To indicate the incidence of adverse reactions (HP) The classification of the World Health Organization is used: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥ 0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%; frequency is unknown (when, according to available data, to estimate the frequency of development HP does not seem possible).
Congenital, hereditary and genetic disorders
Teratogenic risk (see section "Application during pregnancy and during breastfeeding").
Violations of the blood and lymphatic system
Often: anemia, thrombocytopenia (see section "Special instructions").
Infrequently: pancytopenia, leukopenia, neutropenia.
Leukopenia and pancytopenia can be, with or without bone marrow depression. After the drug is stopped, the blood picture returns to normal.
Rarely: disorders of bone marrow hematopoiesis, including isolated plasion / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; a decrease in the content of clotting factors (at least one), a deviation from the norm of the clotting parameters (such as an increase in prothrombin time, an increase in activated partial thromboplastin time, an increase in thrombin time, an increase in INR [international normalized ratio]) (see " pregnancy and during breastfeeding "and" Special instructions "). The emergence of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct a survey.
Laboratory and instrumental data
Rarely: biotin deficiency / biotinidase deficiency.
Disturbances from the nervous system
Often: tremor.
Often: extranramidal disorders, stupor *, drowsiness, convulsions *, memory impairment, headache, nystagmus; dizziness (with intravenous administration, dizziness may occur within a few minutes and pass spontaneously within a few minutes).
Infrequently: coma *, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia.
Rarely: reversible dementia, combined with reversible cerebral atrophy, cognitive disorders.
Frequency unknown: sedation.
* Stupor and lethargy sometimes lead to transient coma / encephalopathy and were either isolated, or combined with increased frequency of convulsive attacks against the background of treatment, and also decreased with withdrawal of the drug or with a decrease in its dose. Most of these cases have been described against a background of combined therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.
Hearing disorders and labyrinthine disorders
Often: reversible and irreversible deafness.
Disturbances on the part of the organ of sight
Frequency unknown: diplopia.
Disturbances from the respiratory organs, thorax and mediastinum
Infrequently: pleural effusion.
Disorders from the digestive system
Often: nausea.
Often: vomiting, gum changes (mainly gum 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. Frequent reactions from the digestive system can be reduced by taking the drug during or after a meal.
Infrequently: pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment, in the case of acute pain in the abdomen, it is necessary to monitor the activity of serum amylase, see section "Special instructions".
Frequency unknown: abdominal cramps, anorexia, increased appetite.
Disorders from the nochek and urinary tract
Infrequently: renal insufficiency.
Rarely: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of affection of proximal tubule tubules with violation of tubular reabsorption of phosphate, glucose, amino acids and bicarbonate),the development mechanism of which is still unclear.
Disturbances from the skin and subcutaneous tissues
Often: hypersensitivity reactions, for example, urticaria, pruritus; transitory (reversible) and / or dose-dependent pathological hair loss (alopecia), including adrogenic alopecia against the background of developed hyperandrogenia, polycystic ovary (see below subsections "Genital and breast disorders" and "Endocrine system disorders"), and also alopecia against the background of developed hypothyroidism (see below section "Endocrine system disorders"), violations from the nails and the nail bed.
Infrequently: angioedema, rash, hair disorders (such as abnormal hair structure, hair color changes, abnormal hair growth [disappearance of waviness and curly hair, or vice versa, appearance of curly hair in persons with initially straight hair]), hirsutism, acne.
Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash syndrome with eosinophilia and systemic symptoms (DRESS-syndrome).
Disturbances from musculoskeletal and connective tissue
Infrequently: reduction of bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid for a long time. The mechanism of the effect of the drug on the metabolism of bone tissue is not established.
Rarely: systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see "With caution", "Special instructions").
Disorders from the endocrine system
Infrequently: syndrome of inadequate secretion of antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or increase in androgen concentrations in the blood).
Rarely: hypothyroidism (see the section on "Application during pregnancy and during breastfeeding").
Disorders from the metabolism and litany
Often: hyponatremia, weight gain (the increase in body weight should be carefully monitored, since weight gain is a factor contributing to the development of the polycystic ovary syndrome).
Rarely: hyperammonemia * (see section "Special instructions"), obesity.
* There may be cases of isolated and moderate hyperammonemia without changing liver function indicators that do not require discontinuation of treatment.There was also reported the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurologic symptoms), which required the cessation of valproic acid intake and additional examination (see section "Special instructions").
Benign, malignant and vague tumors (including cysts and polyps)
Rarely: myelodysplastic syndrome.
Vascular disorders
Often: bleeding and hemorrhage (see sections "Special instructions" and "Use during pregnancy and during breastfeeding").
Infrequently: vasculitis.
General disorders and changes in the site of administration
Infrequently: hypothermia, minor peripheral edema.
Disturbances from the liver and bile ducts
Often: liver damage: abnormal liver function indicators, such as a decrease in the prothrombin index, especially in combination with a significant decrease in fibrinogen and clotting factors, an increase in the concentration of bilirubin and an increase in the activity of "liver" transaminases in the blood; liver failure,in exceptional cases, fatal; it is necessary to monitor patients for possible violations of liver function (see section "Special instructions").
Violations of the genitals and mammary gland
Often: dysmenorrhea.
Infrequently: amenorrhea.
Rarely: male infertility, polycystic ovary.
Frequency unknown: irregular menstruation, increased mammary glands, galactorrhea.
Disorders of the psyche
Often: a state of confusion, hallucinations, aggressiveness *, agitation *, attention violation *; Depression (when combining valproic acid with other anticonvulsants).
Rarely: behavioral disorders *, psychomotor hyperactivity *, learning disabilities *; depression (with monotherapy with valproic acid).
* Undesirable reactions, mainly observed in patients of childhood.