least 3 months after discontinuation of therapy. Male patients must not donate sperm during treatment and for at least 3 months after stopping treatment.

Male patients receiving valproate should have regular check-ups with their physician to assess whether valproate remains the most appropriate treatment for them. If a male patient is planning conception, appropriate alternative treatment options should be considered and discussed. Individual circumstances should be evaluated in each specific case. Specialist advice from a physician experienced in epilepsy management is recommended.

Hepatic function impairment.

There have been isolated reports of severe, and sometimes fatal, cases of liver injury.

Conditions of occurrence. Cases of severe hepatotoxicity have been observed, which may occasionally lead to fatal outcomes.

The group at highest risk includes infants and children under 3 years of age with severe epilepsy, particularly epilepsy associated with brain damage, psychomotor developmental delay, and/or congenital metabolic or neurodegenerative disorders. In children aged over 3 years, the frequency of such complications decreases significantly and progressively with age.

In the majority of cases, such liver damage occurred within the first 6 months of treatment, usually between 2 and 12 weeks, and most frequently during combination antiepileptic therapy.

Signs to watch for. Early diagnosis is primarily based on clinical symptoms. Two types of symptoms, which may precede the onset of jaundice—especially in patients in the risk group (see above "Conditions of occurrence")—should be particularly noted:

• general non-specific symptoms such as malaise, loss of appetite, fatigue, and drowsiness, which usually appear suddenly and are sometimes accompanied by repeated vomiting and abdominal pain;
• recurrence of epileptic seizures despite adequate adherence to treatment.

Patients (and parents, if the patient is a child) should be informed that they must seek immediate medical attention if such clinical symptoms occur. In addition to clinical examination, urgent liver function tests should be performed.

Detection. Liver function should be monitored periodically during the first 6 months of treatment. Among conventional tests, those reflecting the protein-synthetic function of the liver, particularly prothrombin time, are the most important. If a markedly reduced prothrombin time is detected, especially when associated with changes in other laboratory parameters (significant decrease in fibrinogen and clotting factors, increased bilirubin and transaminase levels—see section "Special precautions for use"), valproate therapy should be discontinued.

Salicylate derivatives should be discontinued if they are being co-administered, as they share the same metabolic pathways.

Pancreatitis.

Pancreatitis, sometimes fatal, has been reported very rarely. Pancreatitis with adverse outcomes is most frequently observed in younger children or in patients with severe epilepsy, brain damage, or those receiving combination antiepileptic therapy.

If pancreatitis is associated with liver failure, the risk of a fatal outcome is significantly increased. In the event of acute abdominal pain or gastrointestinal symptoms such as nausea, vomiting, and/or loss of appetite, pancreatitis should be considered (including measurement of serum amylase). Patients with elevated pancreatic enzyme levels should discontinue therapy and appropriate alternative therapeutic measures should be initiated.

Children under 3 years of age.

The medicinal product Convulex should be used in children under 3 years of age only as monotherapy. The clinical benefits and the risk of liver damage or pancreatitis development must be carefully weighed before initiating therapy in patients in this age group. As a precaution, concomitant use of salicylates should be avoided in all patients due to the risk of hepatotoxicity (see section "Interaction with other medicinal products and other forms of interaction").

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 reasons for this increased risk are not known, and available data do not exclude a similar increased risk with valproate treatment. Therefore, patients should be closely monitored for signs of suicidal thoughts or behavior, and appropriate treatment should be initiated. Patients (and caregivers) should be advised to seek medical help if suicidal thoughts or behavior occur.

Interaction with other medicinal products. Concomitant use of this medicinal product with lamotrigine and penems is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

This medicinal product should not be used concomitantly with salicylates in children under 16 years of age (see aspirin/salicylate reference information regarding Reye's syndrome).

Precautions for use. Liver function tests should be performed before initiating treatment (see section "Contraindications") and periodically during the first 6 months of treatment, especially in patients belonging to the risk group (see section "Special precautions for use").

During treatment with this medicinal product, particularly at the beginning and as with other antiepileptic drugs, isolated and transient mild elevations in transaminase levels without clinical symptoms may occur. In such cases, a complete laboratory evaluation (including prothrombin time) is recommended, and the dosage may need to be reviewed, with repeat testing depending on changes in parameters.

Before initiating therapy, prior to any surgical procedure, and in the event of bruising or spontaneous bleeding, blood tests (complete blood count, including platelet count, bleeding time, and coagulation parameters) should be performed (see section "Adverse reactions").

Patients with renal impairment.

An increased concentration of free valproic acid in plasma should be considered, and the dose should be reduced accordingly. Since plasma concentration data may sometimes be difficult to interpret, dosage adjustments should be based on the observed clinical response.

Urea cycle enzyme deficiencies.

This medicinal product is not recommended for patients with deficiencies of enzymes of the urea cycle. Cases of hyperammonemia, sometimes associated with stupor or coma, have been reported in such patients.

Patients with systemic lupus erythematosus.

Although immune system dysfunction during valproate treatment has been reported very rarely, the potential benefits and risks of valproate use should be carefully weighed before prescribing the drug to patients with systemic lupus erythematosus.

Weight gain risk.

Patients should be warned about the risk of weight gain before starting treatment, and appropriate measures, preferably dietary, should be taken to minimize this effect (see section "Adverse reactions").

Carnitine palmitoyltransferase (CPT) type II deficiency.

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

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

Sodium valproate may stimulate HIV replication in various infected cell lines in vitro. Although the clinical significance of these findings is not yet established, particular caution should be exercised when prescribing this medicinal product to HIV-infected patients.

Blood tests.

Blood tests (complete blood count with platelet count, bleeding time, and coagulation profile) are recommended before initiating treatment, prior to any surgical procedure, and in the event of bruising or spontaneous bleeding (see section "Adverse reactions"). Caution is advised if a marked prolongation of prothrombin time (decreased Quick time) is associated with other laboratory abnormalities such as decreased fibrinogen, decreased clotting factors, increased bilirubin, or elevated liver enzymes.

Patients with known or suspected mitochondrial disorders.

Valproate may trigger or worsen clinical symptoms of existing mitochondrial disorders caused by mutations in mitochondrial DNA or in the nuclear gene encoding mitochondrial polymerase γ (POLG).

In particular, cases of valproate-induced acute liver failure and fatal outcomes 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 in those presenting symptoms suggestive of such disorders, including (but not limited to) unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epileptic status, developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. Testing for POLG mutation should be performed according to current clinical practice for diagnostic evaluation of such disorders (see section "Contraindications").

Severe skin reactions and angioedema.

Severe skin reactions associated with valproate treatment have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, and angioedema. Patients should be informed about the signs and symptoms of serious skin manifestations and should be closely monitored. If signs of severe skin reactions or angioedema occur, prompt evaluation is required—treatment should be discontinued if the diagnosis is confirmed.

Alcohol.

During therapy with the medicinal product Convulex, alcohol consumption should be avoided.

Sodium.

Convulex contains 81.5 mg of sodium per 5 ml, equivalent to 4.1% of the WHO recommended maximum daily sodium intake. The maximum daily dose of this product is equivalent to 20.4% of the WHO recommended maximum daily sodium intake.

Convulex is considered a high-sodium product. This is particularly important for individuals on a low-salt diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Teratogenicity and effects on development.

Both valproate monotherapy and polytherapy containing valproate are associated with adverse pregnancy outcomes. Available data indicate that antiepileptic polytherapy including valproate is associated with a higher risk of congenital malformations compared to valproate monotherapy.

Congenital malformations caused by intrauterine exposure to valproate.

Data from a meta-analysis including registry and cohort studies showed that 10.73% of children born to women with epilepsy who received valproate monotherapy during pregnancy had congenital malformations (95% CI [confidence interval]: 8.16–13.29). This risk of the most common malformations is higher than in the general population, where the risk is approximately 2–3%. This risk is dose-dependent; however, available data do not allow determination of a threshold dose below which the risk is absent.

Available data indicate an increased frequency of both rare and common congenital malformations. The most common malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniosynostosis, cardiac malformations, and malformations of the kidneys and genitourinary system (particularly hypospadias), limb defects (including bilateral radial aplasia), and multiple anomalies affecting various organ systems.

Intrauterine exposure to valproate may also lead to hearing impairment or deafness due to developmental defects of the ear and/or nose (secondary effect) and/or direct toxic effects on hearing function. Cases of both unilateral and bilateral deafness or hearing loss have been reported. Outcomes were not known in all cases, but in most cases with known outcomes, recovery did not occur.

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

Developmental disorders caused by intrauterine exposure to valproate.

Available data indicate that intrauterine exposure to valproate may cause adverse effects on cognitive and physical development in exposed children. This risk is likely dose-dependent; however, available data do not allow determination of a threshold dose below which the risk is absent. The exact period of pregnancy during which these effects may occur has not been established, and the possibility of risk throughout the entire pregnancy cannot be excluded.

Studies in preschool-aged children exposed to valproate in utero have shown developmental delays in approximately 30–40% of cases, including delayed speech and walking, reduced intellectual function, impaired language skills (both expressive and receptive language), and memory impairments.

The intelligence quotient (IQ) measured in school-aged children (age 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, evidence suggests that the risk of reduced intellectual function 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-fold) and childhood autism (approximately 5-fold) compared to the general population.

Some data suggest that children exposed to valproate in utero may have a higher likelihood of developing symptoms of attention deficit hyperactivity disorder (ADHD).

Women planning pregnancy.

In epilepsy, if a woman is planning pregnancy, a specialist experienced in managing patients with epilepsy should reassess valproate treatment and consider alternative treatment options. Whenever possible, all measures should be taken to switch valproate to an appropriate alternative treatment before conception and before discontinuation of contraception (see section "Special precautions"). If such a switch is not possible, the woman should receive additional counseling regarding the risks of valproate use for the unborn child to ensure she is adequately informed to make a conscious decision about family planning.

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

Pregnant women.

The use of valproate for the treatment of epilepsy is contraindicated during pregnancy, except when other treatment options are ineffective (see sections "Contraindications" and "Special precautions").

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

If, after careful risk-benefit assessment, the decision is made to continue valproate treatment during pregnancy, the following recommendations should be followed.

The lowest effective dose should be used, and the total daily dose of valproate should be divided into multiple doses administered throughout the day. Extended-release formulations are preferred over other formulations to avoid high peak plasma concentrations (see section "Dosage and administration").

All pregnant patients who have received valproate during pregnancy and their sexual partners should be referred to a teratology specialist for evaluation and counseling regarding treatment during pregnancy.

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

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 decreased 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. Therefore, newborns should be tested for platelet count, plasma fibrinogen levels, coagulation tests, and coagulation factors.

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.

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

Breast-feeding.

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

The decision whether to discontinue breast-feeding or to discontinue/abstain from taking Convulex should be based on the benefits of breast-feeding for the child and the benefits of treatment for the woman.

Men. Risk of nervous system disorders in children born to men who received valproate within 3 months before conception. A retrospective observational study in three Scandinavian countries found an increased risk of nervous system disorders (NSD) in children (aged 0 to 11 years) born to men who received valproate as monotherapy within 3 months before conception, compared to children of men who received lamotrigine or levetiracetam as monotherapy: combined adjusted risk ratio 1.50 (95% CI: 1.09–2.07). The adjusted cumulative risk of NSD ranged from 4.0% to 5.6% in the valproate group versus 2.3–3.2% in the combined lamotrigine/levetiracetam group. The study was not large enough to investigate associations with specific subtypes of NSD, and study limitations included potential confounding by indication and differing follow-up durations across groups. The mean follow-up time 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. Overall, there may be an increased risk of NSD in children of men who received valproate within 3 months before conception; however, a causal role of valproate has not been confirmed. Additionally, the study did not assess the risk of NSD in children born to men who discontinued valproate more than 3 months before conception (i.e., new spermatogenesis without valproate exposure).

Physicians prescribing this drug should inform male patients about this risk and discuss the need for effective contraception, including for their sexual partners, during valproate treatment and for at least 3 months after discontinuation (see section "Special precautions"). Men should not serve as sperm donors during treatment and for at least 3 months after stopping treatment.

Male patients receiving valproate should have regular medical check-ups to determine whether valproate remains the most appropriate treatment for them. For men planning conception, suitable alternative treatment options should be considered. Individual circumstances should be evaluated in each case. Specialist advice from a physician experienced in epilepsy management is recommended.

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 (see section "Adverse reactions"). In reported cases, fertility dysfunction was described as reversible and resolved after discontinuation of the drug.

Ability to influence reaction speed when driving or operating machinery.

Patients who drive vehicles or operate machinery should be warned about the risk of drowsiness, particularly in cases of combined anticonvulsant therapy or concomitant use of other medicinal products that may enhance drowsiness.

Method of Administration and Dosage

In cases where oral administration of the drug is not possible, intravenous administration of sodium valproate is recommended 4–6 hours after the last dose of the tablet form. The drug should be diluted with 0.9% sodium chloride injection solution:

• either as a continuous 24-hour infusion of the daily dose;
• or the daily dose may be divided into 4 infusions, each lasting 1 hour (the usual dose is 20–30 mg/kg/day).

If rapid achievement and maintenance of effective plasma concentration is required:

intravenous bolus injection at a dose of 15 mg/kg over 5 minutes, followed by continuous infusion at a rate of 1 mg/kg/hour, with gradual adjustment of the infusion rate to maintain blood valproate levels of approximately 75 mg/L. Thereafter, the infusion rate should be adjusted according to the patient's clinical response.

After completion of the infusion, oral therapy should be resumed to compensate for the amount of drug administered intravenously. The previously prescribed dose should be used, or an adjusted dose may be initiated.

The prepared solution must be administered within 24 hours of preparation.

The following solutions may be used for the preparation of Convulex infusion solution: isotonic sodium chloride solution, 5% glucose solution, Ringer's lactate solution.

Female children, adolescent girls, women of childbearing potential, and pregnant women. Treatment with this drug should be initiated and supervised by a specialist experienced in the treatment of epilepsy. This drug should be prescribed to female children and women of childbearing potential only when other treatment options are ineffective or not tolerated by the patient (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy and Lactation"). In such cases, valproate must be prescribed in accordance with the requirements of the Pregnancy Prevention Programme (see sections "Contraindications" and "Special Warnings and Precautions for Use"). The benefit and risk of using this drug must be carefully reassessed during regular treatment reviews. In exceptional cases where valproate is the only treatment option during pregnancy for women with epilepsy, it should be prescribed as monotherapy at the lowest effective dose and, if possible, in a prolonged-release formulation to avoid high peak plasma concentrations. If a non-prolonged-release formulation is used, the daily dose should be divided into at least two administrations (see section "Use in Pregnancy and Lactation").

Patients with renal impairment.

Patients with renal impairment may require dose adjustment. Patients undergoing hemodialysis may require dose increases. Valproate is dialyzable (see section "Overdose"). Dosage should be adjusted based on clinical monitoring of the patient (see section "Special Warnings and Precautions for Use").

Male patients. It is recommended that the medicinal product Convulex be prescribed and monitored by a specialist experienced in the treatment of epilepsy (see sections "Special Warnings and Precautions for Use", "Use in Pregnancy and Lactation").

Children.

Valproate is recommended for use in children under 3 years of age only as monotherapy, after careful consideration of the therapeutic benefit versus the risk of liver damage and pancreatitis in this age group.

Prior to initiating therapy or surgical procedures, and in case of spontaneous bruising or bleeding, blood tests (including complete blood count with platelet count, bleeding time, and coagulation tests) should be performed (see section "Adverse Reactions").

Concomitant use of salicylate derivatives should be avoided in children under 16 years of age, as this increases the risk of hepatotoxicity and bleeding.

In children with unexplained symptoms involving the liver and gastrointestinal tract (loss of appetite, vomiting, episodes of cytolysis), episodes of lethargy or coma in medical history, developmental delay, or a family history of infant or child death, metabolic investigations should be performed before initiating valproate therapy, particularly fasting and postprandial ammonia testing.

Overdose

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

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

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

Symptoms may vary; epileptic seizures have been reported at high plasma drug levels. Cases of increased intracranial pressure associated with cerebral edema have been described. The presence of sodium in the valproate formulation may lead to hypernatremia in overdose.

Hospital management should include: gastric lavage, which may be beneficial within 10–12 hours after drug ingestion; continuous monitoring of cardiac and respiratory function is required.

Naloxone has been successfully used in several individual cases. Hemodialysis and hemoperfusion have been successfully applied in cases of massive overdose.

Adverse Reactions

Adverse effects are listed by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Congenital, familial and genetic disorders.

Congenital malformations and developmental disorders (see sections "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 were generally detected systematically but had no clinical consequences.

In patients with asymptomatic thrombocytopenia, if possible, considering platelet counts and disease control, the dose of this medicinal product should be reduced, after which thrombocytopenia usually resolves.

Uncommon: pancytopenia, leukopenia.

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

Isolated cases of decreased fibrinogen levels or prolonged blood clotting time have been reported, particularly with high-dose therapy, but generally without clinical consequences. Valproate inhibits the second phase of platelet aggregation.

Investigations.

Rare: decreased levels of coagulation factors (at least one), abnormal coagulation test results (e.g. prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, increased International Normalised Ratio [INR]) (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Rare: biotin deficiency / biotinidase deficiency.

Nervous system disorders.

Very common: tremor.

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

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

Rare: diplopia, reversible dementia, cognitive disorders, chronic encephalopathy.

During valproate therapy, cases of stupor or lethargy have been observed, sometimes leading to transient coma/encephalopathy. These were either isolated or associated with recurrence of seizures for which treatment was being administered, and resolved after discontinuation or dose reduction of the drug. These effects most frequently occur during combination therapy (especially with phenobarbital or topiramate) or following a rapid increase in sodium valproate dose.

Increased alertness may occur; generally this is a beneficial effect, but cases of sudden aggression, hyperactivity, and worsening of behaviour have been reported.

Ear and labyrinth disorders.

Common: hearing loss (reversible or irreversible).

Frequency not known: tinnitus (ringing in the ears).

Respiratory, thoracic and mediastinal disorders.

Uncommon: pleural effusion (eosinophilic).

Gastrointestinal disorders.

Very common: nausea.

Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, stomach pain, diarrhoea), which usually resolve within a few days without discontinuation of treatment.

Uncommon: cases of pancreatitis requiring discontinuation of the drug in early stages of treatment, sometimes resulting in death (see section "Special precautions for use").

Renal and urinary disorders.

Common: urinary incontinence.

Uncommon: renal failure.

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

Skin and subcutaneous tissue disorders.

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

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

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

Frequency not known: hyperpigmentation.

Endocrine disorders.

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

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

Metabolic and nutritional disorders.

Common: hyponatraemia, weight gain (should be carefully monitored, as it is a factor in polycystic ovary syndrome — see section "Special precautions for use").

Rare: hyperammonaemia (see section "Special precautions for use"), obesity. Isolated cases of mild hyperammonaemia without significant changes in standard liver function tests have been reported. If no clinical symptoms are present, discontinuation of treatment is not necessary. However, if hyperammonaemia is accompanied by neurological symptoms, further investigations are required (see also section "Special precautions for use").

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

Rare: myelodysplastic syndrome.

Vascular disorders.

Common: haemorrhage (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Uncommon: vasculitis.

General disorders and administration site conditions.

Uncommon: mild peripheral oedema, hypothermia. Nausea or dizziness may occur several minutes after injection, resolving spontaneously within several minutes.

Risk of local tissue necrosis with repeated injections.

Hepatobiliary disorders.

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

Cases of severe liver damage, including liver failure, sometimes fatal, have been reported (see sections "Contraindications", "Special precautions for use", "Dosage and administration"). The risk of liver damage is significantly increased in children, especially those receiving multiple antiepileptic therapies (see section "Special precautions for use").

Common: elevated liver enzymes, particularly in early stages of treatment, which usually resolve (see section "Special precautions for use").

Rare: porphyria.

Reproductive system and breast disorders.

Common: dysmenorrhoea.

Uncommon: amenorrhoea.

Rare: adverse effects on spermatogenesis (including reduced sperm motility) (see section "Use during pregnancy or breastfeeding"), polycystic ovaries, male infertility.

Very rare cases of gynaecomastia have been reported.

Musculoskeletal and connective tissue disorders.

Uncommon: decreased bone mineral density, osteopenia, osteoporosis, fractures in patients receiving long-term valproate therapy. The mechanism of valproate's effect on bone metabolism is not established.

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

Psychiatric disorders.

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

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

* These adverse reactions are primarily observed in children.

Paediatric population.

The safety profile of valproate in the paediatric population is comparable to that in adults, but certain adverse reactions are more serious 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 increasing age (see section "Special precautions for use"). Psychiatric disorders such as aggression, agitation, attention disturbances, abnormal behaviour, psychomotor hyperactivity, and learning disorders are mainly observed in the paediatric population. According to some post-marketing data, Fanconi syndrome, enuresis, and gingival hyperplasia occur more frequently in children than in adult patients.

Shelf life. 5 years.

Storage conditions. Store in a dry, light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 5 ml in ampoule, 5 ampoules in a blister pack.

Prescription category. Prescription only.

Manufacturer.

H. L. Pharma GmbH.

Manufacturer's address and location of business activity.

Schlossplatz 1, 8502 Lannach, Austria.