Undesirable reactions are listed in the table below and are systematized according to the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥ 1 / 10,000 and <1 / 1,000), very rarely (<1 / 10,000), the frequency is unknown (it is impossible to estimate from available data).
Infectious and parasitic diseases: infrequent - herpes simple, herpes zoster, nasopharyngitis, pneumonia1, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infection, influenza, urinary tract infections, gastroenteritis, sepsis: rarely - mycosis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely - tumor lysis syndrome.
Violations from the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia; often - pancytopenia, febrile neutropenia; infrequently - thrombocythemia, lymphopenia, oppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy: rarely - hemolytic anemia.
Disorders from the metabolism and nutrition: often - anorexia; infrequently - hypokalemia, increase or decrease in appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely - hyperkalemia, hypomagnesemia.
Disorders of the psyche: often - insomnia: infrequently - depression, anxiety, decreased libido; rarely confusion.
Impaired nervous system: very often - headache2; often - dizziness, paresthesia, taste disorder, hypoesthesia: infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.
Disorders from the side of the organ of vision: often - edema of the eyelids, increased tearing, conjunctival hemorrhage,conjunctivitis, dry eye syndrome, blurred vision; infrequent - eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rarely - cataract, edema of the optic nerve, glaucoma.
Hearing disorders and labyrinthine disturbances: infrequently - vertigo, noise in the ears, hearing loss.
Heart Disease: infrequent - sensation of palpitations, chronic3 heart failure, pulmonary edema, tachycardia; rarely - arrhythmia, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, increased blood pressure.
Vascular disorders: often - "tides"4, hemorrhage4; infrequently - arterial hypertension, hematoma, subdural hematoma, cold extremities, lowering of blood pressure, Raynaud's syndrome.
Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, dyspnea, cough; infrequently - pleural effusion5, pain in the pharynx or larynx, pharyngitis; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.
Disorders from the digestive system: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain6, often - bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; infrequently - stomatitis, ulceration of the mucous membrane of the oral cavity, gastrointestinal bleeding7, belching, melena, esophagitis, ascites, stomach ulcer, vomiting of blood, cheilitis, dysphagia. pancreatitis; rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine.
Disorders from the liver and bile ducts: often - increased activity of "liver" enzymes: infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure9, necrosis of the liver9.
Disturbances from the skin and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often - puffiness of the face, itchy skin, dry skin, erythema, alopecia, night sweats, photosensitivity reactions; infrequently - pustular rash, petechiae, increased sweating, urticaria, ecchymosis, a predisposition to the formation of haematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, damage nails, folliculitis, petechiae, psoriasis, purpura,bullous rash: rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), discoloration of the nails, angioedema, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.
Disturbances from the musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain8; often swelling of the joints; infrequent - stiffness of muscles and joints, rarely - muscle weakness, arthritis.
Disorders from the kidneys and urinary tract: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.
Violations of the genitals and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual disorder, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum.
General disorders and disorders at the site of administration: very often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently - chest pain, general malaise.
Laboratory and instrumental research: infrequently - increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and serum creatinine concentration; rarely - increased activity of amylase in the blood plasma.
1 Pneumonia was most often observed in patients with altered CML and in patients with GIS.
2 Headache was most common in patients with GISD.
3 In terms of patient-years, adverse cardiac events, including congestive heart failure, were more common in patients with altered CML. than in patients with chronic CML.
4 Hyperemia was most often observed in patients with GIS. and hemorrhages (hematomas, bleeding) in patients with GISO and with altered CML (CML-AR and CML-VS).
5 Pleural effusion was more frequent in patients with GISO and in patients with altered CML (CML-AR and CML-VS) than in patients with chronic CML.
6,7 Abdominal pain and gastrointestinal hemorrhage were most often observed in patients with GIS.
8 Individual deaths have been reported due to hepatic insufficiency and liver necrosis.
9 Skeletal-muscular pain and related phenomena were more often observed in patients with CML. than in patients with GISO.
When imatinib was used during the postgrade period, reports of unwanted reactions were received, the relationship of which was not established with imatinib (the size of the patient population is unknown).
Infectious and parasitic diseases: frequency unknown - reactivation of hepatitis B virus.
From the nervous system: frequency unknown - edema of the brain.
From the side of the organ of vision: frequency is unknown - vitreous hemorrhage.
From the cardiovascular system: infrequently - thrombosis / embolism; frequency is unknown - pericarditis, cardiac tamponade.
Allergic reactions: frequency unknown - anaphylactic shock, drug rash with eosinophilia and systemic symptoms (DRESS).
From the respiratory system: frequency unknown - acute respiratory failure1, interstitial pneumonia.
From the gastrointestinal tract: frequency unknown - intestinal obstruction, gastrointestinal perforation2, diverticulitis, vascular ectasia of the antrum of the stomach (GAVE- syndrome).
From the skin and subcutaneous tissues: frequency unknown - palmar-plantar dysaesthesia, lichenoid keratosis, lichen planus, toxic epidermal necrolysis.
From the side of the musculoskeletal and connective tissue: frequency unknown-necrosis of the femoral head, rhabdomyolysis / myopathy, growth retardation in children.
On the part of the genitals: bleeding from the cyst of the yellow body / ovary.
1 - there are isolated reports of the development of severe respiratory acute failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other concomitant diseases.
2 - there are reports of cases of development of gastrointestinal perforations with a lethal outcome.
Description of individual adverse reactions
Inhibition of hematopoiesis
The frequency of oppression of hematopoiesis and the degree of its expression were maximal in the use of the drug in high doses and, apparently, depended on the stage of CML. In general, the oppression of hematopoiesis against imatinib in patients with CML was reversible and in most cases did not require the drug to be withdrawn or its dose reduced. The withdrawal of the drug was required in a small number of cases. Also observed were such phenomena as pancytopenia, lymphopenia and oppression of hematopoiesis.
Hemorrhage / bleeding
The most frequent clinically significant bleeding were bleeding from the gastrointestinal tract.Most often they appeared in patients with advanced stages of CML and patients with malignant stromal tumors of the gastrointestinal tract, in which they can be a consequence of the underlying disease (bleeding from a decaying tumor). It was found that patients with leukemia with acute development of the disease often have bleeding / hemorrhage caused by thrombocytopenia or thrombocytopathy.
Swelling and fluid retention
Edema is a frequent side effect of imatinib. The incidence of edema in patients receiving imatinib for all indications, is more than 50%. The frequency and severity of edema depends on the dose and, apparently, correlates with the concentration of the drug in the blood plasma. Most often there are periorbital edema, with a slightly lower frequency - swelling of the lower extremities. Specific treatment is usually not required. In patients with edema and fluid retention, heart failure is rare. In patients with advanced stages of CML, the incidence of heart failure was higher than in patients of other categories, which can be explained by their weakened state as a whole.The same trend was observed with regard to renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention were elderly (> 65 years).
Rash and severe skin undesirable reactions
In a number of patients who received imatinib. there was generalized erythematous, spotty-papular and itchy rash, which could pass independently despite the continued treatment with the drug. Some patients had itching, not accompanied by a rash; in a number of cases, there was erythroderma. A rash was noted in about a third of all patients who received imatinib for all indications. Often the rash is accompanied by itching and, as a rule, manifests itself in the form of erythematous, patchy-papular lesions on the forearm, trunk or face. Although in most cases the rash is mild and goes away without treatment, in more severe cases a temporary or complete withdrawal of the drug is required. As a rule, the severity of the rash decreases after the administration of antihistamines and glucocorticosteroids for topical application.In some cases, it is required to use glucocorticosteroid preparations for systemic use.
Hepatotoxicity
The drug may have a toxic effect on the liver. Disorders of biochemical parameters of the liver, as a rule, consists in a slight increase in the activity of aminotransferases and an increase in the serum bilirubin concentration. The toxic effect on the liver usually appears during the first two months of treatment, but in a number of cases it manifested itself 6-12 months after the start of treatment. As a rule, after drug cancellation, biochemical parameters of liver function normalize within 1-4 weeks.
There have been cases of cytolytic and cholestatic hepatitis and liver failure, in some cases, accompanied by a fatal outcome.
Obstruction, perforation or ulcer of the stomach or intestines.
A small proportion of patients who received imatinib, ulceration of the gastrointestinal tract was noted, which in some cases may be a consequence of the local irritating effect of imatinib. Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract, were most often observed in patients with malignant stromal tumors of the gastrointestinal tract.In the case of metastatic malignant stromal tumors of the gastrointestinal tract, necrosis of the tumor can occur against a background of a tumor response, which in rare cases leads to perforation. Gastrointestinal obstruction most often occurred in patients with stromal malignant tumors, which can be caused by metastases or adhesions that occurred as a result of an earlier operation on the digestive tract (in the case of the drug as a means of adjuvant therapy).
Severe adverse events on the part of the respiratory system
Severe (sometimes fatal) adverse events were noted with imatinib: acute respiratory failure, pulmonary hypertension, interstitial lung disease, and pulmonary fibrosis. The concomitant pathology of the cardiovascular or respiratory systems can aggravate the severity of the undesirable phenomenon.