DEPAKENE CHRONOSPHERE RETARD GRANULES 1G

Dosage form

Granules of prolonged action

Composition

1 sachet contains sodium valproate 666.6 mg, valproic acid 290.27 mg (total, in terms of sodium valproate - 1000 mg)

Packing

30 pieces

Mechanism of action

Depakene Chronosphere has anti-epileptic effect.

Indications and usage

In adults: as monotherapy or in combination with other antiepileptic drugs in the following conditions:
treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoconic, atonic, Lennox-Gastaut syndrome);
treatment of partial epileptic seizures (partial seizures with or without secondary generalization);
treatment and prevention of bipolar affective disorders.

Contraindications

hypersensitivity to valproate or to any of the components of Depakene Chronosphere;
acute hepatitis;
chronic hepatitis;
cases of severe hepatitis in a patient or in his family history, especially caused by drugs, as well as severe dysfunction of the liver or pancreas;
porphyria;
hemorrhagic diathesis, thrombocytopenia;
combination with mefloquine;
combination with hunter;
this drug is not recommended for use in combination with lamotrigine;
children up to 6 months.
Carefully:
a history of liver and pancreas diseases;
pregnancy;
congenital fermentopathies;
oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
renal failure;
hypoproteinemia.

Pregnancy and Breastfeeding

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

The risk associated with valproate

According to the available data, valproate mainly causes impaired development of the neural tube: myelomeningocele, spina bifida (1-2%).Several cases of facial dysmorphism and malformations of the limbs (especially shortening of the limbs), as well as malformations of the cardiovascular system, have been described.

The risk of malformations is higher with combination antiepileptic therapy than with monotherapy with sodium valproate. However, it is quite difficult to establish a causal relationship between fetal malformations and other factors (genetic, social, environmental factors, etc.).

In connection with the above:

Use of the drug during pregnancy can be prescribed by a doctor only when the expected benefit for a pregnant woman exceeds the possible risk to the fetus.

When pregnancy should not be interrupted by antiepileptic treatment with valproate, if it is effective. In such cases, monotherapy is recommended; the minimum effective daily dose of which should be divided into several doses per day.

In addition to antiepileptic therapy, folic acid preparations can be added (at a dose of 5 mg /), since they minimize the risk of neural tube defects. However, regardless of whether the patient receives folates or not, in any case, a special antenatal monitoring of the neural tube or other malformations should be carried out.

Newborn Risk

Valproate can cause hemorrhagic syndrome in newborns. In the case of valproate, this syndrome appears to be associated with hypofibrinogenemia. Cases of the development of afibrinogenemia with fatal outcome were noted. Perhaps this is due to a decrease in a number of coagulation factors.

In a newborn, it is imperative to determine the number of platelets, plasma fibrinogen levels and blood coagulation factors.

Lactation

Excretion of valproate in milk is low, with a concentration between 1% and 10% of the serum level of the drug.

According to the literature and a small clinical experience, mothers can plan breastfeeding in the course of treatment with this drug in the form of monotherapy, taking into account its safety profile (especially hematological disorders).

Dosage and administration

The initial daily dose is usually 10-15 mg / kg, then it is increased by 5-10 mg / kg per week, until the optimum dose is reached. The average daily dose is 20-30 mg / kg.It is possible to increase the dose of the drug with careful monitoring of the patient's condition, if epilepsy is uncontrollable with the use of average daily doses. The average daily dose for infants (from the 6th month of life) and children is 30 mg / kg / day; for adolescents, 25 mg / kg; for adults, 20 mg / kg.

Adverse reactions

On the part of the digestive system: often (at the beginning of treatment) - nausea, vomiting, gastralgia, diarrhea (usually disappear within a few days and drug withdrawal is not required); <0.01% - pancreatitis, sometimes with a fatal outcome (early termination of treatment is required); from> 0.01% to <0.1% - abnormal liver function.

From the hemopoietic system: often - dose-dependent thrombocytopenia; from> 0.01% to <0.1% - inhibition of bone marrow hematopoiesis, including anemia, leukopenia or pancytopenia.

From the urinary system: <0.01% - enuresis; in isolated cases - reversible Fanconi syndrome (genesis is not clear).

Allergic reactions: skin rash, urticaria, vasculitis; <0.01% - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

On the part of laboratory parameters: often (especially with polytherapy) - isolated and moderate hyperammonemia without changes in the analysis of the functions of the liver (drug withdrawal is not required); also described hyperammonemia associated with neurological symptoms (which requires additional examination); possible increase in liver transaminase activity; in some cases (especially when using high-dose valproate) - a decrease in fibrinogen level or an increase in bleeding time, usually without clinical manifestations; <0.01% - hyponatremia.

On the part of the endocrine system: in isolated cases - gynecomastia, amenorrhea, dysmenorrhea. With an increase in body weight, which is a risk factor for the development of polycystic ovarian syndrome, control of the condition is necessary.

Other: possible hair loss; from> 0.01% to <0.1% - reversible or irreversible hearing loss; <0.01% - mild peripheral edema; weight gain.

Special notes

The prescription of an antiepileptic drug may occasionally be accompanied by the resumption or development of new seizures in a patient, regardless of spontaneous changes in the course of the disease, observed in certain epileptic conditions.

In relation to valproate, this primarily concerns the combined treatment of epilepsy or pharmacokinetic interactions, toxicity (hepato-or encephalopathy) and overdose.

Since sodium valproate is converted into valproic acid in the body, it should not be combined with other medicinal substances that undergo the same type of biotransformation in order to prevent an overdose of valproic acid.

Liver failure

High-risk groups are infants and children under 3 years of age with severe epilepsy, especially epilepsy associated with brain damage, mental retardation and / or congenital metabolic or degenerative diseases. Over the age of 3 years, the frequency of such complications decreases significantly and gradually decreases with age.

In most cases, abnormal liver function was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combined antiepileptic treatment.

Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk.

- on the one hand, non-specific general symptoms that usually appear suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by recurring vomiting and abdominal pain;

- on the other hand, relapse of epileptic seizures on the background of antiepileptic therapy.

It is recommended to inform the patient, and if this is a child, then his family, that with the development of such clinical symptoms, you should immediately consult a doctor. In addition to clinical examination, an immediate analysis of liver function should be carried out.

During the first 6 months of treatment, liver function should be checked periodically. Among the classic tests, the most important are tests that reflect protein synthesis by the liver, and especially the prothrombin index. In case of detection of abnormally low levels of prothrombin, a significant decrease in the level of fibrinogen and coagulation factors, an increase in the level of bilirubin and hepatic transaminases - treatment with the drug Depakin®Chronosphere™ should be suspended.It is also necessary to interrupt treatment with salicylates, if they were included in the treatment regimen, since they share the same metabolic pathway with valproate.

Pancreatitis

In rare cases, severe forms of pancreatitis have been noted, sometimes with a fatal outcome. These cases were observed regardless of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of the patients.

Hepatic insufficiency with pancreatitis increases the risk of death. It is necessary to determine liver function before starting treatment and periodically during the first 6 months of treatment, especially for patients at risk.

It should be emphasized that with treatment as a drug Depakin® Chronosphere™, and other antiepileptic drugs, there may be a slight, isolated and temporary increase in transaminase levels, especially at the beginning of treatment, in the absence of any clinical symptoms.

In this case, it is recommended to conduct a more complete laboratory examination (including, in particular, the determination of the prothrombin index) in order to revise the dosage, if necessary, and repeat the tests depending on changes in parameters.

Before starting therapy or surgery, in the case of hematomas or spontaneous bleeding, it is recommended to carry out a hematological blood test (determine the blood count, including platelet count, bleeding time and coagulation tests).

In patients with renal insufficiency, it is recommended to take into account the increased concentration of free form of valproic acid in serum and reduce the dose.

In acute abdominal pain syndrome and gastrointestinal symptoms such as nausea, vomiting and / or anorexia, you must be able to recognize pancreatitis and, with an increased level of pancreatic enzymes, cancel the drug, taking alternative therapeutic measures.

Sodium valproate is not recommended for patients with a deficiency of carbamide cycle enzymes. In such patients, several cases of hyperammonemia, accompanied by stupor and / or coma, have been described.

Although it has been shown that during treatment with Depakin Chronosphere, dysfunctions of the immune system are extremely rare, the potential benefits of its use should be compared with the potential risk of administering the drug to patients with systemic lupus erythematosus.

Patients should be warned about the risk of weight gain at the beginning of treatment, and it is necessary to take measures, mainly dietary, to reduce this phenomenon to a minimum.

Contraindications:

Meflokhin

The risk of epileptic seizures in patients with epilepsy due to increased metabolism of valproic acid and the convulsive effect of mefloquine.

Hypericum

Danger of reducing the concentration of valproic acid in the blood plasma.

Not recommended combinations:

Lamotrigine

Increased risk of severe skin reactions (toxic epidermal necrolysis). In addition, increasing the concentration of lamotrigine in plasma (its metabolism in the liver is slowed by sodium valproate). If a combination is necessary, careful clinical and laboratory monitoring is required.

Combinations requiring special precautions

Carbamazepine

Increase in plasma active concentration of Carbamazepine with signs of overdose. In addition, a decrease in plasma valproic acid concentrations associated with an increase in hepatic metabolism due to the action of carbamazepine.

It is recommended: clinical observation, determination of drug concentrations in plasma and revision of their dosage, especially at the beginning of treatment.

Carbapenems, monobactams:meropenem, panipenem, and, by extrapolation, aztreonam, imipenem.

Danger of seizures due to a decrease in serum valproic acid concentrations.

It is recommended: clinical observation, determination of drug concentrations in plasma and, possibly, revision of valproic acid dosage during treatment with antibacterial agent and after its withdrawal.

Felbamate

Increased serum valproic acid concentration, with an overdose hazard.

Clinical control, laboratory control and, possibly, revision of the dosage of valproic acid during the treatment with felbamate and after its discontinuation.

Phenobarbital, primidone

Increased plasma concentrations of phenobarbital or primidone with signs of overdose, usually in children. In addition, a decrease in plasma valproic acid concentration is associated with increased hepatic metabolism by phenobarbital or primidone.

Clinical monitoring during the first 15 days of combined treatment with an immediate decrease in the dose of phenobarbital or primidone when signs of sedation appear; determining the level of both anticonvulsants in the blood.

Phenytoin

Changes in the concentration of phenytoin in plasma, the risk of reducing the concentration of valproic acid, associated with an increase in hepatic metabolism of valproic acid under the influence of phenytoin.

Clinical monitoring, monitoring of plasma concentrations of both drugs, and, if necessary, correction of their doses are recommended.

Changes in the concentration of phenytoin in plasma, the risk of reducing the concentration of valproic acid, associated with increased liver metabolism of the last phenytoin.

Clinical monitoring, determination of the level of two antiepileptic drugs in plasma, and possibly modification of their doses, are recommended.

Topiramate

The risk of hyperammonemia or encephalopathy, usually attributed to valproic acid, when combined with topiramate .

Enhanced clinical and laboratory control during the first month of treatment and in the event of ammonium symptoms.

Neuroleptics, MAO inhibitors , antidepressants, benzodiazepines

Valproate potentiates the action of psychotropic drugs such as antipsychotics (neuroleptics), MAO inhibitors, antidepressants and benzodiazepines.

Clinical monitoring and, if necessary, dose adjustment is recommended.

Cimetidine and Erythromycin

Serum levels of valproate increase.

Zidovudine

Valproate can increase the concentration of zidovudine in the plasma, which leads to increased toxicity of the latter.

Combinations to be taken into account

Nimodipine (oral, and, by extrapolation, parenteral)

Strengthening the hypotensive effect of nimodipine in connection with an increase in its concentration in plasma (a decrease in the metabolism of valproic acid).

Acetylsalicylic acid

With the simultaneous use of valproate and Acetylsalicylic acid , there is an increase in the effects of valproate, due to an increase in the concentration of valproate in serum.

Vitamin K Antagonists

Careful monitoring of the prothrombin index is required when co-prescribed with vitamin K-dependent anticoagulants.

Other forms of interaction

Oral contraceptives

Valproate does not have an enzyme-inducing effect and therefore does not affect estrogen-progesterone in women who use hormonal contraceptives.

Symptoms: in acute massive overdose, a coma with muscular hypotonia, hyporeflexia, miosis, respiratory depression, and metabolic acidosis is usually observed. Cases of intracranial hypertension associated with cerebral edema are described.

Treatment: emergency care in the hospital - gastric lavage, which is effective for 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. In very severe cases, dialysis is performed. Usually, the prognosis for overdose is favorable, but several deaths have been described.

In the dark place at a temperature of no higher than 25 ° C.

Depakene Chronosphere