Depakine^® Chronosphere (Granules) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis France (France)

Manufactured By

Sanofi Winthrop Industrie (France)

Contact Information

SANOFI

ATC Code

N03AG01 (Valproic acid)

Active Substance

Valproic acid (Rec.INN registered by WHO)

Dosage Forms

	Depakine® Chronosphere	Prolonged-release granules 100 mg: sachets 30 or 50 pcs.
		Prolonged-release granules 250 mg: sachets 30 or 50 pcs.
		Prolonged-release granules 500 mg: sachets 30 or 50 pcs.
		Prolonged-release granules 750 mg: sachets 30 or 50 pcs.
		Prolonged-release granules 1000 mg: sachets 30 or 50 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release granules almost white or slightly yellowish, waxy, free-flowing, without formation of agglomerates.

Excipients: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

Three-layer sachets (30) – cardboard packs.
Three-layer sachets (50) – cardboard packs.

Prolonged-release granules almost white or slightly yellowish, waxy, free-flowing, without formation of agglomerates.

Excipients: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

Three-layer sachets (30) – cardboard packs.
Three-layer sachets (50) – cardboard packs.

Prolonged-release granules almost white or slightly yellowish, waxy, free-flowing, without formation of agglomerates.

Excipients: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

Three-layer sachets (30) – cardboard packs.
Three-layer sachets (50) – cardboard packs.

Prolonged-release granules almost white or slightly yellowish, waxy, free-flowing, without formation of agglomerates.

Excipients: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

Three-layer sachets (30) – cardboard packs.
Three-layer sachets (50) – cardboard packs.

Prolonged-release granules almost white or slightly yellowish, waxy, free-flowing, without formation of agglomerates.

Excipients: hard paraffin, glyceryl dibehenate, colloidal hydrated silica.

Three-layer sachets (30) – cardboard packs.
Three-layer sachets (50) – cardboard packs.

Clinical-Pharmacological Group

Antiepileptic drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Antiepileptic drug, has central muscle relaxant and sedative effects.

Exhibits antiepileptic activity in various types of epilepsy. The main mechanism of action is apparently associated with the effect of valproic acid on the GABAergic system: increases GABA content in the CNS and activates GABAergic transmission.

Pharmacokinetics

Absorption

The bioavailability of valproic acid after oral administration is close to 100%. Food intake does not affect the pharmacokinetic profile. C_max of valproic acid in blood plasma is reached approximately 7 hours after oral administration of Depakine^® Chronosphere.

Compared to the enteric-coated dosage form, equivalent doses of Depakine^® Chronosphere are characterized by a longer absorption, identical bioavailability, a more linear correlation between doses and plasma concentration of valproic acid (total concentration and free fraction concentration). Furthermore, C_{max and}C_min of the free fraction of valproic acid in plasma are lower (reduction of about 25%), but there is a relatively more stable plateau phase of plasma concentrations from 4 to 14 hours after administration, the magnitude of fluctuations in plasma concentrations when taking Depakine^® Chronosphere compared to the enteric-coated dosage form is halved, resulting in Valproic acid being more evenly distributed in tissues throughout the day.

With course administration of the drug, C_ss of valproic acid in blood serum is reached within 3-14 days.

Effective serum concentrations of valproic acid are usually 40-100 mg/l (300-700 µmol/l) (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

V_d depends on age and is usually 0.13-0.23 l/kg body weight, in young people 0.13-0.19 l/kg body weight. Due to the reduction in the magnitude of plasma concentration fluctuations when taking Depakine^® Chronosphere, Valproic acid is more evenly distributed in tissues throughout the day compared to the immediate-release valproic acid dosage form.

The binding of valproic acid to plasma proteins (mainly albumin) is high (90-95%), dose-dependent and saturable. Valproic acid penetrates into the cerebrospinal fluid and the brain. The concentration of valproic acid in the CSF is 10% of the corresponding concentration in the blood serum, i.e., close to the concentration of the free fraction of valproic acid in the blood serum.

Valproic acid is excreted in breast milk. At steady state, the concentration of valproic acid in breast milk is up to 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 hepatotoxic effects.

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 or the metabolism rate of other substances, such as estrogens, progestogens, and indirect anticoagulants.

Excretion

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

When valproic acid is used as monotherapy, its T_1/2 is 12-17 hours.

Pharmacokinetics in special patient groups

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 may increase to 8.5-20%.

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

When combined with antiepileptic drugs that induce hepatic 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 hepatic microsomal enzymes by other antiepileptic drugs.

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

T_1/2 in children older than 2 months is close to that in adults.

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.

Placental barrier. Valproic acid crosses the placental barrier. Some publications have assessed the valproate concentration in the umbilical cord of newborns at birth. The serum valproate concentration in the umbilical cord, reflecting the valproate concentration in the fetal blood, was the same or slightly higher than in the maternal serum.

Indications

Adults

• As monotherapy or in combination with other antiepileptic agents:
  • 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).

Treatment and prevention of bipolar affective disorders.

Children, including infants (starting from the 6th month of life)

• As monotherapy or in combination with other antiepileptic agents:
  • 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 febrile seizures when such prevention is necessary.

ICD codes

Dosage Regimen

The drug is taken orally. The daily dose is recommended to be taken in one or two doses, preferably with meals. Single-dose administration is possible in well-controlled epilepsy. The mixture should be swallowed immediately, without chewing. The prepared mixture should not be saved for subsequent administration.

Depakine^® Chronosphere is a dosage form that is particularly well suited for the treatment of children (if they are able to swallow soft food) or adults with swallowing difficulties.

Depakine^® Chronosphere is a prolonged-release granule that provides more uniform blood concentrations of valproic acid and, accordingly, a more uniform distribution in tissues throughout the day.

• Depakine^® Chronosphere 100 mg sachets are used only in children and infants;
• Depakine^® Chronosphere 1000 mg sachets are used only in adults.

The drug Depakine^® Chronosphere must be poured onto the surface of cold (or room temperature) soft food or drink (yogurt, orange juice, fruit puree, etc.). Should not be used with hot food or drinks (such as soups, coffee, tea, etc.).

The drug should not be poured into a bottle with a nipple, as the granules may clog the nipple hole.

When taken with liquid, it is recommended to rinse the glass with a small amount of water and drink this water, as granules may stick to the glass.

Manic episodes in bipolar disorders

The dose should be selected and controlled by the attending physician individually. The daily dose is established taking into account the patient’s age and body weight.

The recommended initial dose is 20 mg (in terms of sodium valproate) per kg of body weight. The dose should be increased as quickly as possible to the minimum dose that provides the required therapeutic effect.

The recommended maintenance dose for the treatment of bipolar disorders is in the range between 1000 mg and 2000 mg (in terms of sodium valproate) per day. The dose is selected according to the individual clinical response of the patient.

For the prevention of manic states, the individually selected minimum clinically effective dose should be used.

Epilepsy

In monotherapy, the initial daily dose is usually 5-10 mg (in terms of sodium valproate) per kg of body weight, 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.

Average daily dose

• For children under 14 years of age – 30 mg/kg body weight;
• For adolescents aged 14-18 years – 25 mg/kg body weight;
• For adults and elderly patients (body weight from 60 kg and above) – 20 mg/kg body weight.

Thus, the daily doses presented below are recommended.

* dose in terms of milligrams of sodium valproate

The average daily dose can be increased under the control of 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, serum concentration of valproic acid, and 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 in cases where epilepsy is not controlled or the development of side effects is suspected. Usually, doses that provide serum concentrations of valproic acid of 40-100 mg/l (300-700 µmol/l) are effective. If there is a justified need to achieve higher serum concentrations, the expected benefit-risk ratio of side effects, especially dose-dependent ones, should be carefully weighed, since 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.

When switching from immediate-release or delayed-release dosage forms of Depakine^® that controlled epilepsy well to Depakine^® Chronosphere, it is recommended to continue taking the same daily dose.

For patients who previously took antiepileptic drugs, switching to Depakine^® Chronosphere should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. At the same time, the dose of another antiepileptic drug that the patient took previously should be immediately reduced, especially if it is phenobarbital. Discontinuation of the antiepileptic drug that the patient took previously should be carried out gradually.

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

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

Special patient groups

Female children and adolescents, women of childbearing potential and pregnant women: treatment with Depakine^® Chronosphere should be initiated under the supervision of a specialist experienced in the treatment of epilepsy and bipolar disorders. Treatment should be initiated only if other treatments are ineffective or not tolerated, and during regular treatment review, the benefit-risk ratio should be carefully reassessed. The drug should be prescribed in compliance with the Pregnancy Prevention Programme.

The preferred use is drugs containing valproic acid in monotherapy and in the lowest effective doses and, if possible, in prolonged-release dosage forms. During pregnancy, in the absence of alternative treatments for epilepsy, the daily dose of the drug should be divided into at least 2 doses.

Although in elderly patients there are changes in the pharmacokinetics of valproic acid, 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 (simultaneously free fraction and protein-bound fraction), to avoid possible errors in dose selection.

Concomitant use with estrogen-containing drugs

Valproic acid does not reduce the therapeutic efficacy of hormonal contraceptives. However, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its efficacy. It is necessary to monitor the serum concentration of valproic acid and clinical efficacy (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs.

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (<1/10,000), frequency unknown (cannot be calculated from the available data).

Congenital, hereditary and genetic disorders teratogenic risk.

Blood and lymphatic system disorders common – anemia, thrombocytopenia; uncommon – pancytopenia, leukopenia, neutropenia (leukopenia and pancytopenia may be with or without bone marrow depression; blood picture returns to normal after drug withdrawal); rare – bone marrow disorders, including isolated aplasia/hypoplasia of red blood cells, agranulocytosis, macrocytic anemia, macrocytosis.

Coagulation disorders common – bleeding and hemorrhage; rare – decreased levels of blood clotting factors (at least one), abnormal blood coagulation parameters (such as increased prothrombin time, increased aPTT, increased thrombin time, increased INR). The appearance of spontaneous ecchymoses and bleeding requires drug withdrawal and clinical and laboratory examination.

Nervous system disorders very common – tremor; common – extrapyramidal disorders, stupor*, drowsiness, convulsions*, memory impairment, headache, nystagmus, dizziness (may occur a few minutes after IV 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 convulsions; 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 convulsive seizures during treatment, and decreased upon drug withdrawal or dose reduction. Most of such cases were described during combination therapy, especially with the concomitant use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

Psychiatric disorders common – confusional state, aggression**, agitation, attention disturbance**, 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.

Ear and labyrinth disorders common – reversible and irreversible deafness.

Eye disorders frequency unknown – diplopia.

Respiratory, thoracic and mediastinal disorders uncommon – pleural effusion.

Gastrointestinal disorders 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 usually disappear after a few days and do not require discontinuation of therapy; these reactions can be reduced by taking the drug during or after meals); uncommon – pancreatitis, sometimes fatal (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.

Hepatobiliary disorders common – liver damage, accompanied by abnormalities in liver function parameters, such as decreased prothrombin index, especially in combination with a significant decrease in fibrinogen and blood clotting factors, increased bilirubin concentration and increased activity of liver transaminases in the blood; liver failure, in exceptional cases with a fatal outcome. Patients should be monitored for possible liver function disorders.

Renal and urinary disorders common – involuntary urination; uncommon – renal failure; rare – 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 which is not yet clear.

Immune system disorders common – hypersensitivity reactions, e.g., urticaria; uncommon – angioedema; rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Skin and subcutaneous tissue disorders common – pruritus, transient or dose-dependent alopecia (including androgenic alopecia due to developed hyperandrogenism, polycystic ovary syndrome, as well as alopecia due to developed hypothyroidism), nail and nail bed disorders; uncommon – rash, hair disorders (such as impaired normal hair structure, hair discoloration, abnormal hair growth [loss of waviness and curliness of hair or, conversely, appearance of curliness in individuals with initially straight hair]); rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders uncommon – decreased bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid for a long time (the mechanism of valproic acid’s effect on bone metabolism has not been established); rare – systemic lupus erythematosus, rhabdomyolysis.

Endocrine disorders uncommon – syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperandrogenism (hirsutism, virilization, acne and/or increased blood androgen concentrations); rare – hypothyroidism.

Metabolism and nutrition disorders common – hyponatremia, increased body weight (since weight gain is a factor contributing to the development of polycystic ovary syndrome); rare – hyperammonemia***, obesity.

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

Vascular disorders uncommon – vasculitis.

Reproductive system and breast disorders common – dysmenorrhea; uncommon – amenorrhea; rare – male infertility, polycystic ovaries; frequency unknown – irregular menstruation, breast enlargement, galactorrhea.

Neoplasms benign, malignant and unspecified (including cysts and polyps): rare – myelodysplastic syndrome.

General disorders and administration site conditions uncommon – hypothermia, non-severe peripheral edema.

Investigations: rare – biotin deficiency/biotinidase deficiency.

Contraindications

• Hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or to any of the excipients of the drug;
• Acute and chronic hepatitis;
• Severe liver disease (especially drug-induced hepatitis) in the patient’s history and in the patient’s close blood relatives;
• Severe fatal liver damage with the use of valproic acid in the patient’s close blood relatives;
• Severe liver dysfunction;
• Severe pancreatic dysfunction;
• Hepatic porphyria;
• Established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), e.g., 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;
• Concomitant use with mefloquine;
• Concomitant use with preparations of St. John’s wort (Hypericum perforatum);
• Pregnancy in epilepsy, except in cases where there are no alternative treatment methods;
• Pregnancy in the treatment and prevention of bipolar affective disorders;
• Women with preserved reproductive potential, if all conditions of the Pregnancy Prevention Program are not met;
• Children under 6 months of age.

With caution

• History of liver and pancreatic diseases;
• Congenital enzymopathies;
• Bone marrow depression (leukopenia, thrombocytopenia, anemia);
• Renal failure (dose adjustment required);
• Hypoproteinemia;
• Concomitant use of several anticonvulsant drugs (due to increased risk of liver damage);
• Concomitant use of drugs that provoke convulsive seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking convulsive seizures);
• Concomitant use of neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects);
• Concomitant 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 interaction at the level of metabolism or plasma protein binding, changes in plasma concentrations of either these drugs and/or valproic acid are possible);
• Concomitant use of carbamazepine (risk of potentiation of toxic effects of carbamazepine and decrease in plasma concentration of valproic acid);
• Concomitant use of topiramate or acetazolamide (risk of encephalopathy);
• Concomitant use with estrogen-containing drugs;
• In patients with existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of developing rhabdomyolysis when taking valproic acid).

Use in Pregnancy and Lactation

The use of valproic acid is contraindicated

• During pregnancy in epilepsy, except in cases where there are no alternative treatment methods;
• During pregnancy in the treatment and prevention of bipolar affective disorders;
• In women of childbearing potential, if all conditions of the Pregnancy Prevention Program are not met.

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 during pregnancy

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

Valproic acid has been shown to cross the placental barrier in both animals and humans.

Teratogenicity and congenital malformations

Available clinical data have demonstrated a higher frequency of formation 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 different organ systems, in children born to mothers who took valproic acid during pregnancy, compared to their frequency when taking a number of other antiepileptic drugs during pregnancy. Thus, the risk of congenital malformations in children born to mothers with epilepsy receiving 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 frequency 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 such risk does not exist.

Available data confirm an increased number of cases of malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft palate, craniosynostosis, heart, kidney and genitourinary system malformations, limb defects (including bilateral radial aplasia and multiple anomalies of various body systems).

Valproic acid with in utero exposure may also lead to hearing impairment or loss due to malformations of the ears and/or nose (secondary effect), and/or direct toxic effects on the hearing organs.

Disorders of mental and physical development of children

It has been shown that in utero exposure to valproic acid may have adverse 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 such 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 early developmental delays (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 valproate was on average 7-10 points lower than in children exposed in utero to other antiepileptic drugs. Although the role of other factors that may adversely affect the intellectual development of children exposed to valproic acid in utero cannot be excluded, 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 3-5-fold increase in risk), including childhood autism.

There is evidence that children exposed to valproic acid in utero have an increased risk of developing attention deficit hyperactivity disorder (ADHD) compared to the general population.

Both valproic acid monotherapy and combination therapy including valproic acid are associated with adverse pregnancy outcomes. However, according to available data, combined antiepileptic therapy including valproic acid is associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy (i.e., the risk of fetal abnormalities is lower when valproic acid is used as 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 is contraindicated during pregnancy in epilepsy, except in cases where there are no alternative treatment methods; during pregnancy in the treatment and prevention of bipolar affective disorders.

Concomitant use with estrogen-containing drugs

Valproic acid does not reduce the therapeutic efficacy of hormonal contraceptives. Nevertheless, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its efficacy. It is necessary to monitor the serum concentration of valproic acid and clinical efficacy (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs. The question of the need for use or the possibility of discontinuing the use of the drug should be decided before starting its use or reviewed if a woman taking the drug plans a pregnancy.

Pregnancy planning

If a patient is planning a pregnancy, a specialist in the treatment of epilepsy should evaluate the therapy with drugs containing valproic acid and consider the possibility of prescribing alternative therapy. Every effort should be made to switch the patient from therapy with drugs containing valproic acid before conception and before discontinuing contraception. In the absence of alternative therapy, the patient should be explained the risk associated with the use of drugs containing valproic acid for the unborn child, to help make an informed decision about family planning.

Pregnant women

The use of drugs containing valproic acid is contraindicated during pregnancy, except in cases where there are no alternative treatment methods, in epilepsy and is contraindicated in the treatment and prevention of bipolar affective disorders.

In case of pregnancy, a woman should immediately consult her doctor to evaluate the therapy and consider the possibility of prescribing alternative therapy.

Women of childbearing potential should use effective methods of contraception during treatment with the drug.

Women of childbearing potential should be informed about the risk and benefit of using drugs containing valproic acid during pregnancy.

If, despite the known risk of using drugs containing valproic acid during pregnancy, a woman plans a pregnancy or is diagnosed with pregnancy, the need for treatment with valproic acid should be reassessed depending on the indications

• For the indication “Bipolar affective disorder,” the discontinuation of valproic acid treatment should be considered;
• For the indication “Epilepsy,” the decision to continue or discontinue valproic acid treatment should be made after re-evaluating the benefit-risk ratio. If, after re-evaluating the benefit-risk ratio, treatment with the drug must be continued during pregnancy, it is recommended to use it at the lowest effective daily dose, divided into several administrations. It should be noted that during pregnancy, the use of prolonged-release dosage forms of the drug is preferable compared to other dosage forms;
• If possible, even before pregnancy, folic acid supplementation (at a dose of 5 mg/day) should be initiated, as folic acid may reduce the risk of neural tube defects. However, current data do not confirm its preventive effect on congenital malformations induced by valproic acid;
• Continuous (including during the third trimester of pregnancy) special prenatal diagnostics, including thorough ultrasound examination, should be performed to detect possible neural tube defects or other fetal malformations.

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 levels of other blood clotting factors. Cases of afibrinogenemia, which could be fatal, have also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of hepatic microsomal enzymes.

Therefore, coagulation tests (determination of platelet count in peripheral blood, plasma fibrinogen concentration, blood clotting factors, and coagulogram) must be performed in newborns whose mothers received valproic acid preparations during pregnancy.

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.

Newborns whose mothers took valproic acid in the last trimester of pregnancy may experience withdrawal syndrome (in particular, agitation, irritability, hyperreflexia, tremor, hyperkinesia, muscle tone disorders, convulsions, and feeding difficulties).

Breastfeeding period

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

Based on literature data and limited clinical experience, the possibility of breastfeeding while taking the drug can be considered; however, the drug’s side effect profile, especially the hematological disorders it causes, should be taken into account.

Fertility

Due to the possibility of developing dysmenorrhea, amenorrhea, polycystic ovary syndrome, and increased blood testosterone levels, 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.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment, acute and chronic hepatitis, a history of severe liver disease (especially drug-induced hepatitis) in the patient and their close blood relatives; severe liver damage with a fatal outcome associated with the use of valproic acid in the patient’s close blood relatives.

Use in Renal Impairment

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

Pediatric Use

Contraindicated in children under 6 months of age.

Geriatric Use

The dose of valproic acid in elderly patients should be titrated according to the achievement of seizure control.

Special Precautions

Before starting treatment with Depakine^® Chronosphere 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, a slight increase in liver enzyme activity may occur with valproic acid, especially at the beginning of treatment, which is asymptomatic and transient. In these patients, a more detailed investigation of biological parameters, including prothrombin index, should be performed, and dose adjustment may be required, as well as repeated clinical and laboratory examination if necessary.

Before starting therapy or before surgery, as well as in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine bleeding time, peripheral blood cell count, including platelet count.

Severe liver damage

Predisposing factors

Isolated cases of severe liver damage, sometimes fatal, have been described. Clinical experience shows that patients at risk include those taking several antiepileptic drugs concomitantly, children under 3 years of age with severe seizures, especially against a background of brain damage, mental retardation, and/or congenital metabolic or degenerative diseases; patients concomitantly taking salicylates (since salicylates are metabolized via the same metabolic pathway as Valproic acid).

After 3 years of age, the risk of liver damage significantly decreases and progressively diminishes with increasing age. In most cases, such liver damage occurred within the first 6 months of treatment, most often between 2 and 12 weeks of treatment, and usually with the use of valproic acid as part of combination antiepileptic therapy.

Suspicion of liver damage

Clinical monitoring of patients is essential for the early diagnosis of liver damage. In particular, attention should be paid to the appearance of the following symptoms, which may precede the onset of jaundice, especially in at-risk patients

• Non-specific symptoms, especially those with sudden onset, 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 pediatric patients) should be warned that they must immediately report the occurrence of any of these symptoms to the attending physician. Patients should be immediately clinically examined and laboratory tests of liver function should be performed.

Detection

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

Pancreatitis

Rare cases of severe pancreatitis have been reported in children and adults, occurring independently of age and duration of treatment. Several cases of hemorrhagic pancreatitis with rapid progression from the first symptoms to a fatal outcome have been observed.

Children are at increased risk of developing pancreatitis; this risk decreases with increasing age. Risk factors for 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 elevated pancreatic enzyme levels in the blood, valproic acid should be discontinued and appropriate treatment initiated.

Suicidal thoughts and attempts

Suicidal thoughts or attempts have been reported in patients receiving antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increase in the 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 receiving the drug should be continuously monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and their caregivers are advised to seek immediate medical attention if the patient experiences suicidal thoughts or attempts.

Carbapenems

Concomitant use with carbapenems is not recommended.

Patients with established or suspected mitochondrial diseases

Valproic acid may initiate or worsen the manifestations of existing mitochondrial diseases in the patient, caused by mitochondrial DNA mutations, as well as nuclear gene mutations 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 is associated with a higher incidence of acute liver failure and liver-related fatal outcomes. The presence of diseases due to γ-polymerase defects can be suspected in patients with a family history or symptoms of such diseases, including encephalopathy of unknown origin, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with visual (occipital) aura. 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 have experienced a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures instead of improvement. In case of seizure exacerbation, patients should immediately consult their attending physician.

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

Pregnancy Prevention Programme

Valproic acid has a high teratogenic effect; the use of valproic acid leads to a high risk of congenital malformations and impaired CNS development in the fetus.

The use of valproic acid is contraindicated

• During pregnancy for epilepsy, except in cases where there are no alternative treatment methods;
• During pregnancy for the treatment and prevention of bipolar affective disorders;
• In women of childbearing potential, unless all conditions of the Pregnancy Prevention Programme are met.

When prescribing drugs containing valproic acid, it is necessary

• To conduct an individual assessment of the circumstances of prescribing the drug in each specific case, discuss possible treatment methods, and ensure that the patient understands the potential risks and the need for measures taken to minimize them;
• To ensure that the patient is of childbearing potential;
• To ensure that the patient understands the nature and magnitude of the risks associated with the use of valproic acid during pregnancy, in particular, the risks of teratogenic effects, as well as the risks of impaired mental and physical development of the child;
• To ensure that the patient understands the need to perform a pregnancy test before starting and during treatment;
• To explain the necessary contraceptive methods, ensure that the patient uses reliable methods of contraception continuously during treatment with drugs containing valproic acid;
• To ensure that the patient understands the need to regularly consult a specialist in the treatment of epilepsy and bipolar affective disorders (at least once a year) to re-evaluate the prescribed therapy;
• To ensure that the patient understands the need to consult the attending physician if she is planning a pregnancy, in order to timely assess the possibility of switching to alternative therapy before discontinuing contraception;
• To inform about the need for immediate consultation with the attending physician if pregnancy is suspected;
• To ensure that the patient has received all necessary explanations about the risks and necessary precautions.

The above information is also relevant for women who are currently not sexually active, except in cases where the attending physician has confirmed the absence of childbearing potential.

Female pediatric patients

When prescribing drugs containing valproic acid, it is necessary

• To ensure that female pediatric patients/their legal representatives understand the need to consult the attending physician at the onset of menarche;
• To ensure that female pediatric patients who have reached menarche or their legal representatives have received detailed information about the risks of congenital malformations and impaired CNS development in the fetus.

The attending physician should annually re-evaluate the prescribed therapy with valproic acid drugs and assess the possibility of prescribing alternative therapy. If drugs containing valproic acid are the treatment of choice, it is necessary to ensure the use of reliable contraceptive methods and compliance with the conditions of the Pregnancy Prevention Programme. Before the onset of puberty, the possibility of switching patients to alternative treatments should be constantly considered.

Pregnancy test

Before starting treatment with drugs containing valproic acid, pregnancy must be ruled out. Therapy with drugs containing valproic acid cannot be prescribed to women of childbearing potential in the absence of a healthcare professional-confirmed negative pregnancy test result (blood pregnancy test) to rule out prescribing the drug during pregnancy.

Contraceptive methods

Female patients of childbearing potential who have been prescribed therapy with drugs containing valproic acid must adhere to reliable methods of contraception continuously throughout the entire treatment period.

Female patients of childbearing potential should be provided with detailed information on pregnancy prevention methods. Such patients may also seek advice from their attending physician if they are not using a reliable method of contraception.

At least one reliable method of contraception (preferably used simultaneously with methods such as an intrauterine system or implant) or two complementary methods of contraception, including barrier methods, should be used. When prescribing a contraceptive method to a patient, an individual approach should be applied, and all possible contraceptive options should be discussed with the patient to ensure that the patient adheres to and complies with the regimen. In case of amenorrhea, the patient should also be warned about the use of effective contraceptive methods.

Annual therapy review

At least once a year, the attending physician should assess whether drugs containing valproic acid are the treatment of choice. The risks associated with therapy should be discussed when prescribing the drug and during each annual therapy review, and it should be ensured that the patient understands all the risks.

Pregnancy planning

If a patient is planning a pregnancy, a specialist in the treatment of epilepsy and bipolar affective disorders should assess the therapy with drugs containing valproic acid and consider the possibility of prescribing alternative therapy. Every effort should be made to switch the patient from therapy with drugs containing valproic acid before conception and before discontinuing contraception. In the absence of alternative therapy, the patient should be explained all the risks associated with the use of drugs containing valproic acid for the unborn child, to help make an informed decision about family planning.

Actions in case of pregnancy

In case of pregnancy, the patient should immediately contact her attending physician to assess the therapy and consider the possibility of prescribing alternative therapy.

The healthcare professional must ensure that

• Patients understand all the risks described above;
• Patients have been advised not to discontinue valproic acid therapy and to contact their attending physician immediately when planning a pregnancy.

Concomitant use with estrogen-containing drugs

Valproic acid does not reduce the therapeutic efficacy of hormonal contraceptives. However, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its efficacy. Valproic acid serum concentration and clinical efficacy (seizure control and mood control) should be monitored when initiating or discontinuing estrogen-containing medications.

Use in pediatrics (information applies to dosage forms of the drug 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, monotherapy and the use of a dosage form recommended for children are recommended. In this case, the ratio of the potential benefit of using valproic acid to the risk of liver damage and pancreatitis associated with its use should be assessed before starting treatment.

In children under 3 years of age, the concomitant use of valproic acid and salicylates should be avoided due to the risk of hepatotoxicity.

Renal Failure

A dose reduction 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 Deficiency

If a urea cycle enzyme deficiency is suspected, the use of valproic acid is contraindicated. Several cases of hyperammonemia with the development of stupor or coma have been described in such patients. In these cases, metabolic studies should be performed before starting treatment with valproic acid preparations.

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 preparations.

Patients with SLE

Although immune system dysfunction is extremely rare during treatment with valproic acid preparations, the potential benefit of their use must be weighed against the potential risk when prescribing to patients with SLE.

Weight Gain

Patients should be warned about the risk of weight gain at the beginning of treatment and the need to take measures to follow a diet 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 because Valproic acid is partially excreted by the kidneys in the form of ketone bodies.

HIV-Infected Patients

In vitro studies have established that Valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact is unknown. Furthermore, the significance of data obtained in in vitro studies 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 Preexisting Carnitine Palmitoyltransferase (CPT) Type II Deficiency

Patients with preexisting 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.

Other Special Instructions

The inert matrix of the drug (extended-release preparation) is not absorbed in the gastrointestinal tract due to the nature of its excipients; after the release of the active substances, the inert matrix is excreted by the intestines.

Effect on Ability to Drive Vehicles and Operate Machinery

Driving and operating vehicles is contraindicated.

Information for Patients

Patient Card for Taking a Drug Containing Valproic Acid

Contraception and Pregnancy

What Do You Need to Know*?

• Drugs containing valproic acid are effective medicines for the treatment of epilepsy and bipolar affective disorder.
• Taking drugs containing valproic acid during pregnancy can cause serious harm to the unborn child.
• Always use an effective method of contraception without interruption throughout the entire course of treatment with drugs containing valproic acid.
• Remember to visit your doctor at least once a year.
• Before use, read the instructions for medical use.
• Never stop taking drugs containing valproic acid until your doctor tells you to do so, as your condition may worsen.
• If you are planning a pregnancy, do not stop taking the drug containing valproic acid on your own and do not interrupt contraception until you consult with your doctor.
• If you think you are pregnant, contact your doctor immediately.
• Ask your doctor to give you detailed information about the drug.

* This information applies to all girls and women of childbearing potential taking drugs containing valproic acid. Keep this information for reference if needed.

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 during their overdose can lead to the development of hypernatremia. A fatal outcome is possible with a massive overdose, but the prognosis for overdose is usually favorable. Overdose symptoms may vary; the development of seizures at very high plasma concentrations of valproic acid has been reported.

Treatment In a hospital setting – gastric lavage, which is effective within 10-12 hours after oral administration. The administration of activated charcoal, including via 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 is required, maintaining effective diuresis. Liver and pancreatic functions must be monitored. If breathing is depressed, artificial ventilation may be required. In some cases, naloxone has been used successfully. In very severe cases of significant overdose, hemodialysis and hemoperfusion were 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 is 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 a sedative effect of the latter, especially in children. Therefore, careful medical supervision of the patient is recommended during the first 15 days of combination therapy 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. Furthermore, Valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing overdose symptoms (Valproic acid displaces phenytoin from plasma protein binding 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 is recommended.

When valproic acid and carbamazepine are used simultaneously, 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 capable of inducing 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 it is 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.

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.

Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing 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 efficacy 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 the prothrombin index is required.

The plasma concentration of valproic acid may increase with concomitant use of cimetidine or erythromycin (as a result of slowing 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 valproic acid blood concentrations, leading to loss of the therapeutic effect of valproic acid. Therefore, an increase in the dose of valproic acid may be required.

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 plasma concentrations of valproic acid when used concomitantly with it.

Drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, as a result, a decrease in its efficacy. It is necessary to monitor the serum concentration of valproic acid and clinical efficacy (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs. Valproic acid does not have the ability to induce liver enzymes and therefore does not reduce the efficacy of estrogen-progestogen drugs in women using hormonal methods of contraception.

Other Interactions

Concomitant use of valproic acid and topiramate or acetazolamide was accompanied by encephalopathy and/or hyperammonemia. Patients receiving these combinations require careful medical monitoring for the development of symptoms of hyperammonemic encephalopathy.

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

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 rare cases lead to increased severity of absence status.

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

Storage Conditions

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

Shelf Life

Shelf life – 2 years. Do not take the drug after the expiration date indicated on the packaging.

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.