Depakine^® (Lyophilisate, Syrup) Instructions for Use

ATC Code

N03AG01 (Valproic acid)

Active Substance

Valproic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiepileptic drug

Pharmacotherapeutic Group

Antiepileptic agents; fatty acid derivatives

Pharmacological Action

An anticonvulsant drug, it has a central muscle relaxant and sedative effect. It exhibits antiepileptic activity in various types of epilepsy.

The main mechanism of action is apparently associated with the effect of valproic acid on the GABA-ergic system: increasing the GABA content in the CNS and activating GABA-ergic transmission.

Pharmacokinetics

Absorption

The bioavailability of valproic acid when taken orally is close to 100%. Food intake does not affect the pharmacokinetic profile of the drug. With course administration of the drug, the C_ss of valproic acid in blood serum is achieved within 3-14 days.

Serum concentrations of valproic acid of 40-100 mg/l (300-700 µmol/l) are usually effective (determined before taking the first dose of the drug during the day). With serum concentrations of valproic acid above 100 mg/l, an increase in side effects up to the development of intoxication is expected.

Distribution

Binding to plasma proteins (mainly albumin) is high (90-95%), dose-dependent and saturable.

V_d depends on age and is usually 0.13-0.23 l/kg of body weight or in young people 0.13-0.19 l/kg of body weight.

Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the CSF is 10% of the corresponding concentration in plasma, i.e., close to the concentration of the free fraction of valproic acid in blood serum.

Valproic acid penetrates into the breast milk of nursing mothers. At equilibrium, the concentration of valproic acid in breast milk is 1-10% of its concentration in plasma.

Metabolism

The metabolism of valproic acid occurs in the liver by glucuronidation, as well as beta-, omega-, and omega-1-oxidation. More than 20 metabolites have been identified; metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on the enzymes of the cytochrome P450 metabolic system: unlike most other antiepileptic drugs, Valproic acid does not affect the rate of its own metabolism, nor the rate of metabolism of estrogens, progestogens and indirect anticoagulants.

Elimination

Valproic acid is predominantly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation.

When valproic acid is used in monotherapy, T_1/2 is 12-17 hours. When combined with antiepileptic drugs that induce liver microsomal enzymes (such as primidone, phenytoin, phenobarbital and carbamazepine), the plasma clearance of valproic acid increases and T_1/2 decreases; the degree of their change depends on the degree of induction of liver microsomal enzymes by other antiepileptic drugs.

Pharmacokinetics in special patient groups

In newborns and children under 18 months, T_1/2 from plasma ranges from 10 to 67 hours. The longest T_1/2 was observed immediately after birth. T_1/2 in children over 2 months of age is close to that in adults.

In elderly patients, patients with renal and hepatic insufficiency, binding to plasma proteins decreases.

In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid can increase to 8.5-20%.

In hypoproteinemia, the total concentration of valproic acid (free + protein-bound fractions) may not change, but may also decrease due to increased metabolism of the free (not bound to plasma proteins) fraction of valproic acid.

In patients with liver diseases, the T_1/2 of valproic acid increases.

In case of overdose, an increase in T_1/2 to 30 hours was observed.

Only the free fraction of valproic acid in the blood (5-10%) is subject to hemodialysis.

Pharmacokinetic features during pregnancy

With an increase in V_d of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. At the same time, despite taking the drug at a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the binding of valproic acid to plasma proteins may change, which may lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

Indications

Adults

As monotherapy or in combination with other antiepileptic drugs

• Treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic);
• Lennox-Gastaut syndrome;
• Treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

Children

As monotherapy or in combination with other antiepileptic drugs

• Treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic);
• Lennox-Gastaut syndrome;
• Treatment of partial epileptic seizures (partial seizures with or without secondary generalization);
• Prevention of recurrence of febrile seizures in the presence of a history of one or more episodes of seizures caused by fever, if prevention with benzodiazepine derivatives is ineffective.

ICD codes

Dosage Regimen

Lyophilisate

Simple replacement therapy (e.g., before surgery)

4-6 hours after the last oral dose, intravenous administration of the drug diluted with sodium chloride injection solution (0.9%) is performed

• Either as a continuous infusion of the previously used daily dose;
• Or as 4 infusions, each lasting 1 hour (in this case, 1/4 of the previously used daily dose is administered with each infusion).

The usual average dose is 20-30 mg/kg/day.

Situations requiring rapid achievement and maintenance of an effective plasma concentration of valproic acid

Intravenous bolus administration of the drug at a dose of 15 mg/kg over 5 minutes; then administration is continued as a constant intravenous infusion at a rate of 1 mg/kg/h, with gradual adjustment of the infusion rate to ensure a valproic acid blood concentration of about 75 mg/l. Further, the infusion rate is changed depending on the clinical picture.

After stopping the infusion, the transition to treatment with oral forms of the drug Depakine^® can occur using the previous dose or a dose adjusted according to the patient’s clinical condition.

Special patient groups

Female children and adolescents, women of childbearing potential and pregnant women: treatment with Depakine^® drugs should be initiated under the supervision of a specialist experienced in the treatment of epilepsy and bipolar disorders. Treatment should be started only if other treatments are ineffective or not tolerated, and during regular treatment review, the benefit-risk ratio should be carefully reassessed. The use of Depakine^® drugs for monotherapy and at the lowest effective doses and, if possible, in extended-release dosage forms is preferred. During pregnancy, the daily dose should be divided into at least 2 divided doses.

Although there are changes in the pharmacokinetics of valproic acid in elderly patients, they have limited clinical significance, and the dose of valproic acid in elderly patients should be selected in accordance with achieving control over epileptic seizures.

In patients with renal failure and/or hypoproteinemia, the possibility of an increase in the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and if necessary, the dose of valproic acid should be reduced, focusing when selecting the dose mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction bound to plasma proteins), to avoid possible errors in dose selection.

Syrup

This dosage form of the drug Depakine^® (syrup) is mainly intended for administration to children.

The drug is taken orally. The drug should be taken only using the dosing syringe provided in the cardboard box. The dosing syringe is graduated in milligrams of sodium valproate.

After opening the bottle, it can be stored at a temperature not exceeding 25°C (77°F).

The dose should be set taking into account the patient’s age and body weight.

The daily dose is recommended to be divided

• Into 2 doses for patients under 1 year of age;
• Into 3 doses for patients over 1 year of age.

The initial daily dose for adults and children weighing more than 25 kg is usually 5-10 mg/kg, then it is increased by 5 mg/kg every 4-7 days until the optimal dose is reached, which prevents the occurrence of epileptic seizures.

The average daily dose

• For children (up to 14 years) – 30 mg/kg of body weight (preferably taking the drug in syrup form);
• For adolescents 14-18 years – 25 mg/kg of body weight (preferably taking solid dosage forms of the drug Depakine^®);
• For adults and elderly patients (body weight from 60 kg and above) – 20 mg/kg of body weight (preferably taking solid dosage forms of the drug Depakine^®).

Thus, the average daily doses presented below are recommended.

* dose in terms of the number of milligrams of sodium valproate

The average daily dose can be increased under the control of the valproic acid concentration in the blood.

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops over 4-6 weeks. Therefore, the daily dose should not be increased above the recommended average daily dose before this period.

Although the daily dose is determined depending on the patient’s age and body weight, the wide range of individual sensitivity to valproic acid should be taken into account.

No clear correlation has been established between the daily dose, the serum concentration of valproic acid and the therapeutic effect. Therefore, the optimal dose of the drug should be selected mainly based on the clinical response. Determination of the serum concentration of valproic acid can serve as an addition to clinical observation if epilepsy is not controlled or the development of side effects is suspected. Doses that provide serum concentrations of valproic acid of 40-100 mg/l (300-700 µmol/l) are usually effective. If it is justified to achieve higher serum concentrations, the expected benefit-risk ratio should be carefully weighed, especially for dose-dependent side effects, because with serum concentrations of valproic acid above 100 mg/l, an increase in side effects up to the development of intoxication is expected. Therefore, the serum concentration, determined before taking the first dose of the day, should not exceed 100 mg/l.

For patients who have previously taken antiepileptic drugs, the transition to taking the drug Depakine^® syrup should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks. At the same time, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If the previously taken antiepileptic drug is discontinued, its discontinuation should be carried out gradually.

If it is necessary to combine valproic acid with other antiepileptic drugs, they should be added gradually.

Since other antiepileptic drugs can reversibly induce liver microsomal enzymes, blood concentrations of valproic acid should be monitored for 4-6 weeks after the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), the daily dose of the drug Depakine^® syrup should be reduced.

Special patient groups

Female children and adolescents, women of childbearing potential and pregnant women treatment with Depakine^® syrup should be initiated under the supervision of a specialist experienced in the treatment of epilepsy and bipolar disorders. Treatment should be started only if other treatments are ineffective or not tolerated, and during regular treatment review, the benefit-risk ratio should be carefully reassessed. The use of Depakine^® drugs for monotherapy and at the lowest effective doses and, if possible, in extended-release dosage forms is preferred. During pregnancy, the daily dose should be divided into at least 2 divided doses.

Warning for female patients. In case of pregnancy, valproic acid drugs can cause serious harm to the unborn child. Effective methods of contraception must always be used during treatment. If a patient is planning a pregnancy or becomes pregnant, she should immediately inform her doctor.

Although there are changes in the pharmacokinetics of valproic acid in elderly patients, they have limited clinical significance and the dose of valproic acid in elderly patients should be selected in accordance with achieving control over epileptic seizures.

In patients with renal failure and/or hypoproteinemia, the possibility of an increase in the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and, if necessary, the dose of valproic acid should be reduced, focusing when selecting the dose, mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction bound to plasma proteins), to avoid possible errors in dose selection.

Adverse Reactions

The WHO classification is used to determine the frequency of adverse reactions: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (when it is not possible to estimate the frequency of adverse reactions from the available data).

Congenital, hereditary and genetic disorders teratogenic risk.

From the hematopoietic system common – anemia, thrombocytopenia; uncommon – pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can be with or without bone marrow depression. After drug withdrawal, the blood picture returns to normal. Rare – bone marrow disorders, including isolated aplasia/hypoplasia of red blood cells, agranulocytosis, macrocytic anemia, macrocytosis.

From the blood coagulation system common – bleeding and hemorrhage; rare – decrease in the content of blood clotting factors (at least one), deviation from the norm of blood coagulation parameters (such as increased prothrombin time, increased aPTT, increased thrombin time, increased INR). The appearance of spontaneous ecchymoses and bleeding requires discontinuation of the drug and clinical and laboratory examination.

From the nervous system very common – tremor; common – extrapyramidal disorders, stupor*, drowsiness, convulsions*, memory impairment, headache, nystagmus, dizziness (may occur a few minutes after intravenous injection and disappear spontaneously within a few minutes); uncommon – coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia, increased frequency and severity of convulsive seizures (including the development of status epilepticus) or the appearance of new types of seizures; rare – reversible dementia combined with reversible brain atrophy, cognitive disorders; frequency unknown – sedative effect.

* Stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or combined with an increase in seizure frequency during treatment, and also decreased upon drug withdrawal or dose reduction. Most of these cases were described against the background of combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

From the psyche common – state of confusion, aggression**, agitation, attention impairment**, depression (when valproic acid is combined with other anticonvulsant drugs); rare – behavioral disorders**, psychomotor hyperactivity**, learning disabilities**, depression (with valproic acid monotherapy).

** Adverse reactions mainly observed in pediatric patients.

From the hearing organ common – reversible and irreversible deafness.

From the organ of vision frequency unknown – diplopia.

From the respiratory system uncommon – pleural effusion.

From the digestive system very common – nausea; common – vomiting, gum changes (mainly gum hyperplasia), stomatitis, epigastric pain, diarrhea (which often occur in some patients at the beginning of treatment, but, as a rule, disappear after a few days and do not require discontinuation of therapy); uncommon – pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment; in case of acute abdominal pain, serum amylase activity should be monitored); frequency unknown – abdominal cramps, anorexia, increased appetite. Frequent reactions from the digestive system can be reduced by taking the drug during or after meals.

From the liver and biliary tract frequently – hepatic lesions, which are accompanied by deviations from the norm in indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with a significant decrease in fibrinogen content and blood clotting factors, an increase in bilirubin concentration and an increase in the activity of hepatic transaminases in the blood; hepatic failure, in exceptional cases with a fatal outcome. Monitoring of patients for possible liver function disorders is necessary.

From the urinary system infrequently – renal failure; rarely – enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of renal tubule damage with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is not yet clear.

From the immune system frequently – hypersensitivity reactions, for example, urticaria; infrequently – angioedema; rarely – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

From the skin and subcutaneous tissues frequently – pruritus, transient or dose-dependent alopecia (including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome, as well as alopecia against the background of developed hypothyroidism), disorders of the nails and nail bed; infrequently – rash, hair disorders (such as disruption of the normal hair structure, change in hair color, abnormal hair growth [disappearance of waviness and curliness of hair or, conversely, the appearance of curliness in individuals with initially straight hair]); rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

From the musculoskeletal system and connective tissue infrequently – decreased bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid long-term (the mechanism of valproic acid’s effect on bone metabolism has not been established); rarely – systemic lupus erythematosus, rhabdomyolysis.

From the endocrine system infrequently – syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilization, acne, male-pattern baldness and/or increased blood androgen concentrations); rarely – hypothyroidism.

From metabolism frequently – hyponatremia, weight gain (since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely – hyperammonemia***, obesity.

*** Cases of isolated and moderate hyperammonemia without changes in liver function parameters and without the need to discontinue treatment may occur. The occurrence of hyperammonemia accompanied by the appearance of neurological symptoms, including the development of encephalopathy, vomiting, ataxia, which required discontinuation of valproic acid and additional examination, has also been reported.

From blood vessels infrequently – vasculitis.

From the reproductive system frequently – dysmenorrhea; infrequently – amenorrhea; rarely – male infertility, polycystic ovaries; frequency unknown – dysmenorrhea, breast enlargement, galactorrhea.

Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely – myelodysplastic syndrome.

General disorders infrequently – hypothermia, non-severe peripheral edema.

Laboratory and instrumental data: rarely – biotin deficiency/biotinidase deficiency.

Contraindications

• Hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or to any of the components of the drug;
• Acute hepatitis;
• Chronic hepatitis;
• Severe liver disease (especially drug-induced hepatitis) in the patient’s history and/or in the patient’s close blood relatives;
• Severe liver damage with a fatal outcome when using valproic acid in the patient’s close blood relatives;
• Severe impairment of liver or pancreatic function;
• Hepatic porphyria;
• Established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlocher syndrome, and suspected diseases due to γ-polymerase defects in children under 2 years of age;
• Patients with established disorders of the urea cycle;
• Hemorrhagic diathesis, thrombocytopenia;
• Combination with mefloquine;
• Combination with preparations of St. John’s wort (Hypericum perforatum);
• Sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption, because the drug contains sucrose and sorbitol.

With caution

• History of liver and pancreatic diseases;
• Pregnancy;
• Congenital enzymopathies;
• Bone marrow depression (leukopenia, thrombocytopenia, anemia);
• Renal failure (dose adjustment required);
• Hypoproteinemia;
• Simultaneous use of several antiepileptic drugs (due to an increased risk of liver damage);
• Simultaneous use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);
• Simultaneous use of neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiation of their effects);
• Simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rufinamide (especially in children), protease inhibitors (lopinavir, ritonavir), cholestyramine (due to pharmacokinetic interactions at the level of metabolism or at the level of plasma protein binding, changes in plasma concentrations of either the drugs and/or valproic acid are possible);
• Simultaneous use of carbamazepine (risk of potentiation of toxic effects of carbamazepine and decrease in plasma concentration of valproic acid);
• Simultaneous use of topiramate or acetazolamide (risk of encephalopathy);
• In patients with pre-existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of rhabdomyolysis when taking valproic acid);
• Children under 3 years of age.

Use in Pregnancy and Lactation

Pregnancy

Risk associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia may pose a particular risk, both for the mother and the fetus, due to the possibility of a fatal outcome.

Risk associated with the use of the drug Depakine^® syrup during pregnancy

Experimental studies of reproductive toxicity conducted in mice, rats and rabbits have demonstrated the teratogenic effect of valproic acid.

Congenital malformations

Available clinical data have demonstrated a higher incidence of minor and severe malformations, in particular, congenital neural tube defects, craniofacial deformities, limb and cardiovascular system malformations, hypospadias, as well as multiple malformations affecting various organ systems, in children born to mothers who took valproic acid during pregnancy, compared to their incidence when taking a number of other antiepileptic drugs during pregnancy. Thus, the risk of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was approximately 1.5, 2.3, 2.3 and 3.7 times higher, compared with monotherapy with phenytoin, carbamazepine, phenobarbital and lamotrigine, respectively.

Data from a meta-analysis including registry and cohort studies showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% confidence interval 8.16-13.29). This risk is greater than the risk of severe congenital malformations in the general population, which was 2-3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which this risk does not exist.

Impaired mental and physical development

It has been shown that in utero exposure to valproic acid may have undesirable effects on the mental and physical development of children exposed to it. This risk appears to be dose-dependent, but it is not possible to establish a threshold dose below which this risk does not exist. The exact gestational period for the risk of developing these effects has not been established, and the risk is not excluded throughout pregnancy.

Studies of preschool children exposed to valproic acid in utero have shown that up to 30-40% of such children had delays in early development (such as delayed walking and delayed speech development), as well as lower intellectual abilities, poor language skills (expressive speech and speech comprehension) and memory problems.

The intelligence quotient (IQ) determined in children aged 6 years with a history of in utero exposure to valproic acid was on average 7-10 points lower than in children exposed in utero to other antiepileptic drugs. Although the role of other factors that could adversely affect the intellectual development of children exposed to valproic acid in utero cannot be ruled out, it is obvious that in such children the risk of intellectual impairment may be independent of the mother’s IQ.

Data on long-term outcomes are limited.

There is evidence suggesting that children exposed to valproic acid in utero have an increased risk of developing autism spectrum disorders (approximately a three- to five-fold increase in risk), including childhood autism. Limited data suggest that children exposed to valproic acid in utero are more likely to develop attention deficit/hyperactivity disorder (ADHD).

Valproic acid monotherapy and combination therapy including valproic acid are associated with adverse pregnancy outcomes, but according to available data, combination antiepileptic therapy including valproic acid is associated with a higher risk of adverse pregnancy outcomes compared to valproic acid monotherapy (i.e., the risk of fetal abnormalities is lower when using valproic acid in monotherapy).

Risk factors for the occurrence of fetal malformations are: a dose of more than 1000 mg/day (however, a lower dose does not exclude this risk) and the combination of valproic acid with other anticonvulsant drugs.

In connection with the above, the drug Depakine^® syrup should not be used during pregnancy and in women of childbearing potential unless absolutely necessary, that is, its use is possible in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of the need to use the drug Depakine^® syrup or the possibility of discontinuing its use should be decided before starting the drug or reviewed if a woman taking Depakine^® syrup is planning a pregnancy.

Women of childbearing potential should use effective methods of contraception during treatment with Depakine^® syrup.

Women of childbearing potential should be informed about the risks and benefits of using valproic acid during pregnancy.

If a woman with epilepsy is planning a pregnancy, or if she is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed. The decision to continue treatment with valproic acid or to withdraw it is made after reassessing the benefit-risk ratio. If, after reassessing the benefit-risk ratio, treatment with Depakine^® syrup still needs to be continued during pregnancy, it is recommended to use it in the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of prolonged-release dosage forms of the drug is preferable to other dosage forms.

If possible, even before pregnancy, additional folic acid should be started (at a dose of 5 mg/day), as folic acid may reduce the risk of neural tube defects. However, currently available data do not confirm its preventive effect on congenital malformations caused by valproic acid.

Constant (including in the third trimester of pregnancy) special prenatal diagnosis should be carried out to identify possible neural tube formation defects or other fetal malformations, including detailed ultrasound examination.

Before childbirth

Before delivery, coagulation tests should be performed in the mother, in particular, determination of platelet count, fibrinogen concentration and clotting time (APTT).

Risk for newborns

Isolated cases of hemorrhagic syndrome have been reported in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and/or a decrease in the content of other blood clotting factors. The development of afibrinogenemia, which could lead to a fatal outcome, has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of liver microsomal enzymes. Therefore, in newborns whose mothers received treatment with valproic acid drugs during pregnancy, coagulation tests must be performed (determination of platelet count in peripheral blood, plasma fibrinogen concentration, blood clotting factors and coagulogram).

Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid in the third trimester of pregnancy.

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

In newborns whose mothers took valproic acid in the third trimester of pregnancy, withdrawal syndrome may occur (in particular, the appearance of agitation, irritability, hyperreflexia, trembling, hyperkinesis, muscle tone disorders, tremor, convulsions and feeding difficulties).

Fertility

Due to the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, and increased blood testosterone concentration, fertility may decrease in women. In men, Valproic acid may reduce sperm motility and impair fertility. It has been established that these fertility disorders are reversible after discontinuation of treatment.

Breastfeeding period

The excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in blood serum.

There are limited clinical data on the use of valproic acid during breastfeeding, therefore the use of the drug during this period is not recommended.

Based on literature data and limited clinical experience, breastfeeding during monotherapy with Depakine^® syrup can be considered, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Use in Hepatic Impairment

Contraindicated in acute hepatitis; chronic hepatitis; severe liver disease (especially drug-induced hepatitis) in the patient’s history and/or in the patient’s close blood relatives; severe liver damage with a fatal outcome when using valproic acid in the patient’s close blood relatives; severe impairment of liver or pancreatic function; hepatic porphyria.

Use in Renal Impairment

The drug should be prescribed with caution in renal failure (dose adjustment required).

Pediatric Use

The drug should be prescribed with caution in children under 3 years of age.

Geriatric Use

The dose of valproic acid in elderly patients should be selected in accordance with achieving control over epileptic seizures.

Special Precautions

Before starting the use of the drug Depakine^® syrup and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.

As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of liver enzymes is possible, especially at the beginning of treatment, which proceeds without clinical manifestations and is transient. In these patients, a more detailed examination of biological parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and if necessary, repeated clinical and laboratory examination.

Before starting therapy or surgery, as well as with the spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine bleeding time, the number of formed elements in the peripheral blood, including platelet count.

Severe liver damage

Predisposing factors clinical experience shows that patients at risk are patients receiving several antiepileptic drugs simultaneously, children under 3 years of age with severe convulsive seizures, especially against the background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients simultaneously taking salicylates (since salicylates are metabolized by the same metabolic pathway as Valproic acid).

In children over 3 years of age, the risk of liver damage is significantly reduced and progressively decreases with increasing patient age. In most cases, liver damage occurs within the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when using valproic acid as part of combination antiepileptic therapy.

Symptoms suspicious for liver damage for early diagnosis of liver damage, clinical monitoring of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms, which may precede the occurrence of jaundice, especially in patients at risk

• Non-specific symptoms, especially those that started suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
• Recurrence of seizures in patients with epilepsy.

Patients or their family members (when the drug is used in children) should be warned that they must immediately inform the attending physician about the occurrence of any of these symptoms. If these symptoms appear, patients should immediately undergo a clinical examination and laboratory testing of liver function parameters.

Detection Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among the routine tests, the most informative are those reflecting the state of the liver’s protein-synthetic function, especially the prothrombin index. Confirmation of an abnormal prothrombin index, especially in combination with abnormalities in other laboratory parameters (significant decrease in fibrinogen and blood clotting factors, increased bilirubin concentration and increased transaminase activity), as well as the appearance of other symptoms indicating liver damage, requires discontinuation of Depakine^® syrup. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued.

Pancreatitis

There have been reported rare cases of severe forms of pancreatitis in children and adults, developing regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis with rapid progression of the disease from the first symptoms to a fatal outcome have been observed.

Children are at an increased risk of developing pancreatitis, and this risk decreases with increasing age of the child. Risk factors for the development of pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. Liver failure combined with pancreatitis increases the risk of a fatal outcome.

Patients who experience severe abdominal pain, nausea, vomiting and/or anorexia should be examined immediately. If pancreatitis is confirmed, particularly with increased activity of pancreatic enzymes in the blood, valproic acid should be discontinued and appropriate treatment initiated.

Suicidal thoughts and attempts

Suicidal thoughts and attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled studies of antiepileptic drugs also showed an increased risk of suicidal thoughts and attempts by 0.19% in all patients taking antiepileptic drugs (including an increase in this risk by 0.24% in patients taking antiepileptic drugs for epilepsy), compared to their frequency in patients taking placebo. The mechanism of this effect is unknown. Therefore, patients taking Depakine^® syrup should be constantly monitored for suicidal thoughts and attempts, and if they occur, appropriate treatment should be provided. Patients and their caregivers are advised to consult a doctor immediately if the patient experiences suicidal thoughts or attempts.

Carbapenems

Concomitant use of carbapenems is not recommended.

Patients with established or suspected mitochondrial diseases

Valproic acid may initiate or worsen the manifestations of a patient’s existing mitochondrial diseases caused by mutations in mitochondrial DNA, as well as the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding γ-polymerase (POLG); for example, in patients with Alpers-Huttenlocher syndrome, the use of valproic acid was associated with a higher incidence of acute liver failure and liver-related fatal outcomes. Diseases caused by γ-polymerase defects may be suspected in patients with a family history of such diseases or symptoms suggestive of their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical developmental delay, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with visual (occipital) aura and others. In accordance with current clinical practice, testing for γ-polymerase (POLG) gene mutations should be performed to diagnose such diseases.

Paradoxical increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures

As with the use of other antiepileptic drugs, some patients taking valproic acid experienced, instead of improvement, a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures. If seizures worsen, patients should immediately consult their doctor.

Female children and adolescents, women of childbearing potential and pregnant women

Warning for female patients. In case of pregnancy, valproic acid preparations can cause serious harm to the unborn child. Effective methods of contraception should always be used during treatment. If a patient is planning a pregnancy or becomes pregnant, she should immediately inform her doctor.

Depakine^® syrup should not be used in female children and adolescents, women of childbearing potential and pregnant women, except in cases where alternative treatments are ineffective or not tolerated. This restriction is associated with a high risk of teratogenic effects and disorders of mental and physical development in children who were exposed to valproic acid in utero. The benefit/risk ratio should be carefully reassessed in the following cases: during regular treatment review, when a girl reaches puberty, and urgently, in case of planning or occurrence of pregnancy in a woman taking valproic acid.

During treatment with valproic acid, women of childbearing potential should use reliable methods of contraception, and they should be informed about the risks associated with taking Depakine^® syrup during pregnancy. To help the patient understand these risks, the physician prescribing valproic acid to her should provide the patient with comprehensive information about the risks associated with taking Depakine^® syrup during pregnancy.

In particular, the physician prescribing valproic acid should ensure that the patient understands

• The nature and extent of the risk when using valproic acid during pregnancy, in particular the risk of teratogenic effects, as well as the risk of disorders of the child’s mental and physical development;
• The need to use effective contraception;
• The need for regular treatment review;
• The need for urgent consultation with her doctor if she suspects that she is pregnant, or when she considers this a possibility.

A woman planning a pregnancy should definitely be attempted, if possible, to be switched to alternative treatment before she attempts conception.

Treatment with valproic acid should be continued only after a physician experienced in the treatment of epilepsy and bipolar disorders has reassessed the benefit-risk ratio of treatment for her.

Children (information applies to dosage forms of Depakine^® that can be taken by children under 3 years of age)

In children under 3 years of age, if it is necessary to use the drug, its use as monotherapy and in the dosage form recommended for children is recommended. In this case, before starting treatment, the ratio of the potential benefit of using valproic acid and the risk of liver damage and pancreatitis when using it should be weighed.

In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of toxic effects on the liver.

Renal failure

A reduction in the dose of valproic acid may be required due to an increase in the concentration of its free fraction in the blood serum. If monitoring of valproic acid plasma concentrations is not possible, the drug dose should be adjusted based on clinical observation of the patient.

Urea cycle enzyme deficiencies

If urea cycle enzyme deficiency is suspected, the use of valproic acid is not recommended. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be performed before starting treatment with valproic acid.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, mental retardation, or a family history of neonatal or child death, metabolic studies, in particular determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after a meal, should be performed before starting treatment with valproic acid.

Patients with systemic lupus erythematosus

Although it has been shown that immune system disorders are extremely rare during treatment with Depakine^® syrup, the potential benefit of its use must be weighed against the potential risk when prescribing the drug to patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures should be taken, mainly dietary correction, to minimize this phenomenon.

Patients with diabetes mellitus

Given the possibility of an adverse effect of valproic acid on the pancreas, blood glucose concentrations should be carefully monitored when using the drug in patients with diabetes mellitus. When testing urine for ketone bodies in patients with diabetes mellitus, false-positive results may be obtained, since Valproic acid is excreted by the kidneys, partially in the form of ketone bodies.

HIV-infected patients

In vitro studies have shown that Valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact, if any, is unknown. Furthermore, the significance of these in vitro data for patients receiving maximum suppressive antiretroviral therapy has not been established. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.

Patients with existing carnitine palmitoyltransferase (CPT) type II deficiency

Patients with existing CPT type II deficiency should be warned about a higher risk of developing rhabdomyolysis when taking valproic acid.

Ethanol

Alcohol consumption is not recommended during treatment with valproic acid.

Effect on ability to drive vehicles and machinery

Patients should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or when Depakine^® syrup is combined with benzodiazepines.

Overdose

Symptoms Clinical manifestations of acute massive overdose usually occur in the form of coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure and vascular collapse/shock. Cases of intracranial hypertension associated with cerebral edema have been described. The presence of sodium in valproic acid preparations in case of their overdose can lead to the development of hypernatremia. Fatal outcome is possible with massive overdose, but the prognosis for overdose is usually favorable. Overdose symptoms may vary; the development of seizures has been reported at very high plasma concentrations of valproic acid.

Treatment In a hospital setting – gastric lavage, which is effective within 10-12 hours after oral ingestion of the contents of the vial with lyophilisate or solution for intravenous administration. Administration of activated charcoal, including through a nasogastric tube, may be effective in reducing the absorption of valproic acid. Monitoring and correction of the functional state of the cardiovascular and respiratory systems, maintenance of effective diuresis, and symptomatic therapy are required. Liver and pancreatic functions should be monitored. If breathing is depressed, mechanical ventilation may be required. In some cases, naloxone has been used successfully. In very severe cases of significant overdose, hemodialysis and hemoperfusion have been effective.

Drug Interactions

Effect of valproic acid on other drugs

Valproic acid may potentiate the effect of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (with simultaneous use, careful medical supervision and, if necessary, dose adjustment are recommended).

Valproic acid does not affect the serum concentration of lithium.

Valproic acid increases the plasma concentration of phenobarbital (due to a decrease in its hepatic metabolism), which may lead to the development of its sedative effect, especially in children. Therefore, careful medical supervision of the patient during the first 15 days of combination therapy is recommended, with immediate reduction of the phenobarbital dose if a sedative effect develops and, if necessary, determination of the plasma concentration of phenobarbital.

Valproic acid increases the plasma concentration of primidone, which leads to an increase in its side effects (such as sedative effect); these symptoms disappear with long-term treatment. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy, with adjustment of the primidone dose if necessary.

Valproic acid reduces the total plasma concentration of phenytoin. In addition, Valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of overdose (Valproic acid displaces phenytoin from binding to plasma proteins and slows its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentration of phenytoin and its free fraction in the blood are recommended.

When valproic acid and carbamazepine are used concomitantly, clinical manifestations of carbamazepine toxicity have been reported, because Valproic acid may potentiate the toxic effects of carbamazepine. Careful clinical monitoring of such patients is recommended, especially at the beginning of combination therapy, with adjustment of the carbamazepine dose if necessary.

Valproic acid slows the hepatic metabolism of lamotrigine and increases the T_1/2 of lamotrigine by almost 2 times. This interaction may lead to increased toxicity of lamotrigine, in particular the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, adjustment (reduction) of the lamotrigine dose is recommended.

Valproic acid may increase the plasma concentrations of zidovudine, leading to increased toxicity of zidovudine.

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

Valproic acid may decrease the plasma concentrations of olanzapine.

Valproic acid may lead to an increase in the plasma concentration of rufinamide. This increase depends on the blood concentration of valproic acid. Caution should be exercised, especially in children, as this effect is more pronounced in this population.

Valproic acid may lead to an increase in the plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when used concomitantly with valproic acid.

Enhancement of the hypotensive effect of nimodipine (for oral administration and, by extrapolation, for parenteral administration) due to an increase in its plasma concentration (inhibition of nimodipine metabolism by valproic acid).

Concomitant administration of temozolomide with valproic acid leads to a slight but statistically significant decrease in the clearance of temozolomide.

Effect of other drugs on valproic acid

Antiepileptic drugs that can induce hepatic microsomal enzymes (including phenytoin, phenobarbital, carbamazepine), reduce the plasma concentration of valproic acid. In case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the blood concentration of valproic acid.

The concentration of valproic acid metabolites in the blood serum may be increased when used concomitantly with phenytoin or phenobarbital. Therefore, patients receiving these combinations should be carefully monitored for signs and symptoms of hyperammonemia, as some valproic acid metabolites may inhibit urea cycle enzymes.

Aztreonam increases the risk of seizures due to a decrease in the plasma concentration of valproic acid. Clinical monitoring, determination of valproic acid plasma concentrations and possible adjustment of the dose of the anticonvulsant drug during treatment with this antibacterial drug and after its discontinuation are necessary.

When felbamate and valproic acid are combined, the clearance of valproic acid decreases by 22-50% and the plasma concentration of valproic acid increases accordingly. The plasma concentration of valproic acid should be monitored.

When used concomitantly with carbamazepine, a decrease in the plasma concentration of valproic acid is possible due to acceleration of its hepatic metabolism. Clinical monitoring, determination of plasma concentrations and, if necessary, dose adjustment of both anticonvulsant drugs are necessary.

An increase in the plasma concentration of lamotrigine is possible (due to slowing of lamotrigine hepatic metabolism by valproate). If concomitant use of these drugs is necessary, clinical monitoring is required.

Mefloquine accelerates the metabolism of valproic acid and itself can cause seizures, so when used concomitantly, an epileptic seizure may develop.

When valproic acid and St. John’s wort preparations are used concomitantly, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

In case of concomitant use of valproic acid and drugs that have high and strong binding to plasma proteins (acetylsalicylic acid), an increase in the concentration of the free fraction of valproic acid is possible.

When valproic acid and indirect anticoagulants (warfarin and other coumarin derivatives) are used concomitantly, careful monitoring of INR and prothrombin index is required.

The plasma concentration of valproic acid may increase when used concomitantly with cimetidine or erythromycin (as a result of slowing of its hepatic metabolism).

A decrease in valproic acid blood concentrations when used concomitantly with carbapenems (panipenem, meropenem, imipenem) over 2 days of combined therapy, a 60-100% decrease in the plasma concentration of valproic acid was observed, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients with an adjusted dose of valproic acid due to their ability to rapidly and significantly reduce the plasma concentration of valproic acid. If treatment with carbapenems cannot be avoided, careful monitoring of valproic acid blood concentrations should be performed during treatment with the carbapenem and after its discontinuation.

Rifampicin may reduce the concentrations of valproic acid in the blood, which leads to a loss of the therapeutic effect of valproic acid. Therefore, an increase in the dose of valproic acid may be required during concurrent use of rifampicin and after its discontinuation.

Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid when used concomitantly with it.

Cholestyramine may lead to a decrease in the plasma concentrations of valproic acid when used concomitantly with it.

Other Interactions

Concomitant use of valproic acid and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. Patients receiving these combinations require careful medical monitoring for the development of symptoms of hyperammonaemic encephalopathy.

Concomitant use of valproic acid and quetiapine may increase the risk of developing neutropenia/leukopenia.

Valproic acid does not have the ability to induce liver enzymes and, consequently, Valproic acid does not reduce the effectiveness of estrogen-progestagen drugs in women using hormonal contraception.

When ethanol and other potentially hepatotoxic drugs are taken simultaneously with valproic acid, the hepatotoxic effect of valproic acid may be enhanced.

Concomitant use of clonazepam with valproic acid may in isolated cases lead to an increased severity of absence status.

When drugs with myelotoxic action are used concomitantly with valproic acid, the risk of suppression of bone marrow hematopoiesis increases.

Storage Conditions

The drug should be stored out of the reach of children, protected from direct sunlight, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

After opening, the vial can be stored at a temperature not exceeding 25°C (77°F) for 1 month.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.