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

Seizures, Epilepsy

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

• for treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaud syndrome;
• for treatment of partial epileptic seizures: Partial seizures with or without secondary generalization;
• treatment and prevention of bipolar affective disorder.

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

• for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaud syndrome;
• for the treatment of partial epileptic seizures: Partial seizures with or without secondary generalization;
• prevention of seizures in high fever, when such prevention is necessary.

.

Active ingredient

Valproic acid

Composition

Associates:

paraffin solid – 506.31 mg,

Glycerol dibegenate – 530.25 mg,

silicon dioxide colloidal aqueous*.

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

How to take, the dosage

Depakin^® Chronosphere^™ is a dosage form that is particularly good for treating children (if they can swallow soft foods) or adults with difficulty swallowing.

Depakin^® Chronosphere^™ is a prolonged-acting pellet that provides more even concentrations of valproic acid in the blood and therefore a more even distribution in the tissues overnight.

Bipolar affective disorder

The dose should be adjusted and monitored individually by the treating physician. The daily dose should be adjusted for the patient’s age and body weight. The recommended starting 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 desired therapeutic effect.

The recommended maintenance dose for the treatment of bipolar disorders is between 1000 mg and 2000 mg (converted to sodium valproate) per day. The dose should be adjusted according to the individual clinical response of the patient. An individually selected minimum clinically effective dose should be used to prevent manic states.

Epilepsy

In monotherapy, the initial daily dose is usually 5-10 mg (in terms of sodium valproate) per kg body weight, then it is increased by 5 mg/kg every 4-7 until the optimal dose to prevent the onset of epilepsy attacks is reached.

The average daily dose:

• for children (under 14 years), 30 mg/kg body weight;
• for adolescents 14-18 years, 25 mg/kg body weight;
• for adults and elderly patients (body weight 60 kg or more), 20 mg/kg body weight.

Accordingly, the daily doses shown below are recommended.

. * Dose in terms of milligrams of sodium valproate

The average daily dose may be increased under control of blood valproic acid concentrations.

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

While the daily dose is determined according to the patient’s age and body weight, a wide range of individual sensitivities to valproic acid should be taken into account.

There is no clear correlation between daily dose, serum valproic acid concentrations, and therapeutic effect. Therefore, the optimal dose of the drug should be chosen primarily on the basis of clinical response.

The determination of serum valproic acid concentrations may serve to supplement clinical monitoring if epilepsy is uncontrollable or the development of side effects is suspected. Doses providing serum valproic acid concentrations of 40-100 mg/L (300-700 μmol/L) are usually effective. When a higher serum concentrations are reasonably necessary, the balance between the expected benefits and the risk of side effects, especially dose-dependent side effects, should be carefully weighed, as increased side effects up to and including intoxication are expected at serum valproic acid concentrations above 100 mg/L. Therefore, the serum concentration determined before the first dose per day should not exceed 100 mg/L.

When switching from immediate-release or slow-release dosage forms of Depakin^®, which controlled epilepsy well, to Depakin^® Chronosphere^™ is recommended to maintain the same daily dose.

For patients who have previously taken antiepileptic drugs, conversion to Depakin^® Chronosphere^™ should be done gradually, reaching the optimal dose of the drug over approximately 2 weeks. The dose of a previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previous antiepileptic drug is withdrawn, it should be withdrawn gradually.

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

Because other antiepileptic drugs may reversibly induce microsomal liver enzymes, blood valproic acid concentrations should be monitored for 4-6 weeks after the last dose of these antiepileptic drugs and the daily dose of Depakine should be reduced as necessary (as the metabolism-inducing effects of these drugs decrease).sup>® Chronosphere^™.

While there are changes in valproic acid pharmacokinetics in elderly patients, they are of limited clinical significance and the valproic acid dose in elderly patients should be adjusted according to achieving seizure control of epilepsy.

. In patients with renal insufficiency and/or hypoproteinemia, the possibility of increasing the concentration of free (therapeutically active) fraction of valproic acid in blood serum should be considered, and if necessary, valproic acid dose should be reduced, Focusing on the clinical picture rather than the total serum valproic acid concentration (free fraction and plasma protein-bound fraction together) when adjusting the dose to avoid possible dosing errors.

Method of administration

The drug is taken orally.

Packets of Depakin^® Chronosphere^™ 100 mg are used only in children and infants.

Depakin^® Chronosphere^™ 1000 mg sachets are used in adults only.

The daily dose is recommended to be taken in 1 or 2 doses, preferably with meals. 1-dose use is possible in well-controlled epilepsy.

The drug Depakin^® Chronosphere^™ should be poured on the surface of soft food or drink, cold or room temperature (yogurt, orange juice, fruit puree, etc.).

Depakin^® Chronosphere^™ should not be used with hot food or drinks (such as soups, coffee, tea, etc.).

Depakine^® Chronosphere ^{should not be poured into a bottle with a teat, because the pellets may clog the hole in the teat.}

If Depakine^® Chronosphere^™ is taken with liquid, it is recommended to rinse the glass with a small amount of water and drink this water as the pellets may stick to the glass.

The mixture should always be swallowed immediately, without chewing. It should not be saved for later ingestion.

Given the duration of release of the active ingredient and the nature of the excipients, the inert matrix of the pellet is not absorbed from the digestive tract, but is excreted with the feces after complete release of the active ingredient.

Interaction

The effect of valproic acid on other drugs

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines

Valproic acid may potentiate the effects of other psychotropic drugs such as neuroleptics, MAO inhibitors, antidepressants and benzodiazepines; Therefore, close medical supervision and, if necessary, dose adjustments are recommended when they are used concomitantly with valproic acid.

Lithium preparations

Valproic acid has no effect on serum concentrations of lithium.

Phenobarbital

Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism); therefore, the latter may develop sedative effects, especially in children. Therefore, it is recommended that the patient be closely monitored during the first 15 days of combined therapy with immediate reduction in the dose of phenobarbital if sedation develops and, if necessary, determination of plasma concentrations of phenobarbital.

Primidone

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

Phenytoin

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

Carbamazepine

The occurrence of clinical manifestations of carbamazepine toxicity has been reported with concomitant use of valproic acid and carbamazepine because valproic acid may potentiate the toxic effects of carbamazepine. Close clinical monitoring of such patients is recommended, especially at the beginning of combination therapy with adjustment of carbamazepine dose if necessary.

Lamotrigine

Valproic acid slows down lamotrigine metabolism in the liver and increases lamotrigine elimination half-life by almost 2-fold. This interaction may lead to increased lamotrigine toxicity, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, correction (reduction) of lamotrigine dose is recommended.

Zidovudine

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

Felbamate

Valproic acid can decrease the average clearance of felbamate by 16%.

Nimodipine (oral and, by extrapolation, parenteral solution)

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

The effect of other drugs on valproic acid

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

Felbamate

When felbamate and valproic acid are combined, valproic acid clearance is decreased by 22-50% and, accordingly, valproic acid plasma concentrations are increased. Valproic acid plasma concentrations should be monitored.

Mefloquine

Mefloquine accelerates the metabolism of valproic acid and itself can cause seizures, so if they are used simultaneously, an epileptic seizure may occur.

Drugs of St. John’s wort

The simultaneous use of valproic acid and preparations of St. John’s wort may decrease the anticonvulsant effectiveness of valproic acid.

Drugs with strong binding to blood plasma proteins (acetylsalicylic acid)

In case of concomitant use of valproic acid and drugs with strong binding to blood plasma proteins (acetylsalicylic acid), concentration of free fraction of valproic acid may increase.

Indirect anticoagulants

When concomitant use of valproic acid and indirect anticoagulants, careful control of the prothrombin index is required.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase if cimetidine or erythromycin are used concomitantly (due to inhibition of its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem)

Decreased concentrations of valproic acid in the blood when used simultaneously with carbapenems, resulting in a 60-100% decrease in valproic acid blood concentrations over two days of combined therapy, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems in patients with dose-matched valproic acid should be avoided due to their ability to rapidly and intensively reduce valproic acid blood concentrations. If carbapenem treatment cannot be avoided, blood valproic acid concentrations should be monitored closely.

Rifampicin

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

Other interactions

Topiramate

The 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 symptoms of hyperammonemic encephalopathy.

Estrogen-progestogen drugs

Valproic acid does not have the ability to induce liver enzymes, and therefore valproic acid does not decrease the effectiveness of estrogen-progestogen drugs in women who use hormonal contraception.

Ethanol and other potentially hepatotoxic drugs

If used concomitantly with valproic acid, the hepatotoxic effect of valproic acid may be increased.

Clonazepam

The concomitant use of clonazepam with valproic acid may lead in single cases to increased severity of absences.

Myelotoxic drugs

Concomitant use with valproic acid increases the risk of inhibition of medullary hematopoiesis.

Special Instructions

Hepatic function tests should be performed before initiating Depakine^® Chronosphere and periodically during the first 6 months of treatment, especially in patients at risk for liver damage.

As with most antiepileptic drugs, valproic acid may cause a slight increase in hepatic enzyme activity, especially at the beginning of treatment, which is without clinical manifestations and is transient. In these patients more detailed investigation of biological parameters, including prothrombin index, is necessary and dosage adjustment and, if necessary, repeated clinical and laboratory examination may be required.

Before therapy or surgery, a hematologic blood count (determine the white blood cell count, including platelet count; bleeding time and coagulogram) is recommended in case of spontaneous subcutaneous hematomas or bleeding.

Severe liver damage

Clinical experience shows that patients at risk are patients receiving multiple antiepileptic drugs at the same time, children less than 3 years old with severe seizures, especially against a background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients taking salicylates simultaneously (because they are metabolized by salicylates).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 with increasing age of the patient. In most cases, liver damage occurs during the first 6 months of treatment, most often between weeks 2 and 12, and usually when valproic acid is used as part of combined antiepileptic therapy.

In order to make an early diagnosis of liver damage, clinical follow-up of patients is mandatory. In particular, attention should be paid to the occurrence of the following symptoms, which may precede the occurrence of jaundice, especially in patients at risk:

• unspecific symptoms, especially those that start suddenly, such as asthenia, anorexia, lethargy, somnolence, which are sometimes accompanied by recurrent vomiting and abdominal pain;
• resumption of seizures in patients with epilepsy.

Patients or family members (if using the drug in children) should be warned to immediately report the occurrence of any of these symptoms to the treating physician. If these symptoms occur, patients should immediately undergo clinical examination and laboratory testing of liver function parameters.

Liver function tests should be performed before starting treatment and periodically thereafter during the first 6 months of treatment. Among routine investigations, the most informative are those reflecting the state of protein-synthetic liver function, especially the prothrombin index. Confirmation of abnormal prothrombin index, especially in combination with abnormal other laboratory parameters (significant decrease of fibrinogen and clotting factors, increase of bilirubin concentration and elevated transaminase activity), as well as appearance of other symptoms indicating liver damage, requires discontinuation of therapy.

Pancreatitis

Children are at increased risk of pancreatitis, the risk decreases with increasing age of the child. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for 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, particularly if pancreatic enzyme activity is elevated 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. The mechanism of this effect is unknown. Therefore, patients receiving Depakine^® Chronosphere^™ should be monitored constantly for suicidal thoughts or attempts, and if they occur, appropriate treatment should be given. Patients and caregivers are advised to see a physician immediately if a patient has suicidal thoughts or attempts.

Renal failure

The dose of valproic acid may need to be reduced due to increased concentrations of its free fraction in the blood serum. If plasma concentrations of valproic acid cannot be monitored, the dose should be adjusted based on clinical observation of the patient.

Carbamide cycle enzyme insufficiency

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

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

Patients with systemic lupus erythematosus

While treatment with Depakine^® Chronosphere^™ has been shownimmune system dysfunction is exceptionally rare, the potential benefit of its use must be compared to the potential risks of prescribing the drug in patients with systemic lupus erythematosus.

Body weight gain

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

Patients with diabetes mellitus

With the potential for adverse effects of valproic acid on the pancreas, blood glucose concentrations should be monitored closely when using the drug in patients with diabetes mellitus. When testing urine for ketone bodies in diabetic patients, false-positive results are possible because valproic acid is excreted by the kidneys, partially as ketone bodies.

Pediatric use

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

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

Ethanol

The use of alcohol is not recommended during treatment.

Impact on the ability to drive and operate machinery

Patients should be warned. Patients should be advised of the risk of somnolence, especially when combined anticonvulsant therapy or when Depakin^® Chronosphere^™ is combined with benzodiazepines.

Contraindications

• acute hepatitis;
• chronic hepatitis;
• severe liver disease (especially drug-induced hepatitis) in the history of the patient and his or her close blood relatives;
• severe hepatic impairment or lethal outcome of valproic acid use
• severe liver disease or severe liver impairment or lethal impairment of the patient’s close blood relatives
• severe hepatic impairment with fatal outcome when valproic acid is used in the patient’s close blood relatives;
• severe hepatic or pancreatic dysfunction;
• hepatic porphyria;
• hemorrhagic diathesis, thrombocytopenia;
• combinations with preparations of St. John’s wort;
children under 6 months;
• High sensitivity to sodium valproate, valproic acid, valproate seminatrium, valpromide, or any of the drug’s components.
• With caution
• in a history of liver and pancreatic disease;
• in pregnancy;
• in congenital fermentopathies;
• in case of renal insufficiency (dose adjustment is required);
• in case of hypoproteinemia;
• patients receiving several antisuppressantsin patients receiving multiple anticonvulsants due to increased risk of liver damage;
• in patients receiving multiple anticonvulsantsconcomitant use of drugs that induce seizures or decrease the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of triggering seizures);
• concomitantly taking neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (possible potentiation of their effects);
• Concomitant use of carbamazepine (risk of potentiation of the toxic effects of carbamazepine and decreased plasma concentrations of valproic acid);
• Concomitant use of topiramate (risk of encephalopathy).

Application in liver function disorders

The drug is contraindicated in acute hepatitis, chronic hepatitis, in cases of severe hepatitis in the patient or in the patient’s family history, especially caused by medications, in severe liver function disorders.

The use in renal function disorders

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

Side effects

Frequency of adverse reactions (WHO): very common (≥10%), common (≥1% and

Hematopoietic system: common – anemia, thrombocytopenia; infrequent – pancytopenia, leukopenia. After discontinuation of the drug the blood picture returns to normal. Rarely – disorders of medullary hematopoiesis (including isolated aplasia of red blood cells, agranulocytosis), macrocytic anemia, macrocytosis.

With the clotting system: often – bleeding and hemorrhage; rarely – decrease of blood clotting factors (at least one), such as increased prothrombin time, increased chTB, increased thrombin time, increased MHO. The occurrence of spontaneous bruising and bleeding require discontinuation of the drug and clinical and laboratory examination.

Nervous system disorders: very common – tremor; common – extrapyramidal disorders, stupor*, somnolence, seizures*, memory disturbances, headache, nystagmus, dizziness (may occur a few minutes after IV injection and disappear spontaneously within a few minutes); infrequent – coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia; rare – reversible dementia combined with reversible brain atrophy, cognitive disorders; frequency unknown – sedation, alertness.

*Stupor and lethargy sometimes resulted in transient coma/encephalopathy and were either isolated or combined with increased seizures in the background of treatment, and decreased when the drug was withdrawn or when the dose was reduced. Most of these cases have been described with combination therapy, especially when phenobarbital or topiramate were used concomitantly or after a sharp increase in the valproic acid dose.

Psychiatric disorders: infrequent – mental confusion, aggression, agitation, attention deficit (aggression, agitation, attention deficit were mostly observed in pediatric patients); rarely – behavioral disorders, psychomotor hyperactivity, learning disabilities (these adverse reactions were mostly observed in pediatric patients).

Hearing organ: often – deafness.

Gastrointestinal system disorders: very common – nausea (including may occur a few minutes after IV administration and disappear spontaneously after a few minutes); common – epigastric pain, diarrhea (which often occurs in some patients at the beginning of treatment, but usually disappears after a few days and does not require discontinuing therapy); infrequent – pancreatitis, sometimes with lethal outcome.

Hepatic and biliary tract disorders: often – liver lesions accompanied by abnormal liver function tests, such as prothrombin index decrease, especially in combination with significant decreasing of fibrinogen and clotting factors, increasing of bilirubin concentration and increasing of liver transaminases activity in blood; liver failure, exceptionally with fatal outcome.

Respiratory system disorders: infrequent pleural effusion.

Urinary system disorders: very rarely – enuresis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of renal tubules damage with disorders of tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of which is still unknown.

Immune system disorders: frequent – hypersensitivity reactions, such as urticaria; infrequent – angioedema; rare – syndrome of drug rash with eosinophilia and systemic symptoms (DRESS syndrome), systemic lupus erythematosus.

Muscular system disorders: Infrequent – decreased bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakin^® Chronosphere™ for a long time (the mechanism of the effect of Depakin^® Chronosphere™ on bone metabolism is not established).

Skin and subcutaneous tissue side effects: Frequent, transient or dose-dependent alopecia (including androgenic alopecia amid developed hyperandrogenism, polycystic ovarian disease, and alopecia amid developed hypothyroidism); infrequent, rash; rare, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; very rare, hirsutism, acne.

Endocrine system: infrequent – syndrome of inadequate secretion of ADH, hyperandrogenism; rarely – hypothyroidism.

Mechanisms: often – hyponatremia, weight gain (because weight gain is a contributing factor in the development of polycystic ovary syndrome); rarely – hyperammonemia (cases of isolated and moderate hyperammonemia without changes in liver function parameters and the need to stop the treatment; cases of hyperammonemia, accompanied with the appearance of neurological symptoms, including the development of encephalopathy.(e.g., development of encephalopathy, vomiting, ataxia), which required discontinuation of valproic acid and additional evaluation.

Vascular disorders: infrequent – vasculitis.

Perior genital system disorders: frequently – dysmenorrhea; infrequently – amenorrhea; rarely – male infertility.

General disorders: infrequent – non-serious peripheral edema.

Overdose

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

The symptoms of overdose can vary, and seizures have been reported in very high plasma concentrations of valproic acid.

Treatment: the emergency treatment for overdose in hospital should be as follows – gastric lavage, which is effective within 10-12 h after taking the drug, monitoring of the cardiovascular and respiratory system and maintaining effective diuresis. Naloxone has been used successfully in individual cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Pregnancy use

In pregnancy, the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia may be a risk factor for fatal outcome for both mother and fetus.

In experimental studies of reproductive toxicity conducted in mice, rats and rabbits, teratogenic effects of valproic acid have been shown.

The available clinical data confirm that in children born of mothers with epilepsy who received valproic acid there is an increased incidence of intrauterine abnormalities of varying severity (neural tube malformations; craniofacial deformities; limb malformations; cardiovascular malformations; and multiple fetal malformations involving multiple organ systems) compared to their rates with some other antiepileptic drugs in pregnant women.

The data from a meta-analysis including registry and cohort studies showed a 10.73% incidence of birth defects in children born to mothers who received valproic acid as monotherapy during pregnancy. Evidence suggests a dose-dependent adverse effect of valproic acid on the fetus.

The evidence suggests a causal relationship between intrauterine exposure to valproic acid and the risk of developmental delay, particularly reduced verbal IQ, in children born to mothers with epilepsy who have taken valproic acid. Developmental delay is often combined with malformations and phenomena of dysmorphism. However, in cases of developmental delay in these children, it is difficult to accurately determine a causal relationship to valproic acid intake because of the possible simultaneous effects of other factors, such as low intelligence of the mother or both parents; genetic, social, environmental factors; and inadequate treatment to prevent epileptic seizures in the mother during pregnancy.

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

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

The risk factors for fetal malformations are: a dose greater than 1000 mg/day (but a lower dose does not eliminate this risk) and combining valproic acid with other anticonvulsant medications.

In view of the above, Depakine^® Chronosphere^™ should not be used in 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 whether Depakine^® Chronosphere^™ should be used or the possibility of not using it should be decided before starting the drug or reconsidered if a woman who is receiving Depakine^® Chronosphere^™ is planning a pregnancy.

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

Pregnancy should be ruled out before prescribing the drug.

If a woman is planning to become pregnant or has been diagnosed with a pregnancy, the need for valproic acid treatment should be reassessed based on the indication:

• when bipolar disorders are indicated, discontinuation of valproic acid treatment should be considered;
• when epilepsy is indicated, continuation or withdrawal of valproic acid treatment is decided after reassessing the benefit-risk ratio.

If a decision is made to continue treatment with Depakin^® Chronosphere in pregnancy after reassessment of the benefit-risk ratio, it is recommended that it be used at the lowest effective daily dose divided into multiple doses. It should be noted that in pregnancy, the use of sustained-release dosage forms of the drug is preferable.

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

Prenatal special ongoing prenatal monitoring should be performed to detect possible neural tube defects or other fetal malformations.

Hemorrhagic syndrome has been reported in single cases in newborns whose mothers have taken valproic acid during pregnancy. This hemorrhagic syndrome, is associated with thrombocytopenia, hypofibrinogenemia and/or decreased clotting factors. The development of afibrinogenemia with a fatal outcome has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

In newborns born to mothers who received valproic acid during pregnancy, blood platelet counts, plasma fibrinogen concentration, clotting factors, and coagulograms should therefore always be determined.

Hypoglycemia has been reported in infants whose mothers took valproic acid in the third trimester of pregnancy.

Hypothyroidism has been reported in infants whose mothers took valproic acid during pregnancy.

The excretion of valproic acid in breast milk is low; its concentration in breast milk is 1-10% of its concentration in plasma. Taking into account the data of literature and a little clinical experience, it is possible to plan breast feeding in monotherapy with Depakine^® Chronosphere^™, but the side effect profile of this medicine, especially hematologic disorders caused by it, should be taken into consideration.

Fertility

In men, valproic acid may decrease sperm motility and cause male infertility. In addition, due to the possibility of adverse effects on the endocrine system and genitals in women (such as dysmenorrhea, amenorrhea, polycystic ovaries, hyperandrogenism), women may have reduced fertility.

Performance in children

The average daily dose for children, including infants (from the 6th month of life) is 30 mg/kg.

Similarities

Convullex, Depakine, Depakine 300 enteric, Valparin XP, Encorat chrono