Universal reference book for medicines
Product name: DEPAKINE ® CHRONOSPHERE (DEPAKINE ®CHRONOSPHERE )

Active substance: valproic acid

Type: Anticonvulsant drug

Manufacturer: SANOFI WINTHROP INDUSTRIE (France)
Composition, form of production and packaging

The granules of prolonged action are almost white or slightly yellowish in color, waxy, easily flowing, without the formation of agglomerates.

1 pack.

valproate sodium 66.66 mg

valproic acid 29.03 mg

in terms of sodium valproate 100 mg

Excipients: paraffin solid - 101.26 mg, glycerol dibehenate - 106.05 mg, silicon dioxide colloidal water *.

Sachets three-layer (30) - packs cardboard.

Sachets three-layer (50) - packs cardboard.

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

1 pack.

sodium valproate 166.76 mg

valproic acid 72.61 mg

in terms of sodium valproate 250 mg

Excipients: paraffin solid - 253.32 mg, glycerol dibehenate - 265.3 mg, silicon dioxide colloidal water *.

Sachets three-layer (30) - packs cardboard.

Sachets three-layer (50) - packs cardboard.

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

1 pack.

sodium valproate 333.3 mg

valproic acid 145.14 mg

in terms of sodium valproate 500 mg

Excipients: paraffin solid - 506.31 mg, glycerol dibehenate - 530.25 mg, silicon dioxide colloidal water *.

Sachets three-layer (30) - packs cardboard.

Sachets three-layer (50) - packs cardboard.

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

1 pack.

sodium valproate 500.06 mg

valproic acid 217.75 mg

in terms of sodium valproate 750 mg

Excipients: paraffin solid - 759.64 mg, glycerol dibehenate - 795.55 mg, silicon dioxide colloidal water *.

Sachets three-layer (30) - packs cardboard.

Sachets three-layer (50) - packs cardboard.

The granules of prolonged action are almost white or slightly yellowish in color, waxy, easily flowing, without the formation of agglomerates.

1 pack.

sodium valproate 666.6 mg

valproic acid 290.27 mg

in terms of sodium valproate 1000 mg

Excipients: paraffin solid - 1012.63 mg, glycerol dibehenate - 1060.5 mg, silicon dioxide colloidal water *.

Sachets three-layer (30) - packs cardboard.

Sachets three-layer (50) - packs cardboard.

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

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Antiepileptic drug, has a central muscle relaxant and sedative effect.

It shows antiepileptic activity in various types of epilepsy.
The main mechanism of action, apparently, is associated with the action of valproic acid on the GABA -ergic system: it increases the GABA content in the central nervous system and activates GABA-ergic transmission.
Depakin ® Chronosphere is a sustained release pellet that provides more uniform drug concentrations during the day.

PHARMACOKINETICS

Suction

The bioavailability of valproic acid for oral administration is close to 100%.
Eating does not affect the pharmacokinetic profile. C max of the drug in the plasma are reached approximately 7 hours after ingestion.
Compared with the enteric coated form, equivalent doses of Depakin® Chronosphere ™ are characterized by a longer absorption, identical to bioavailability, a more linear correlation between doses and plasma concentrations of valproic acid (total concentration and free-fraction concentration).
In addition, Cmax and Cmax of the free fraction of valproic acid in plasma are lower (a decrease of about 25%), but there is a relatively more stable plateau plasma concentration phase from 4 to 14 hours after administration, the plasma plasma concentration of the drug Depakin ® Chronosphere ™ is reduced in comparison with the enteric coated form by a factor of two, as a result of which valproic acid is more evenly distributed in the tissues during the day.
With the course of taking the drug C ss valproic acid in the blood serum is achieved within 3-14 days.

Usually, serum concentrations of valproic acid of 40-100 mg / l (300-700 μmol / L) are effective (determined before taking the first dose of the drug within 24 hours).With serum concentrations of valproic acid in excess of 100 mg / l, an increase in side effects is expected up to the development of intoxication.

Distribution

V d depends on the 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 decrease in the plasma concentration fluctuations with the administration of Depakin ® Chronosphere , valproic acid is more evenly distributed in the tissues during the day compared with the immediate release dosage form of valproic acid.
The binding of valproic acid with blood plasma proteins (mainly with 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 CSF is 10% of the corresponding serum concentration, that is, close to the free valproic acid concentration in serum.
Valproic acid penetrates the breast milk of nursing mothers.
In the state of achieving C ss valproic acid in the serum, its concentration in breast milk is up to 10% of its serum concentration.
Metabolism

The metabolism of valproic acid is carried out in the liver by glucuronation, as well as beta, omega, and omega-1 oxidation.
More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect.
Valproic acid does not have an inducing effect on the enzymes that enter the metabolic system of cytochrome P450: unlike most other antiepileptic drugs, valproic acid does not affect the extent of both its own metabolism and the degree of metabolism of other substances such as estrogens, progestogens and indirect anticoagulants.

Excretion

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

When using valproic acid in monotherapy, its T 1/2 is 12-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes (such as primidon, phenytoin, phenobarbital and carbamazepine), the plasma clearance of valproic acid increases, and T 1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.
T 1/2 in children older than 2 months is close to that in adults.
Pharmacokinetics in special clinical cases

In elderly patients, patients with renal and hepatic insufficiency, binding to plasma proteins decreases.

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

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

In patients with liver disease, T 1/2 valproic acid increases.

Overdose showed an increase in T 1/2 to 30 hours. Only free fraction of valproic acid in the blood (510%) underwent hemodialysis.

Peculiarities of pharmacokinetics in pregnancy

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

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

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic;

- Lennox-Gastaut syndrome;

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;

- treatment and prevention of bipolar affective disorders.

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

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic;

- Lennox-Gastaut syndrome;

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;

- prevention of seizures at high temperature, when such prophylaxis is necessary.

DOSING MODE

Depakin ® Chronosphere is a dosage form that is especially suitable for treating children (if they are able to swallow soft food) or adults with difficulty swallowing.

Depakin ® Chronosphere is a sustained release pellet that provides more uniform concentrations of valproic acid in the blood and, consequently, a more uniform distribution of the valproic acid in the tissues over the course of a day.

Bipolar affective disorders

The dose should be selected and monitored by the attending physician individually.
The daily dose should be set taking into account the age and body weight of the patient. The recommended initial dose is 20 mg (in terms of sodium valproate) per kg of body weight. The dose should be as quickly as possible to the minimum dose providing the desired therapeutic effect.
The recommended maintenance dose for the treatment of bipolar disorders is in the range between 1000 mg and 2000 mg (in terms of sodium valproate) per day.
The dose should be selected according to the individual clinical response of the patient. For the prevention of manic conditions, an individually selected minimum clinically effective dose should be used.
Epilepsy

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

Average daily dose:

for children under 14 years of age - 30 mg / kg of body weight;

for adolescents 14-18 years - 25 mg / kg body weight;

for adults and elderly patients (body weight from 60 kg and above) - 20 mg / kg body weight.

Thus, the daily doses presented below are recommended.

Age of patients Mass of body Average daily dose *

Breast children aged 6 to 12 months About 7.5-10 kg 150-300 mg

Children from 1 to 3 years About 10-15 kg 300-450 mg

Children from 3 to 6 years About 15-25 kg 450-750 mg

Children from 7 to 14 years About 25-40 kg 750-1200 mg

Adolescents from 14 years About 40-60 kg 1000-1500 mg

Adults From 60 kg and above 1200-2100 mg

* The dose in terms of the number of milligrams of sodium valproate

The average daily dose can be increased by monitoring the concentration of valproic acid in the blood.

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks.
Therefore, do not increase the daily dose above the recommended average daily dose before this time.
Although the daily dose is determined depending on the age and body weight of the patient, a wide range of individual sensitivity to valproic acid should be taken into account.

A clear correlation between the daily dose, the concentration of valproic acid in the blood serum and the therapeutic effect is not established.
Therefore, the optimal dose of the drug should be selected, mainly on the basis of a clinical response.
Determination of the concentration of valproic acid in the blood serum can serve as a supplement to clinical observation in cases where epilepsy is not susceptible to control or suspected of the development of side effects.
In general, doses providing serum concentrations of valproic acid of 40-100 mg / l (300-700 μmol / L) are usually effective. If the need to achieve higher concentrations in the serum is warranted, the ratio of expected benefits and the risk of side effects, especially dose-dependent, should be weighed carefully. with serum concentrations of valproic acid above 100 mg / l, an increase in side effects is expected up to the development of intoxication. Therefore, the serum concentration, determined before taking the first dose per day, should not exceed 100 mg / l.
When switching from dosage forms of Depakin® immediate release or delayed release, which controlled epilepsy, it is recommended that Depakin® Chronosphere continue to receive the same daily dose.

For patients who have taken antiepileptic drugs earlier, the transfer to the drug Depakin ® Chronosphere should be carried out gradually, reaching the optimal dose of the drug for about 2 weeks.
At the same time, the dose of an antiepileptic drug previously taken, especially phenobarbital, is immediately reduced. If previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.
If necessary, combinations of valproic acid with other antiepileptic drugs, they should be added gradually.

Because
other antiepileptic drugs can reversibly induce microsomal liver enzymes, should monitor the concentrations of valproic acid in the blood within 4-6 weeks after the last dose of these antiepileptic drugs and, if necessary (as the metabolic-inducing effect of these drugs decreases), reduce the daily dose of Depakin® Chronosphere .
Special patient groups

Female children and adolescents, women with childbearing potential and pregnant women: treatment with Depakin ® Chronosphere should be started under the supervision of a specialist with experience in the treatment of epilepsy and bipolar disorders.
Treatment should be started only if other treatments are ineffective or not tolerated, and with a regular review of treatment, the benefit / risk ratio should be carefully reassessed. The use of Depakin ® for monotherapy and at the lowest effective doses and, if possible, in sustained release dosage forms is preferred. During pregnancy, the daily dose should be divided, at least, into 2 single doses.
Although elderly patients have changes in the pharmacokinetics of valproic acid, they have limited clinical relevance and the dose of valproic acid in elderly patients should be selected in accordance with the achievement of control over epileptic seizures.

In patients with renal insufficiency and / or hypoproteinemia , the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and, if necessary, to reduce the dose of valproic acid, guided by the dose selection, mainly on the clinical picture, and not on the general the content of valproic acid in the blood serum (free fraction and plasma protein bound fractions together) to avoid possible errors in the selection of the dose.

Mode of application

The drug is taken internally.

Packages Depakin ® Chronosphere 100 mg are used only in children and infants.

Packages Depakin ® Chronosphere 1000 mg are used only in adults.

The daily dose should be taken in 1 or 2 doses, preferably during meals.
Use in 1 reception is possible with well-controlled epilepsy.
Depakin ® Chronosphere should be poured on the surface of a soft food or drink, cold or at 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.).

Preparation Depakin ® Chronosphere can not be poured into a bottle with a pacifier;
The granules can clog the nipple opening.
If Depakin ® Chronosphere ™ is taken with a liquid, it is recommended to rinse the glass with a little water and drink this water,
The granules can stick to the glass.
The mixture should always be swallowed immediately, without chewing.
It should not be stored for later use.
SIDE EFFECT

Determination of the frequency of adverse reactions (WHO classification): very often (? 10%), often (? 1% and <10%), infrequently (? 0.1% and <1%), rarely (≥0.01% and <0.1%), very rarely (<0.01%) , the frequency is unknown (it is impossible to determine from the available data).

Congenital, hereditary and genetic disorders: teratogenic risk.

From the hemopoietic system: often - anemia, thrombocytopenia;
infrequently - pancytopenia, leukopenia, neutropenia. Leukopenia, pancytopenia, and may be a depression of bone marrow blood, and without it. After discontinuation of the drug, the blood picture returns to normal.
From the blood coagulation system: often - bleeding and hemorrhage; rarely - reduction of blood clotting factors (at least one), abnormal blood clotting parameters (such as increased prothrombin time, increased APTT, thrombin time increase, increase MHO). The appearance of spontaneous ecchymosis and bleeding requires the preparation and conduct of clinical and laboratory examination.
From the nervous system:very often - tremor; often - extrapyramidal disorders, stupor *, drowsiness, seizures *, memory disorders, headache, nystagmus, dizziness (can occur in a few minutes after i / v injection and disappear spontaneously within a few minutes); infrequently - * coma, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia, increased severity of seizures; rarely - reversible dementia, combined with reversible cerebral atrophy, cognitive disorders; frequency is unknown - sedation.
* ctupor and lethargy sometimes led to transient coma / encephalopathy and were either isolated or combined with an increase in seizures during the treatment, and decreased to remove the drug or reducing its dose. Most of these cases has been described in combination therapy, particularly when simultaneous application of phenobarbital or topiramate, or after an abrupt increase in the dose of valproic acid.
On the part of the psyche: infrequently - a state of confusion, aggressiveness, ** agitation **, ** attention deficits, depression (with a combination of valproate with other anticonvulsants); rarely - behavioral disorders **, psychomotor hyperactivity **, learning disabilities, ** depression (monotherapy with valproic acid).
** adverse reactions, mainly observed in pediatric patients.
From the senses: often - reversible and irreversible deafness; the frequency is unknown - diplopia.
From the digestive system:very often - nausea; often - vomiting, changes in the gums (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhea (which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy); rarely - pancreatitis, sometimes with fatal outcome (development of pancreatitis, possibly for the first 6 months of treatment, in case of acute abdominal pain is necessary to monitor the activity of serum amylase); the frequency is unknown - abdominal cramps, anorexia, appetite increase. Some of the reactions of the digestive system can be reduced by taking the drug during or after a meal.
Of the liver and biliary tract:often - liver injury, accompanied by abnormal liver function indices such as reduced Prothrombin index, especially when combined with a significant decrease of fibrinogen and blood clotting factors, the increase in the concentration of bilirubin and an increase of liver transaminases in the blood; liver failure, in exceptional cases, with fatal consequences. Necessary to monitor patients for possible liver dysfunction.
The respiratory system: rarely - pleural effusion.
From the urinary system:rarely - renal failure; rarely - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex biochemical and clinical manifestations of renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), of the mechanism of which is unclear.
Immune system: often - hypersensitivity reactions such as hives; infrequently - angioedema; rarely - syndrome drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).
Skin and subcutaneous tissue disorders:often - transient and dose-dependent alopecia (including androgenic alopecia evolved against a background of hyperandrogenism, polycystic ovaries, and alopecia on the background of established hypothyroidism), disorders of the nail and nail bed; seldom - rash, disorders of the hair (such as disturbance of the normal structure of the hair, change in hair color, abnormal hair growth [disappearance of the undulations and hair curl, or, on the contrary, the appearance of the hair curl in patients with initially straight hair]); seldom - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme).
On the part of the musculoskeletal system and connective tissue:infrequently - decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long valproic acid (mechanism of the effect of valproic acid on bone metabolism is not installed); systemic lupus erythematosus.
Endocrine system: infrequently - syndrome of inappropriate secretion of ADH, hyperandrogenism (hirsutism, virilization, acne, male pattern alopecia and / or an increase in androgen concentrations in the blood); rarely - hypothyroidism.
Metabolism: often - hyponatremia, increased body weight (weight gain as a factor contributing to the development of polycystic ovary syndrome); rarely - * hyperammonemia, obesity.
* May be cases isolated and moderate hyperammonemia without changes in liver function and the need to stop treatment. It was also reported the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms, including encephalopathy, emesis, ataxia), which required discontinuation of valproic acid and of the additional examination.
On the part of the vessels: infrequently - vasculitis.
On the part of the reproductive system: often - dysmenorrhea; infrequently - amenorrhea; rare - male infertility, polycystic ovary syndrome; frequency is unknown - dysmenorrhea, breast enlargement, galactorrhea.
Benign and malignant tumors of uncertain (including cysts and polyps): rarely - myelodysplastic syndrome.
General disorders: rarely - hypothermia, not heavy peripheral edema.
Laboratory and instrumental data: rarely - biotin deficiency / insufficiency biotinidase.
CONTRAINDICATIONS

- increased sensitivity to sodium valproate, valproic acid, valproate seminatriya, valpromidu or any of the auxiliary components of the formulation;
- acute hepatitis;
- chronic hepatitis;

- severe liver disease (especially drug-induced hepatitis) in the history of the patient and his close blood relatives;
- severe liver damage with lethal when using valproic acid in close blood relatives of the patient;
- severe hepatic dysfunction;
- severe disorders of the pancreas;
- hepatic porphyria;
- established mitochondrial diseases caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase (POLG), for example, Alpers-Huttenlohera syndrome, and a suspicion of the disease caused by defects polymerase, in children younger than 2 years?
- Patients with urea cycle disorders set (urea cycle);
- hemorrhagic diathesis, thrombocytopenia;
- Combination with mefloquine;
- a combination of Hypericum perforatum preparations;
- Children up to age 6 months.
Carefully

- liver and pancreas history;
- Pregnancy;

- congenital fermentopathy;
- inhibition of bone marrow hematopoiesis (leucopenia, thrombocytopenia, anemia);
- renal failure (dose adjustments);
- hypoproteinemia;
- simultaneous reception of several anticonvulsant drugs (because of the increased risk of liver disease);
- simultaneous administration of drugs, provoking seizures or reduce seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitor; phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);
- simultaneous reception neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (the ability of potentiating effects);
- simultaneous reception phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, olanzapine, propofol, aztreonam, acetylsalicylic acid, anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rufinamida (especially in children), protease inhibitor (lopinavir, ritonavir ), cholestyramine (in connection with the pharmacokinetic interaction at the level of metabolism or binding to plasma proteins may change or plasma concentrations of these agents and / or valproic acid);
- simultaneous with carbamazepine (risk of potentiating the toxic effects of carbamazepine and lowering plasma concentrations of valproic acid);
- Simultaneous reception with topiramate and acetazolamide (risk of encephalopathy);
- in patients with carnitine palmitoyltransferase deficiency available (CBT) of type II (the higher the risk of rhabdomyolysis with valproic acid).
PREGNANCY AND LACTATION

Pregnancy
drug Depakine ® Chronosphere should not be used in children and female adolescents, women of childbearing age and pregnant women, except in cases where other treatments are ineffective or not tolerated patient.
Women who are planning a pregnancy before conception should make every effort to transfer the patient to an appropriate alternative treatment, if possible.
The risk associated with the development of epileptic seizures during pregnancy.During pregnancy, the development of generalized tonic-clonic seizures, status epilepticus with hypoxia may be of particular risk for both the mother and the fetus, due to the possibility of death.
The risk associated with the use of the drug Depakine ® Chronosphere during pregnancy. Experimental studies of reproductive toxicity in mice, rats and rabbits have shown the presence of valproate teratogenicity.
Congenital malformations.The available clinical data demonstrated greater frequency of small and severe malformations, such as congenital neural tube defects, craniofacial deformities, malformations of the limbs and the cardiovascular system, hypospadias and multiple malformations affecting different organ systems in children born to mothers who had taken during pregnancy valproic acid, as compared with their frequency in the reception during pregnancy a number of other anti-epileptic drugs. So the risk of congenital malformations in infants born to mothers with epilepsy, monotherapy with valproic acid during pregnancy was approximately 1.5, 2.3, 2.3 and 3.7 times higher compared to monotherapy with phenytoin, carbamazepine, phenobarbital and lamotrigine, respectively.
Meta-analysis involving register and cohort studies have shown that the incidence of congenital defects in babies born to mothers with epilepsy who received during pregnancy monotherapy valproic acid was 10.73% (95% confidence interval 8.16-13.29). This risk is greater than the risk of severe birth defects in the general population is 2-3%. This risk is dose-dependent. but the threshold dose below which there is no such risk, it is not possible to establish.
Impaired mental and physical development
It is shown that prenatal exposure to valproic acid could have adverse effects on mental and physical development of children exposed to such exposure. Apparently, this risk is dose-dependent, but the threshold dose below which there is no such risk, it is not possible to establish. The exact gestation period for the risk of these effects is not set, and the risk can not be excluded throughout the pregnancy. Studies of preschool children exposed in utero to valproic acid, has shown that up to 30-40% of these children had delays of early development (such as the delay in mastering the skills of walking and speech delay), and lower intellectual ability, poor language skills (on site speech and speech understanding), and memory problems.
Intelligence Quotient (IQ index) determined in children aged 6 years of age with a history of in utero exposure to valproate had an average of 7-10 points lower than children exposed in utero effects of other anti-epileptic drugs. Although we can not exclude the role of other factors that could undesirably affect the intellectual development of children exposed in utero to valproic acid, it is clear that these children risk of intellectual disability can be independent of the index of IQ mother.
Data on long-term outcomes are limited.
There is evidence in favor of the fact that children exposed in utero effects of valproic acid have an increased risk of developing the spectrum of autism spectrum disorders (approximately three-fold increase in risk), including infantile autism (about a five-fold increase in risk).
Limited data support the fact that children exposed prenatally exposed to valproic acid, it has a greater likelihood of developing attention deficit / hyperactivity disorder (ADHD).
Valproate monotherapy and combination therapy with inclusion of valproic acid are associated with a poor outcome of pregnancy, but according to reports, combined antiepileptic therapy comprising valproic acid, associated with a higher risk of adverse outcome of pregnancy, compared with valproate monotherapy (i.e. the risk of abnormalities in the fetus is less than in the application of valproic acid, when used as monotherapy).
Risk factors for fetal malformations are a dose of 1000 mg / day (yet smaller dose does not exclude this risk) and a combination of valproic acid with other anticonvulsant.
In connection with the above, the drug Depakinum ® Chronosphere should not be used during pregnancy and in women with childbearing potential unless absolutely necessary, ie its use is possible only in situations where other antiepileptic drugs are ineffective or the patient can not tolerate them.
The need of the drug Depakine ® Chronosphere or possible rejection of its application must be resolved before the start of the drug or revised if a woman takes the drug Depakine ® Chronosphere , planning to become pregnant.
Women should be informed of the need to plan the pregnancy and monitor its course.
Women with childbearing potential must use effective contraception during treatment with Depakine ® Chronosphere .
Women with childbearing potential should be informed of the risks and benefits of the use of valproic sour
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