Expiration date: 05/2025

Structure and Composition:

The long-acting granules, 1 package contains:

Depakine Chronosphere ™ 100 mg:

66.66 mg sodium valproate

valproic acid 29.03 mg

(All calculated as sodium valproate - 100 mg)

Depakine Chronosphere ™ 250 mg:

166.76 mg sodium valproate

valproic acid 72.61 m

(All calculated as sodium valproate - 250 mg)

Depakine Chronosphere ™ 500 mg:

333.3 mg sodium valproate

valproic acid 145.14 mg

(All calculated as sodium valproate - 500 mg)

Depakine Chronosphere ™ 750 mg:

500.06 mg sodium valproate

valproic acid 217.75 mg

(All calculated as sodium valproate - 750 mg)

Depakine Chronosphere ™ 1000 mg:

666.6 mg sodium valproate

valproic acid 290.27 mg

(All calculated as sodium valproate - 1000 mg)

Excipients: solid paraffin glycerol dibehenate Silica colloidal aqueous

bags of three-layer complex (paper / aluminum / ionomer resin) paper cartons 30 or 50 packets.

Description pharmaceutical form:

Easily free-flowing without the formation of agglomerates waxy microgranules, almost white or slightly yellowish.

Pharmacokinetics:

Different pharmacokinetic studies conducted with valproate demonstrated the following:

Bioavailability valproate in blood after oral administration is close to 100%.

Valproate penetrates into the cerebrospinal fluid in the brain.

T1 / 2 is 15-17 hours.

For therapeutic effect is required in the serum Cmin 40-50 mg / l, fluctuating within 40-100 mg / liter. At levels above 200 mg / l dose reduction is required.

Stable plasma concentration is achieved in 3-4-th day.

Linking blood plasma - high, dose-dependent and saturable.

Valproate mainly excreted in the urine as glucuronide.

The molecule may dialyzed valproate but hemodialysis affects only the free form of valproate in the blood (about 10%).

Valproate has no effect on inducing enzymes belonging to the cytochrome P450 metabolic: Unlike most other antiepileptic drugs, valproate has no effect on the degree of biotransformation as the own and other substances such as estroprogestageny antagonists and vitamin K.

Compared to immediate release form of valproate, in equivalent doses Depakine Chronosphere ™ characterized by:

• Prolonged absorption
  
• Identical bioavailability
  
• Cmax of the drug in plasma is reached after about 7 hours after ingestion
  
• Total Cmax and Cmax freeform valproate in lower plasma (decrease in Cmax of approximately 25%, but with a relatively stable phase plateau from 4 to 14 hours after administration) as a result of this reduction, valproic acid concentrations are more regular and have a more uniform distribution in the during the day: after twice daily application of the same dose, the amount of fluctuation in plasma concentrations is halved
  
• A linear correlation between the dose and concentration in plasma (total and free form).
  

Food does not affect the pharmacokinetic profile.

Description of the pharmacological actions:

The antiepileptic drug, providing a central muscle relaxant and sedative effect.

Antiepileptic activity manifests in various types of epilepsy.

The main mechanism of action appears to be associated with exposure to valproic acid in the GABAergic system: increases the content of gamma-aminobutyric acid (GABA) in the central nervous system and activates the GABAergic transmission.

Indications:

In adults: as monotherapy or in combination with other antiepileptic drugs under the following conditions:

• treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, miokonicheskie, atonic Lennox-Gastaut syndrome)
  
• treatment of partial seizures (partial seizures with secondary generalization or without it)
  
• treatment and prophylaxis of bipolar affective disorder.
  

In infants (starting from the 6th month of life) and children: as monotherapy or in combination with other antiepileptic drugs under the following conditions:

• treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, miokonicheskie, atonic Lennox-Gastaut syndrome)
  
• treatment of partial seizures (partial seizures with secondary generalization or without it)
  
• prophylaxis of seizures, at high temperature, when such prevention is needed.
  

Contraindications:

• Increased sensitivity to valproate or any of the components of the drug
  
• acute hepatitis
  
• chronic hepatitis
  
• cases of severe hepatitis in a patient or his family history, particularly those caused by drugs, as well as severe liver or pancreas
  
• porphyria
  
• hemorrhagic diathesis, thrombocytopenia
  
• combination with mefloquine
  
• combination with St. John's wort
  
• this drug is not recommended for use in combination with lamotrigine
  
• Children up to age 6 months.
  

Carefully:

• liver disease and a history of the pancreas
  
• pregnancy
  
• congenital fermentopathy
  
• inhibition of bone marrow hematopoiesis (leucopenia, thrombocytopenia, anemia)
  
• kidney failure
  
• hypoproteinemia.
  

Application of pregnancy and breastfeeding:

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

Risk associated with valproate

According to reports, mainly valproate causes a disturbance of neural tube development: myelomeningocele, spina bifida (1-2%). It described several cases of facial dysmorphia and limb malformations (in particular, the shortening of the limbs), and malformations of the cardiovascular system.

The risk of malformations above when combined antiepileptic therapy than with monotherapy with valproate sodium. However, quite difficult to establish a causal link between fetal malformations and other factors (genetic, social, environmental factors, etc.).

In connection with the above:

1. Use of the drug during pregnancy can be assigned a doctor only when the expected benefit to pregnant women than the potential risk to the fetus.

2. During the period of pregnancy should not discontinue antiepileptic treatment with valproate if it is effective. In such cases, the minimum effective daily monotherapy dose which should be divided into several doses per day.

3. The addition of folic acid preparations (5 mg / day) can be added to antiepileptic therapy, because they allow you to minimize the risk of neural tube defects. However, regardless of whether the patient receives foliaty or not, in any case should be a special antenatal monitoring of the neural tube or other malformations.

The risk of neonatal

Valproate can cause a hemorrhagic syndrome in newborns. In this case, valproate syndrome, apparently linked to hypofibrinogenemia. afibrinogenemia cases of fatalities were reported. This may be due to a decrease of a number of blood clotting factors.

A newborn is required to carry out determination of the number of platelets, fibrinogen level in plasma and clotting factors.

Lactation

Valproate excretion into milk is low, with a concentration between 1 and 10% of the serum level of the drug.

According to the literature, and given the small clinical experience, the mother can plan breastfeeding during treatment with this drug in the form of monotherapy, based on its safety profile (especially hematological disorders).

Side effect:

CNS: ataxia (from & ge0,1 to <1%) cases of cognitive impairment with progressive onset (giving a complete picture of dementia syndrome), reversible within a few weeks or months after discontinuation of the drug (& le0,01%) state of confusion or convulsions : in some cases the treatment valproate described stupor or lethargy sometimes led to transient coma (encephalopathy), these cases were isolated or associated with a paradoxical increase in the incidence of convulsions during the treatment, their frequency decreased as the suspension of the treatment process, or by reducing the dose. Most often, these cases are described in the complex treatment (in particular with phenobarbital) or after a sharp increase in the dose of valproate isolated cases of reversible parkinsonian headache, light postural tremor and drowsiness.

From the digestive system: in some patients early in treatment often develop gastrointestinal disorders (nausea, vomiting, gastralgia, diarrhea), but they usually go away without treatment discontinuation medication for several days cases of pancreatitis, sometimes with fatal outcome (<0.01% ) requiring early discontinuation of treatment the liver (from & ge0,01 to <0.1%).

From the side of hematopoiesis: thrombocytopenia frequently occurring dose-dependent inhibition of bone marrow hematopoiesis (from & ge0,01 to <0.1%), including anemia, leucopenia or pancytopenia.

From the urinary system: bedwetting (<0.01%), isolated cases of reversible Fanconi syndrome (genesis is not clear).

Allergic reactions: skin rash, urticaria, vasculitis. In some cases (<0.01%) have been described toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Laboratory findings: common isolated and moderate hyperammonemia without change in liver function assays, especially in polytherapy. Drug withdrawal in this case is not required. However, as described hyperammonemia associated with neurological symptoms. This status requires further examinations. Perhaps an increase in liver transaminases. Describes some cases lowering fibrinogen level or increase bleeding time, usually without associated clinical manifestations and particularly at high doses (sodium valproate has an inhibitory effect on platelet aggregation second step). Hyponatremia (<0.01%)

Other: teratogenic risk (see "Pregnancy and breastfeeding".) Hair loss, rare reports of hearing loss (from & ge0,01 to <0.1%) as a reversible and irreversible, very rare cases of mild peripheral edema ( <0.01%), weight gain (as a body mass gain is a risk factor for polycystic ovary syndrome, we recommend careful monitoring of patients), there are also reports of gynecomastia, amenorrhea, violation of the regularity of the menstrual cycle.

Drug Interactions:

contraindicated combinations

Mefloquine. The risk of seizures in patients with epilepsy due to increased metabolism of valproic acid and konvulsantnym effect of mefloquine.

St. John's wort. Risk reduction in plasma valproic acid concentrations.

Not recommended combinations

Lamotrigine. The increased risk of severe skin reactions (toxic epidermal necrolysis), moreover, increased plasma concentrations of lamotrigine (his liver metabolism slows sodium valproate). If the combination is necessary, it requires careful clinical and laboratory monitoring.

Combinations requiring special precautions

Carbamazepine. Increasing the concentration of the active metabolite in plasma carbamazepine overdose with signs, in addition, reduction of valproic acid concentration in plasma associated with an increase in hepatic metabolism of the latter under the effect of carbamazepine.

Recommended clinical observation, determination of drug concentrations in plasma and revise their dosages, especially at the beginning of treatment.

Carbapenem, monobactams: meropenem, panipenem and by extrapolation - aztreonam, imipenem. Risk of seizures, due to the decrease in the serum valproic acid concentration. Recommended clinical observation, determination of drug concentrations in plasma and possible revision dosage valproic acid treatment during and antibacterial drug after its cancellation.

Felbamate. Increasing the concentration of valproic acid in serum, with the danger of overdose. Requires clinical monitoring, laboratory control and possible revision of valproic acid dosage during treatment with felbamate and after its cancellation.

Phenobarbital, primidone. Increasing the concentration of phenobarbital or primidone plasma with signs of overdose, usually in children, in addition, reduced valproic acid plasma concentrations associated with increased hepatic metabolism of phenobarbital or primidone. It is necessary to carry out clinical monitoring during the first 15 days of combined treatment with immediate reduction in the dose of phenobarbital or primidone with signs of sedation to determine the level of both anticonvulsants in the blood.

Phenytoin. Changes of phenytoin plasma concentrations, reducing the risk of valproic acid concentrations associated with increased hepatic metabolism of phenytoin last. It is recommended clinical monitoring, determining the level of the two antiepileptics plasma possible - modification of their doses.

Topiramate. Risk of hyperammonemia or encephalopathy, usually ascribed to valproic acid, when combined with topiramate. We need to strengthen the clinical and laboratory monitoring during the first month of treatment, and in case of ammoniemii symptoms.

Antipsychotics, MAO inhibitors, antidepressants, benzodiazepines. Valproate potentiates their action.

Recommended clinical monitoring and, if necessary, the adjustment of the dose.

Cimetidine and erythromycin. Increased serum levels of valproate.

Zidovudine. Valproate can increase the concentration of AZT in the plasma, leading to increased toxicity latter.

Combinations to be taken into account

Nimodipine (oral and by extrapolation - parenteral). Amplification nimodipine hypotensive effect due to higher plasma concentration (decrease valproic acid metabolism).

Acetylsalicylic acid. At the same time taking valproate and acetylsalicylic acid has been increasing effects of valproate, due to an increase in serum concentrations of valproate.

Vitamin K antagonists should be closely monitored prothrombin index with a joint appointment with the vitamin K-dependent anticoagulant.

Other forms of interactions

Oral contraceptives. Valproate has not enzyme-inducing effect, and therefore has no effect on estrogen-progesterone in women using hormonal contraceptives.

Dosage and administration:

Inside.

Bags Depakine Chronosphere ™ 100 mg are used only in children and infants.

Bags Depakine Chronosphere ™ 1000 mg are used only in adults.

The daily dose is recommended to take in one or two stages, preferably during meals.

Application in one step is possible with a well controlled epilepsy.

The drug Depakine Chronosphere ™ should be poured onto the surface of a soft food or drink, cold or at room temperature (yogurt, orange juice, fruit pulp, etc.).

The drug Depakine Chronosphere ™ can not be used with hot food or drinks (such as soups, coffee, tea, etc.).

The drug Depakine Chronosphere ™ can not pour into a bottle with a pacifier, because beads can clog the hole nipples.

If Depakine Chronosphere ™ taken with liquid, it is recommended to rinse the glass with a little water and drink this water, because pellets may stick to the glass.

The mixture should always be swallowed immediately without chewing. It should not be stored for later administration.

Given the duration of the process the active substance release and the nature of the excipients, granules of an inert matrix is ??not absorbed from the digestive tract it is excreted in the feces after the complete release of the active substance.

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

Depakine Chronosphere ™ is a sustained-release granules, ensuring a uniform concentration of the drug throughout the day.

Dosage

The initial daily dose is usually 10-15 mg / kg, to achieve the optimal dose, then it was raised to 5.10 mg / kg per week (cm. "Start treatment").

The average daily dose is 20-30 mg / kg. May increase the dose with careful monitoring of the condition of the patient, if the epilepsy can not be controlled using the average daily dose.

The average daily intake for infants (starting from the 6th month of life) and children - 30 mg / kg / day for teenagers - 25 mg / kg for adults - 20 mg / kg.

Age	Body Weight in kg	The average daily intake in mg / day
Infants 6 to 12 months	about 7,5–10	200–300
Children 1 to 3 years	about 10–15	300–450
Children 3 to 6 years	about 15–25	450–750
Children 7 to 14 years	about 25–40	750–1200
Teenagers from 14 years	about 40–60	1000–1500
Adults	from 60 kg or more	1200–2100

* Dose in mg in terms of sodium valproate.

In elderly patients the dose should be set according to their clinical status.

The daily dose is determined depending on the age and body weight of the patient but it should take into account the wide range of individual sensitivity to valproate.

A good correlation between the established daily dose serum concentration and therapeutic effect of the drug: the dose should be placed primarily on the basis of the clinical response.

Determination of valproic acid plasma levels may serve as a complement to the clinical observation, if epilepsy can not be controlled or is suspected side effects. The range of therapeutic efficiency is typically 40-100 mg / l (300-700 micromol / L).

Starting treatment

In the transition from Depakin, forms of immediate-release or sustained-release valproate, which provided disease control, drug Depakine Chronosphere ™, it is recommended to maintain a daily dose in well-controlled epilepsy.

For patients previously treated with other antiepileptic drugs, to replace them with Depakine Chronosphere ™ should be carried out gradually, reaching the optimal dose of valproate for about 2 weeks. At the same time, depending on the condition of the patient, decreases the dose of the previous drug.

For patients who are not taking other antiepileptic drugs, dosage should be increased by 2-3 days in order to achieve the optimal dose for about one week.

If necessary, combination with other antiepileptic agents, it should be introduced gradually (see. "Interaction").

Overdose:

Symptoms: The clinical manifestations of acute massive overdose usually occur in a coma with hypotonia of muscles, hyporeflexia, miosis, respiratory depression, metabolic acidosis. We describe a case of intracranial hypertension, edema associated with brain.

Treatment: acute care hospital with an overdose should be as follows: gastric lavage, which is effective within 10-12 hours after ingestion, monitor the status of the cardiovascular and respiratory systems and the maintenance of effective diuresis. In very severe cases, dialysis is performed.

Usually the prognosis of overdose is favorable, but several cases of death have been described.

Special instructions:

Assigning the antiepileptic drug can occasionally be accompanied by renewal or development of new attacks in a patient, regardless of spontaneous changes of the disease observed in certain epileptic states.

In respect of valproate, it is primarily concerned with the combined regimen of epilepsy or pharmacokinetic interactions (see. Section "Interactions"), toxicity (hepato or encephalopathy) (see. Sections "Special Instructions" and "Side effects") and overdose.

Since sodium valproate in the body is transformed into valproic acid, it should not be combined with other drugs undergoing biotransformation of the same type, in order to prevent an overdose of valproic acid.

Liver failure. high-risk group consists of infants and children up to 3 years with severe epilepsy, especially epilepsy, linked with brain damage, mental retardation and / or congenital metabolic or degenerative diseases. At the age of 3 years, the frequency of such complications is significantly reduced and gradually decreases with age.

In most cases, abnormal liver function observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often in combined anti-epileptic medication.

Early diagnosis is based mainly on clinical examination. In particular, it should be taken into account two factors which may be preceded by jaundice, particularly for patients at-risk:

1. On the one hand, non-specific general symptoms usually appear suddenly, such as fatigue, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain.

2. On the other hand, recurrent epileptic seizures on the background antiepileptic therapy.

It is recommended to inform the patient, and if it is a child, his family, that the development of clinical symptoms should immediately consult a doctor Besides clinical examination, there should be an urgent analysis of liver function.

During the first 6 months of treatment should be periodically check liver function. Among the most important classical tests, tests which reflect protein synthesis by the liver, and especially prothrombin index. In the case of abnormally low levels of prothrombin, a significant reduction of fibrinogen levels and coagulation factors, increased bilirubin and hepatic transaminases, treatment with Depakine Chronosphere ™ should be suspended. It is also necessary to interrupt treatment with salicylates, if they were included in the treatment regimen, as they share common pathways with valproate.

Pancreatitis. In rare cases, we observed severe forms of pancreatitis, sometimes with fatal consequences. These cases were observed regardless of the patient's age and the duration of treatment, although the risk of developing pancreatitis decreased with increasing patient age.

Hepatic failure with pancreatitis increases the risk of death.

It is necessary to carry out identification of liver function before initiation of treatment and periodically during the first 6 months of treatment, especially in patients at risk.

It should be emphasized that in the treatment of both drug Depakine Chronosphere ™, and other antiepileptic drugs, there may be a small, isolated and transient 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, the determination of prothrombin index) in order to reconsider the dosage, if necessary, and repeat the tests, depending on the setting.

For children under 3 years are recommended to use valproate (at the recommended dosage form) in monotherapy, but before the start of treatment should be to evaluate the potential benefit of treatment with respect to the risk of developing liver disease or pancreatitis.

Before therapy or surgery, in case of spontaneous bruising or bleeding, it is recommended to hematology blood test (to determine blood count, including platelet count, bleeding time and coagulation tests hold).

Avoid combined use with salicylates in children younger than 3 years because of the risk of hepatotoxicity.

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 such gastrointestinal symptoms such as nausea, vomiting and / or anorexia, you must recognize and pancreatitis, elevated levels of pancreatic enzymes, stop the drug, taking alternative therapeutic measures.

Sodium valproate is not recommended in patients with urea cycle enzyme deficiency. In such patients has been described several cases of hyperammonemia accompanied by stupor and / or coma.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolytic), lethargy or coma in history, with mental retardation or family history of a newborn or child death, before treatment with sodium valproate should be carried out the study of metabolism, especially ammoniemii at fasting and postprandial.

Although it is shown that in the course of treatment with Depakine Chronosphere ™ dysfunction of the immune system occur only rarely, the potential benefits of its use must be weighed against the potential risk of the drug when administered to patients suffering from systemic lupus erythematosus.

Patients should be warned about the risk of weight gain at the beginning of treatment, and care should be taken, mainly dietary, for the information of the phenomenon to a minimum.

Effects on ability to drive vehicles or other mechanisms. During the period of treatment must be careful when driving and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions.