Depakine Chronosphere, 500 mg sachets 30 pcs

The drug has a central myorelaxant and sedative effect.

It shows antiepileptic activity on different types of epilepsy. It is obvious that the main mechanism of action is related to the effect of valproic acid on the GABA-ergic system: it increases the GABA content in the CNS and activates the GABA-ergic transmission.

Depakine^® Chronosphere^™ is a sustained-action pellet that provides more even concentrations of the drug throughout the day.

Pharmacokinetics

Intake

The bioavailability of valproic acid with oral administration is close to 100%. Food intake has no effect on the pharmacokinetic profile. C_max drug in plasma is reached approximately 7 h after oral administration.

In comparison with the enteric-coated dosage form, equivalent doses of Depakin^® Chronosphere^™ are characterized by longer absorption, identical bioavailability, and a more linear correlation between doses and plasma concentrations of valproic acid (total and free fraction concentrations). In addition, the C_max and C_max free fraction of valproic acid in plasma are lower (approximately 25% reduction), but there is a relatively more stable plateau phase of plasma concentrations from 4 to 14 h after administration, the amount of variation in plasma concentrations when taking Depakine^®Chronosphere^™ compared to the enteric-coated dosage form is reduced by half, resulting in valproic acid being more evenly distributed in the tissues overnight.

When taken as a course of medication, C_ss valproic acid in serum is reached within 3-14 days.

Serum valproic acid concentrations of 40-100 mg/L (300-700 µmol/L) are usually effective (determined before taking the first dose of the drug of the day) If serum valproic acid concentrations above 100 mg/L are expected to increase side effects to the point of intoxication.

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 reduced magnitude of fluctuations in plasma concentrations when taking Depakine^®Chronosphere^™, valproic acid is more evenly distributed in the tissues overnight compared to the immediate-release form of valproic acid.

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

Valproic acid penetrates the breast milk of nursing mothers. In the state of reaching C_ss valproic acid in serum, its concentration in breast milk is up to 10% of its serum concentration.

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 has no inducing effect on enzymes that are part of the cytochrome P450 metabolic system: unlike most other antiepileptic drugs, valproic acid has no effect on both its own metabolism and the metabolism of other substances, such as estrogens, progestagens and indirect anticoagulants.

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

When valproic acid is used in monotherapy its T_1/2 is 12-17 h. When combined with antiepileptic agents that induce microsomal liver enzymes (such as primidone, phenytoin, phenobarbital and carbamazepine), the plasma clearance of valproic acid is increased and T_1/2 is decreased, the degree of change depending on the degree of induction of microsomal liver enzymes by other antiepileptic agents. T_1/2 in children older than 2 months is similar to that in adults.

Pharmacokinetics in special clinical cases

In elderly patients, patients with renal and hepatic impairment, plasma protein binding is decreased.

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

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

In patients with liver disease, the T_1/2 valproic acid is increased.

In overdose, an increase in T_1/2 up to 30 h has been observed. Only the free fraction of valproic acid in blood (510%) is subject to hemodialysis.

Peculiarities of pharmacokinetics in pregnancy

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

Indications

In adults (as monotherapy or in combination with other antiepileptic drugs):

for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic; Lennox-Gastaut syndrome;
for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;
treatment and prevention of bipolar affective disorders.

In infants (from 6 months of age) and children (as monotherapy or in combination with other antiepileptic drugs):

for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic; Lennox-Gastaut syndrome;
for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;
prevention of seizures at high temperatures, when such prevention is necessary.

Pharmacological effect

The drug has a central muscle relaxant and sedative effect.

Shows antiepileptic activity in various types of epilepsy. It is obvious that the main mechanism of action is associated with the effect of valproic acid on the GABAergic system: it increases the content of GABA in the central nervous system and activates GABAergic transmission.

Depakine® Chronosphere™ is a long-acting granule that provides more uniform concentrations of the drug throughout the day.

Pharmacokinetics

Suction

The bioavailability of valproic acid when administered orally is close to 100%. Food intake does not affect the pharmacokinetic profile. Cmax of the drug in plasma is reached approximately 7 hours after oral administration.

Compared to an enteric-coated dosage form, equivalent doses of Depakine® Chronosphere™ are characterized by longer absorption, identical bioavailability, and a more linear correlation between doses and plasma concentrations of valproic acid (total concentration and concentration of the free fraction). In addition, Cmax and Cmax of the free fraction of valproic acid in plasma are lower (the decrease is 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 the drug Depakin®Chronosphere™ compared to the enteric-coated dosage form is halved, resulting in valproic acid more evenly distributed in tissues throughout the day.

With a course of taking the drug, Css of valproic acid in the blood serum is achieved within 3-14 days.

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

Distribution

Vd depends on age and is usually 0.13-0.23 l/kg body weight; in young people it is 0.13-0.19 l/kg body weight. Due to a decrease in the magnitude of fluctuations in plasma concentrations when taking the drug Depakin®Chronosphere™, valproic acid is more evenly distributed in tissues throughout the day compared to the immediate-release dosage form of valproic acid.

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

Valproic acid passes into the breast milk of nursing mothers. When the Css of valproic acid in the blood serum is reached, its concentration in breast milk is up to 10% of its concentration in the blood serum.

Metabolism

Valproic acid is metabolized 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 enzymes that are part of the cytochrome P450 metabolic system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of its own metabolism or the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Removal

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

When valproic acid is used in monotherapy, its T1/2 is 12-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes (such as primidone, phenytoin, phenobarbital and carbamazepine), plasma clearance of valproic acid increases and T1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs drugs. T1/2 in children over 2 months is close to that in adults.

Pharmacokinetics in special clinical situations

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%.

With hypoproteinemia, the total concentration of valproic acid (free + fraction bound to plasma proteins) may not change, but may decrease due to an increase in the metabolism of the free (not bound to plasma proteins) fraction of valproic acid.

In patients with liver diseases, T1/2 of valproic acid increases.

In case of overdose, an increase in T1/2 up to 30 hours was observed. Only the free fraction of valproic acid in the blood (510%) is subject to hemodialysis.

Features of pharmacokinetics during pregnancy

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

Special instructions

Before starting the use of 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, when using valproic acid, a slight increase in the activity of liver enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In these patients, a more detailed study 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 examinations.

Before starting therapy or surgery, in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to conduct a hematological blood test (determine the leukocyte formula of the blood, including the number of platelets; bleeding time and coagulogram).

Severe liver damage

Clinical experience shows that patients at risk include patients receiving multiple antiepileptic drugs at the same time, children under 3 years of age with severe seizures, especially in the presence of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients simultaneously taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).

In children over 3 years of age, the risk of liver damage is significantly reduced and decreases progressively as the patient ages. 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 valproic acid is used as part of combination antiepileptic therapy.

For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, you should pay attention to the appearance of the following symptoms, which may precede the onset of jaundice, especially in patients at risk:

nonspecific symptoms, especially those that suddenly begin, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
resumption of seizures in patients with epilepsy.

Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. If these symptoms occur, patients should immediately undergo clinical examination and laboratory testing of liver function tests.

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of an abnormal prothrombin index, especially in combination with abnormalities in other laboratory parameters (significant decreases in fibrinogen and coagulation factors, increased bilirubin concentrations and increased transaminase activity), as well as the appearance of other symptoms indicating liver damage, requires discontinuation of therapy.

Pancreatitis

Children are at increased risk of developing pancreatitis, and the risk decreases as the child ages. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure combined with pancreatitis increases the risk of death.

Patients who experience severe abdominal pain, nausea, vomiting and/or anorexia should be evaluated immediately. If pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of 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 ideation and attempts. The mechanism of this effect is unknown. Therefore, patients receiving Depakine® Chronosphere™ should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts.

Kidney failure

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Carbamide cycle enzyme deficiency

If a deficiency of carbamide cycle enzymes 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, with mental retardation or a family history of the death of a newborn or child, metabolic studies should be carried out before starting treatment with valproic acid, in particular the determination of ammonemia (the presence of ammonia and its compounds in the blood) on an empty stomach and after meals.

Patients with systemic lupus erythematosus

Although it has been shown that during treatment with Depakine® Chronosphere™, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks 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 adjustments, to minimize this phenomenon.

Patients with diabetes mellitus

Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false positive results, because valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Use in pediatrics

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

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

Ethanol

Drinking alcohol is not recommended during treatment.

Impact on the ability to drive vehicles and operate machinery

Patients should be warned about the risk of developing drowsiness, especially in the case of combined anticonvulsant therapy or when combining the drug Depakine® Chronosphere™ with benzodiazepines.

Active ingredient

Valproic acid

Composition

1 pack
sodium valproate
333.3 mg
valproic acid
145.14 mg
in terms of sodium valproate
500 mg

Excipients:

solid paraffin – 506.31 mg,

glycerol dibehenate – 530.25 mg,

silicon dioxide colloidal aqueous*.

* added by splashing after the melt cooling process and expressed as a percentage of the amount of the other four components: 0.7% (approximate amount absorbed on the granules: 0.56%).

Pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia can be a risk factor for death for both the mother and the fetus.

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

Available clinical data confirm that children born to mothers with epilepsy who received valproic acid have an increased incidence of intrauterine developmental disorders of varying severity (neural tube malformations; craniofacial deformities; malformations of the limbs, cardiovascular system; as well as multiple intrauterine malformations affecting different organ systems) compared with the incidence of their occurrence when pregnant women take certain other antiepileptic drugs.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers who received valproic acid as monotherapy during pregnancy was 10.73%. Available data indicate a dose-dependent adverse effect of valproic acid on the fetus.

Based on available evidence, a causal relationship is suggested between prenatal exposure to valproic acid and the risk of developmental delays, particularly decreased verbal IQ, in children born to mothers with epilepsy who took valproic acid. Developmental delay is often combined with developmental defects and dysmorphism. However, in cases of developmental delay in such children, it is difficult to accurately establish a cause-and-effect relationship with valproic acid due to the possibility of simultaneous influence of other factors, such as low intelligence level of the mother or both parents; genetic, social factors, environmental factors; insufficient effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy.

The development of various autistic disorders has also been reported in children exposed to valproic acid in utero.

Both valproic acid monotherapy and combination therapy containing valproic acid are associated with adverse pregnancy outcomes, but combination antiepileptic therapy containing valproic acid is reported to be associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy (i.e., the risk of fetal impairment is lower when valproic acid is used as monotherapy).

Risk factors for fetal malformations are: a dose of more than 1000 mg/day (but a lower dose does not eliminate this risk) and a combination of valproic acid with other anticonvulsants.

In connection with the above, Depakin® Chronosphere™ should not be used during pregnancy and in women of childbearing age unless absolutely necessary. Its use is possible, for example, in situations where other antiepileptic drugs are ineffective or the patient cannot tolerate them.

The question of the need to use the drug Depakine® Chronosphere™ or the possibility of refusing its use should be decided before starting to use the drug or reconsidered if a woman receiving Depakine® Chronosphere™ is planning a pregnancy.

Women of childbearing age should use effective methods of contraception during treatment with Depakine® Chronosphere™. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy.

Before prescribing the drug, pregnancy should be excluded.

If a woman is planning a pregnancy or has been diagnosed with pregnancy, the need for treatment with valproic acid should be re-evaluated depending on the indication:

if bipolar disorder is indicated, discontinuation of treatment with valproic acid should be considered;
when epilepsy is indicated, the question of continuing treatment with valproic acid or its discontinuation is decided after reassessing the benefit-risk ratio.

If, after reassessing the balance of benefit and risk, a decision is made to continue treatment with Depakin® Chronosphere™ 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, it is preferable to use extended-release dosage forms of the drug.

Before pregnancy, folic acid (5 mg/day) should be added to antiepileptic treatment to reduce the risk of neural tube defects.

Constant special prenatal monitoring should be carried out to identify possible defects in the formation of the neural tube or other malformations of the fetus.

The development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy has been reported. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and/or decreased levels of coagulation factors. Fatal afibrinogenemia has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns born to mothers who received valproic acid during pregnancy, it is necessary to determine the number of platelets in the blood, plasma fibrinogen concentration, blood coagulation 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.

Excretion of valproic acid in breast milk is low, its concentration in breast milk is 1-10% of its plasma concentration. Based on literature data and limited clinical experience, breastfeeding can be planned during monotherapy with Depakine® Chronosphere™, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Fertility

In men, valproic acid can reduce sperm motility and cause male infertility. In addition, due to the possibility of developing undesirable effects on the endocrine system and genital organs in women (such as dysmenorrhea, amenorrhea, polycystic ovary syndrome, hyperandrogenism), a decrease in fertility in women is possible.

Use in children

Average daily dose for children, incl. infants (starting from 6 months of life) – 30 mg/kg.

Contraindications

acute hepatitis;
chronic hepatitis;
a history of severe liver disease (especially drug-induced hepatitis) in the patient and his close blood relatives;
severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;
severe dysfunction of the liver or pancreas;
hepatic porphyria;
hemorrhagic diathesis, thrombocytopenia;
combination with mefloquine;
combinations with St. John’s wort preparations;
children up to 6 months;
hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or any of the components of the drug.
With caution
with a history of liver and pancreas diseases;
during pregnancy;
for congenital enzymopathies;
with suppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
for renal failure (dose adjustment required);
with hypoproteinemia;
in patients receiving multiple anticonvulsants due to an increased risk of liver damage;
while taking 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);
while taking antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects);
while taking phenobarbital, primidine, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interactions at the level of metabolism or communication with plasma proteins, plasma concentrations may change or these drugs and/or valproic acid);
with simultaneous use of carbamazepine (the risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid);
with simultaneous use of topiramate (risk of developing encephalopathy).

Use for liver dysfunction

The drug is contraindicated in acute hepatitis, chronic hepatitis, in cases of severe hepatitis in the patient or in his family history, especially those caused by drugs, in severe liver dysfunction.

Use for renal impairment

The drug should be used with caution in case of renal failure.

Side Effects

Determination of the frequency of adverse reactions (WHO): very common (≥10%), common (≥1% and

From the hematopoietic system: often – anemia, thrombocytopenia; infrequently – pancytopenia, leukopenia. After discontinuation of the drug, the blood picture returns to normal. Rarely – disorders of bone marrow hematopoiesis (including isolated red blood cell aplasia, agranulocytosis), macrocytic anemia, macrocytosis.

From the blood coagulation system: often – bleeding and hemorrhage; rarely – a decrease in the content of blood coagulation factors (at least one), such as an increase in prothrombin time, an increase in APTT, an increase in thrombin time, an increase in MHO. The appearance of spontaneous bruising and bleeding requires discontinuation of the drug and clinical and laboratory examination.

From the nervous system: very often – tremor; often – 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; rarely – reversible dementia combined with reversible brain atrophy, cognitive disorders; frequency unknown – sedation, alertness.

*Stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or combined with an increase in seizures during treatment, and also decreased when the drug was discontinued or its dose was reduced. Most of these cases have been described during combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

From the mental side: infrequently – a state of confusion, aggressiveness, agitation, impaired attention (aggression, agitation, impaired attention were mainly observed in pediatric patients); rarely – behavioral disorders, psychomotor hyperactivity, learning disabilities (these adverse reactions were mainly observed in pediatric patients).

On the part of the hearing organ: often – deafness.

From the digestive system: very often – nausea (including may occur a few minutes after intravenous administration of the drug and spontaneously disappear after a few minutes); often – epigastric pain, diarrhea (which often occurs in some patients at the beginning of treatment, but, as a rule, disappears after a few days and does not require cessation of therapy); infrequently – pancreatitis, sometimes fatal.

From the liver and biliary tract: often – liver damage, which is 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 the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of liver transaminases in the blood; liver failure, in exceptional cases with death.

From the respiratory system: infrequently – pleural effusion.

From the urinary system: very rarely – enuresis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of damage to the renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.

From the immune system: often – hypersensitivity reactions, for example, urticaria; infrequently – angioedema; rarely – drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome), systemic lupus erythematosus.

From the musculoskeletal system: infrequently – a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakin® Chronosphere™ for a long time (the mechanism of influence of the drug Depakin® Chronosphere™ on bone metabolism has not been established).

From the skin and subcutaneous tissues: often – 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); uncommon – rash; rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; very rarely – hirsutism, acne.

From the endocrine system: infrequently – syndrome of inadequate secretion of ADH, hyperandrogenism; rarely – hypothyroidism.

On the metabolic side: often – hyponatremia, weight gain (since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely – hyperammonemia (cases of isolated and moderate hyperammonemia without changes in liver function tests and the need to discontinue treatment; cases 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.

From the side of blood vessels: infrequently – vasculitis.

From the reproductive system: often – dysmenorrhea; infrequently – amenorrhea; rarely – male infertility.

General disorders: uncommon – mild peripheral edema.

Interaction

Effect of valproic acid on other drugs

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines

Valproic acid may potentiate the effect of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; Therefore, when used concomitantly with valproic acid, careful medical monitoring and, if necessary, dose adjustment are recommended.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism), and therefore the sedative effect of the latter may develop, especially in children. Therefore, careful medical monitoring of the patient is recommended during the first 15 days of combination therapy with an immediate reduction in the dose of phenobarbital in case of sedation and, if necessary, determination of plasma concentrations of phenobarbital.

Primidon

Valproic acid increases plasma concentrations of primidone with increased side effects (such as sedation); with long-term treatment these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy, with dose adjustment of primidone if necessary.

Phenytoin

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

Carbamazepine

Clinical manifestations of carbamazepine toxicity have been reported with concomitant use of valproic acid and carbamazepine, as 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, if necessary, of the dose of carbamazepine.

Lamotrigine

Valproic acid slows down the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 2 times. This interaction may result in increased toxicity of lamotrigine, particularly severe skin reactions including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, dose adjustment (reduction) of lamotrigine are recommended.

Zidovudine

Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity.

Felbamate

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

Nimodipine (oral and, by extrapolation, solution for parenteral administration)

Increased hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition of nimodipine metabolism by valproic acid).

Effect of other drugs on valproic acid

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

Felbamate

When felbamate and valproic acid are combined, the clearance of valproic acid is reduced by 22-50% and, accordingly, plasma concentrations of valproic acid increase. Plasma concentrations of valproic acid should be monitored.

Mefloquine

Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.

Preparations of St. John’s wort

With the simultaneous use of valproic acid and St. John’s wort preparations, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

Drugs that are strongly bound to plasma proteins (acetylsalicylic acid)

In the case of simultaneous use of valproic acid and drugs that are strongly bound to plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free fraction of valproic acid.

Indirect anticoagulants

When valproic acid and indirect anticoagulants are used simultaneously, careful monitoring of the prothrombin index is required.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase with simultaneous use of cimetidine or erythromycin (as a result of slowing its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem)

A decrease in the concentration of valproic acid in the blood when used simultaneously with carbapenems, leading to a 60-100% decrease in the concentration of valproic acid in the blood within two days of joint therapy, which was sometimes combined with the occurrence of seizures. The simultaneous use of carbapenems should be avoided in patients with a selected dose of valproic acid due to their ability to rapidly and intensely reduce the concentration of valproic acid in the blood. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed.

Rifampicin

Rifampicin may decrease blood concentrations of valproic acid, resulting in loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of the drug while using rifampicin.

Other interactions

Topiramate

Concomitant use of valproic acid and topiramate has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs concomitantly should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.

Estrogen-progestogen drugs

Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen drugs in women using hormonal methods of contraception.

Ethanol and other potentially hepatotoxic drugs

When used simultaneously with valproic acid, the hepatotoxic effect of valproic acid may be enhanced.

Clonazepam

The simultaneous use of clonazepam with valproic acid can lead in isolated cases to increased severity of absence status.

Myelotoxic drugs

When used simultaneously with valproic acid, the risk of suppression of bone marrow hematopoiesis increases.

Overdose

Symptoms: clinical manifestations of acute massive overdose usually occur in the form of a coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, and metabolic acidosis. Cases of intracranial hypertension associated with cerebral edema have been described. With a massive overdose, death is possible, but usually the prognosis for an overdose is favorable.

Symptoms of overdose may vary, and seizures have been reported at very high plasma concentrations of valproic acid.

Treatment: emergency care in case of overdose in a hospital should be as follows – gastric lavage, which is effective within 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. Naloxone has been used with success in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

2 years

Manufacturer

Sanofi Winthrop Industries, France