Depakine chronosphere

Active material: Valproic Acid
When ATH: N03AG01
CCF: Anticonvulsants
ICD-10 codes (testimony): F31, G40, R25.2
When CSF: 02.05.05
Manufacturer: SANOFI-AVENTIS France (France)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Granules of prolonged action almost white or slightly yellowish, waxy, easily bulk, without formation of agglomerates.

Excipients: solid paraffin, glycerol dibehenate, aqueous colloidal silica.

Sandwich bags (30) – packs cardboard.
Sandwich bags (50) – packs cardboard.

Granules of prolonged action almost white or slightly yellowish, waxy, easily bulk, without formation of agglomerates.

Excipients: solid paraffin, glycerol dibehenate, aqueous colloidal silica.

Sandwich bags (30) – packs cardboard.
Sandwich bags (50) – packs cardboard.

Granules of prolonged action almost white or slightly yellowish, waxy, easily bulk, without formation of agglomerates.

Excipients: solid paraffin, glycerol dibehenate, aqueous colloidal silica.

Sandwich bags (30) – packs cardboard.
Sandwich bags (50) – packs cardboard.

Granules of prolonged action almost white or slightly yellowish, waxy, easily bulk, without formation of agglomerates.

Excipients: solid paraffin, glycerol dibehenate, aqueous colloidal silica.

Sandwich bags (30) – packs cardboard.
Sandwich bags (50) – packs cardboard.

Granules of prolonged action almost white or slightly yellowish, waxy, easily bulk, without formation of agglomerates.

Excipients: solid paraffin, glycerol dibehenate, aqueous colloidal silica.

Sandwich bags (30) – packs cardboard.
Sandwich bags (50) – packs cardboard.

Pharmacological action

Anticonvulsants, It has a central muscle relaxant and sedative effect.

Exhibits protivojepilepticheskuju activity in different types of epilepsy. The main mechanism of action, apparently, associated with exposure to valproeva acid on GABA-jergicheskuju system: increases the concentration of GABA in the CNS and activates the GABA-jergicheskuju transfer.

Depakin^® Hronosfera is a prolonged action granules, to ensure more uniform concentrations of the drug within 24 hours.

Pharmacokinetics

Absorption

The bioavailability of oral valproate use close to 100%. Eating does not affect the PK profile.

For the development of therapeutic effect requires a minimum concentration in serum 40-50 mg / l, the fluctuating within 40-100 mg / l. At concentrations of more than 200 mg/l dose reduction is required.

Distribution

Plasma protein binding is high, dose-dependent and nasyshhaemoe. C_ss plasma is to 3-4 Day.

Valproate penetrates cerebrospinal fluid and the brain.

Metabolism

Valproate not induces cytochrome P450 system Isoenzymes: Unlike most other antiepileptic drugs, valproate does not affect the degree of their biotransformation, and other substances, such as a combination of estrogen and progestagen and vitamin k antagonists.

Deduction

T_1/2 is 15-17 no. Valproate is predominantly presented with urine in the form of glucuronide.

Pharmacokinetics in special clinical situations

Valproate can molecule dializirovat'sja, but hemodialysis will only affect the free-form blood valproate (about 10%).

Compared to valproate immediate-release form in equivalent doses Depakin^® Hronosfera is characterized by the following: extended absorption; identical biodostupnostthew; C_max drug plasma achieved after approx. 7 hours after ingestion; total (C)_max and the concentration of free plasma valproate form below (decrease in C_max is about 25%, but with the relatively stable plateau phase from 4 to 14 h after administration); as a result of the decline in the concentration of valproeva acid more constant and more evenly distributed during the day (after application 2 times per day the same dose, range of fluctuations in plasma concentration decreases by half); more linear correlation between doses and concentration of plasma (common and free forms).

Testimony

In Adult (as monotherapy or in combination with other antiepileptic means):

— to treat Generalized epileptic seizures: clonic, tonic, tonico-clauniceskie, absences, myoclonic, atonic; Lennox-Gastaut syndrome;

— to treat complex partial epileptic seizures: partial seizures with secondary generalization or without it;

— treatment and prophylaxis of bipolar affective disorder.

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

— to treat Generalized epileptic seizures: clonic, tonic, tonico-clauniceskie, absences, miokonicheskie, atonic; Lennox-Gastaut syndrome;

— to treat complex partial epileptic seizures: partial seizures with secondary generalization or without it;

-Prevention of convulsions at high temperature, When such prophylaxis is needed.

Dosage regimen

Depakin^® Hronosfera is a drug form, which is especially suitable for treatment of children (If they are able to swallow soft food) or adults with difficulty swallowing.

The drug is prescribed inside. Daily dose is determined depending on the age and body mass index patient, should also take into account a wide range of individual sensitivity to valproatu.

The initial daily dose is 10-15 mg / kg body weight, then it increased at 5-10 mg/kg/week to achieve optimal dose.

The average daily dose is 20-30 mg / kg. In the absence of adequate protivojepilepticheskogo effect dose can be increased under the close supervision of the condition of the patient.

Average daily dose Adult is 20 mg / kg; to Adolescents – 25 mg / kg; to children, incl. infants (beginning with 6 months of life) – 30 mg / kg.

* dose in mg sodium valproate in terms

In patients older dose should be installed in accordance with their clinical condition.

Installed a good correlation between daily dose, the concentration of drug in the blood serum and therapeutic effect: dose should be established primarily on the basis of clinical response. Determination of the concentration of valproic acid in the plasma could serve as a complement to clinical observation, If epilepsy is uncontrollable or suspected side effects. The range of therapeutic effectiveness is usually 40-100 mg / l (300-700 mmol / l).

At transition with Depakina^® in the form of immediate-release or delayed-release of valproate, to ensure that control of the disease, to Depakin^® Hronosfera, We recommend that you keep the daily dose when well controlled epilepsy.

To patients, taking earlier other antiepileptic means, their replacement on Depakin^® Hronosfera should be gradually, reaching the optimal dose of valproate for approximately 2 weeks. Depending on the condition of the patient decreases dose previous drug.

To patients, do not take other antiepileptic drugs, the dose should be increased through 2-3 day, so as, to achieve optimal dose for about a week.

At need a combination drug Depakin^® Hronosfera with other antiepileptic means should be introduced gradually.

Terms of use of the drug

Depakin^® Hronosfera bags on 100 mg used only in children and infants. Depakin^® Hronosfera bags on 1 g use only in adults.

Daily dose recommended 1 or 2 admission, preferably at mealtimes. Application in 1 admission is possible with well controlled epilepsy.

Paketika contents should be poured on the surface of soft food or beverages cold or room temperature (incl. yogurt, Orange juice, fruit puree). If Depakin^® Hronosfera is a liquid, It is recommended to rinse the glass with a small amount of water and drink this water, tk. granules can stick to glass. Blend always should be swallowed immediately, without chewing. It should not be saved for later admission.

Drug Depakin^® Hronosfera cannot be used with hot food or drinks (such as soups, coffee, tea, etc.). Drug Depakin^® Hronosfera you cannot fill the bottle with teat, tk. granules can clog the hole nipples.

Given the length of the process of release of the active substance and excipients nature, inert matrix granules are not absorbed from the digestive tract; It is excreted with the feces after full release of the active substance.

Side effect

CNS: from > 0.1% to <1% – ataxia; < 0.01% – cognitive impairment with progressive onset (give a complete picture of the dementia syndrome and reversible over several weeks or months); in some cases (increasingly in complex treatment, especially with phenobarbital, or after skyrocketing dose valproate) – stupor or lethargy, sometimes caused by transient coma (encephalopathy), these cases were isolated or associated with paradoxical increased frequency of seizures during therapy, their frequency declined in case of suspension of treatment or at the same time reducing the dose of the drug; in a few cases – reversible Parkinsonism; possible headache, easy postural tremor and sleepiness.

From the digestive system: often (at the beginning of treatment) – nausea, vomiting, gastralgia, diarrhea (usually disappear within a few days and do not require removal products); < 0.01% – pancreatitis, sometimes with fatal consequences (requires early discontinuation of treatment); from > 0.01% to < 0.1% – abnormal liver function.

From the hematopoietic system: often – dozozawisimaya thrombocytopenia; from > 0.01% to < 0.1% – suppression of bone marrow hematopoiesis, including anaemia, leukopenia or pancytopenia.

From the urinary system: < 0.01% – enuresis; in a few cases – reversible Fanconi syndrome (Genesis is not clear).

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

From the laboratory parameters: often (especially when politerapii) – isolated and mild hyperammonemia without changes in liver function analyses (discontinuation of the drug is not required); also describes hyperammonemia, associated with neurological symptoms (that requires further survey); the increase in the liver transaminaz; in some cases (especially in the application of valproate in high doses) – reduction of the level of Fibrinogen or increased bleeding time, usually without clinical manifestations; < 0.01% – giponatriemiya.

On the part of the endocrine system: in a few cases – gynecomastia, amenorrhea, dysmenorrhoea. With the increase in body mass index, that is a risk factor for the development of cystic ovaries syndrome, requires control state.

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

Contraindications

- Acute hepatitis;

- Chronic hepatitis;

— cases of severe hepatitis in a patient or his family history, especially caused by drugs;

- Severe liver;

- Severe violations of the pancreas;

- Porphyria;

- Gyemorragichyeskii diatyez, thrombocytopenia;

-combination with Mefloquine, St. John's wort preparations, with lamotriginom;

- Children up to age 6 months;

-hypersensitivity to valproatu or to any of the components of the drug.

FROM caution the drug should be used in diseases of the liver and pancreas in history, Pregnancy, congenital fermentopatijah, the oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia), in renal failure, gipoproteinemii.

Pregnancy and lactation

Pregnancy development of generalized tonico-klonicakih epileptic seizures, epileptic status with the development of hypoxia can carry the risk of death for both mother, and to the fetus.

Application of Depakin^® Hronosfera when pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.

Valproate reportedly mainly causes neural tube development: myelomeningocele, Spina bifida (1-2%). Describes several cases of facial dismorfii and malformations of extremities (especially, shortening of the limbs), as well as malformation of the cardiovascular system. The risk of birth defects is higher when combination therapy protivojepilepticheskoj, than when alone valproatom sodium. However, it is quite difficult to establish a causal link between fetal malformation and other factors (incl. genetic, social, external factors Wednesday).

If pregnancy should not interrupt protevoepilepticescoe treatment valproatom, If it effectively. In such cases it is recommended to monotherapy: minimum effective daily dose which should be divided into several events per day.

In addition to protivojepilepticheskoj therapy can be prescribed drugs folic acid (dose 5 mg / day), t. to. They allow you to minimize the risk of neural tube defects. However, regardless of, gets the patient drugs folic acid or not, in any case, you should conduct special monitoring of antenatal or other neural tube defects.

Valproate can cause hemorrhagic syndrome in newborns. In the case of valproate this syndrome, apparently, associated with gipofibrinogenemiej. There were cases of lethal afibrinogenemii development. Maybe, This is due to the reduced number of clotting factors. A newborn will definitely carry out the determination of the number of platelets, the level of Fibrinogen in the plasma and the clotting factors.

Valproate excretion in breast milk is low, concentration, component 1-10% of plasma concentration.

According to the literature and based on small clinical experience, can you recommend breastfeeding during monotherapy drug, given its security profile (especially Hematological Disorders).

Cautions

Treatment with anticonvulsant medication occasionally possible renewal or development of new attacks, regardless of spontaneous changes the course of the disease, observed in some epileptic conditions. In respect of valproate is first and foremost to the combination treatment of epilepsy, Pharmacokinetic interactions, Toxicity (scarp- or encephalopathy) and overdose.

Because valproate sodium in the body turns into val'proevuju acid, It should not be combined with other drugs, subjected to the same type of biotransformation, in order to prevent overdose valproeva acid.

Hepatic failure

High risk account for infants and children under the age of 3 years with severe epilepsy, especially epilepsy, associated with brain damage, delayed mental development and/or congenital metabolic or degenerative diseases. In children older than 3 years the frequency of such complications is greatly reduced and gradually decreases with age.

In most cases, the liver was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and more often than not in the combined treatment of protivojepilepticheskom.

Early diagnosis is based primarily on clinical examination. In particular, should take into account two factors, that may precede jaundice, especially in patients, components of risk. One side – common symptoms are nonspecific, usually appear suddenly, such as fatigue, anorexia, extreme fatigue, drowsiness, sometimes accompanied by recurrent vomiting and abdominal pain. On the other hand – relapse of epileptic seizures on background protivojepilepticheskoj therapy.

It is recommended to inform the patient, and if it's a child, his family, that, in developing such symptoms should immediately contact a doctor. In addition to clinical examination should immediately undertake a study of the liver.

For the first 6 months of treatment should be periodically monitored liver function. Among the classical tests the most important tests, reflecting the liver protein synthesis, and, especially, prothrombin index. In case of detection of an abnormally low level of prothrombin, significant lowering of Fibrinogen and coagulation factors, raising cium and transaminaz liver, treatment with Depakin^® Hronosfera should be suspended. There is also a need to interrupt treatment salicilatami, If they were included in the treatment regimen, because their metabolism uses shared with valproatom way.

Pancreatitis

In rare cases there have been severe pancreatitis, sometimes with fatal consequences. These cases observed regardless of patient age and duration of treatment, Although the risk of developing pancreatitis declined with increasing age patients.

Liver failure in acute pancreatitis increases risk of death. It is necessary for the determination of the liver before the beginning of treatment and periodically during the first 6 months of treatment, particularly at-risk patients.

It should be emphasized, that in the treatment of Depakinom^® Hronosfera, like other antiepileptic drugs, There may be a small, isolated and temporary increase in transaminases, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case it is recommended to carry out a more complete laboratory examination (including, in particular, determination of prothrombin index) so as, to review the dose, if required, and repeat analyses depending on parameter changes.

Before therapy or surgery, in the case of formation of hematoma or spontaneous bleeding, it is recommended to perform Hematology blood (define formula blood, including the number of platelets, bleeding time and coagulation tests).

In patients with renal insufficiency are advised to take into account the increased concentration of free form valproeva acid in serum and reduce the dose.

Acute abdominal pain syndrome and gastro-intestinal symptoms, nausea, vomiting, and/or anorexia, You must be able to recognize the pancreatitis and high level of pancreatic enzymes cancel product, taking alternative therapeutic measures.

Sodium valproate is not recommended to appoint patients with deficiency of the enzymes of the urea cycle. In such patients has been documented several cases hyperammoniemia, accompanied by Stupar and/or coma.

Although shown, that in the course of drug treatment Depakin^® Hronosfera immune system dysfunction occur only rarely, You should evaluate the potential benefits of therapy and the risk of drug patients, suffering from SLE.

Patients should be warned about the risk of increased body weight at the beginning of treatment; to minimize this effect, the patient must comply with the appropriate diet.

Use in Pediatrics

In children under 3 years It is recommended to use valproate (the recommended dosage form) as monotherapy, but prior to the start of treatment should be to evaluate the potential benefits from drug treatment in relation to the risk of liver disease or pancreatitis.

You should avoid combined use with salicilatami u children under 3 years because of the risk of Hepatotoxicity.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), lethargy or coma in history, with delayed mental development or with family history of death a newborn or child, prior to the start of treatment valproatom sodium metabolism studies should be conducted, especially ammoniemii when fasting and after eating.

Effects on ability to drive vehicles and management mechanisms

During the period of treatment must be careful when driving and occupation of other potentially hazardous activities, require high concentration and speed of psychomotor reactions.

Overdose

Symptoms: in acute massive overdose coma is usually observed with muscular hypotonia, giporefleksiej, miozom, respiratory depression, metabolic acidosis. Describes cases of intracranial hypertension, associated with brain edema.

Treatment: emergency care in hospital – gastric lavage, that effectively within 10-12 h after dosing, monitoring of the cardiovascular and respiratory system and maintaining effective diuresis. In very severe cases, hold dialysis. Usually the prognosis is favorable overdose, However, it described several cases of death.

Drug Interactions

Combinations contraindicated

Mefloquine can cause convulsions and strengthen metabolism valproeva acid, that increases the risk of seizures in patients with epilepsy, receiving val'proevuju acid.

St. John's wort is able to reduce the concentration of valproic acid in plasma.

Combinations are not recommended

Together with the use of lamotriginom increases the risk of severe skin reactions (toxic epidermal necrolysis). Besides, lamotrigina concentration increases in plasma due to slowing its metabolism in the liver under the influence of sodium valproate. If this combination is necessary, requires careful clinical and laboratory monitoring.

Combinations, require special care

Carbamazepine

If you are applying an increase in concentrations of the active metabolite of carbamazepine in plasma with symptoms of overdose. Besides, decreases the concentration of valproic acid in the plasma, that is associated with the induction of hepatic metabolism of valproate under the action of carbamazepine. Recommended clinical observation, determination of the concentrations of drugs in plasma and revision of their doses, especially at the beginning of treatment.

Carbapenem, monobaktamy

Together with the application karbapenemami, monobaktamami (incl. with meropenemom, panipenemom, and, to extrapolate from aztreonamom, imipenem) There is a risk of convulsions, due to lower concentrations of valproic acid in the plasma. Recommended: clinical observation, determination of the concentrations of drugs in plasma and, perhaps, revision dose valproeva acid during treatment of antimicrobial means and after its abolition.

Felʙamat

Together with the use of felbamatom increases the concentration of valproic acid in plasma, There is a risk of overdose. Clinical and laboratory monitoring is required and, perhaps, revision dose valproeva acid during treatment felbamatom and after its abolition.

Phenobarbital, prymydon

Together with the use of valproic acid or phenobarbital concentrations rise primidona plasma with signs of overdose, usually in children. Besides, There has been a decrease in the concentration of valproic acid in the plasma, associated with increased hepatic metabolism under the action of phenobarbital or primidona. Required clinical monitoring during the first 15 days of combined treatment with immediate decrease in dose of phenobarbital or primidona when signs of sedative action; determination of the concentrations of both anticonvulsants in plasma.

Phenytoin

Changes fenitoina concentration in the plasma, risk concentration valproeva acid, associated with increased under the influence of fenitoina pechenerngo metabolism valproeva acid. Recommended clinical monitoring, control of concentrations of both drugs in plasma, if necessary – correction their doses.

Topiramate

In combination with topiramatom there is a risk of hyperammoniemia or encephalopathy, what, believed, due to the action of valproeva acid. A careful clinical and laboratory monitoring during the first months of treatment and in case of symptoms ammoniemii.

Antipsychotics, MAO inhibitors, antidepressants, benzodiazepines

Valproate potenziruet of psychotropic drugs, such as antipsychotic means (neuroleptics), MAO inhibitors, Antidepressants and benzodiazepines. Recommended clinical monitoring and, if necessary, correction dose.

Cimetidine and erythromycin

Increase concentration in plasma valproate.

Zidovudine

Valproate may increase the concentration of zidovudine in plasma, that leads to increased toxicity of the latter.

Combinations, that should be taken into account

Due to inhibition of metabolism Nimodipine (the ingestion and, apparently, when administered parenterally) under the influence of valproic acid, Nimodipine increased gipotenzivnogo effect occurs in connection with increase of its concentration in the blood plasma.

While receiving valproate and acetylsalicylic acid There is an increasing effects of valproate, as a result of the increase in plasma valproate concentrations.

There is a need for careful monitoring of prothrombin index with a joint appointment with indirect antikoagulyantami (Vitamin k antagonists).

Other forms of interaction

Valproate does not possess the enzyme-have inductive effect and therefore does not affect the effectiveness of hormonal contraceptives, containing a combination of estrogen and progesterone.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored at temperatures above 25 ° C; not cool and not freezing. Shelf life – 2 year.