At the advanced stage of malignant diseases, the evaluation of unwanted reactions (HP) Imatinib is difficult due to a number of symptoms associated with multiple concomitant disorders, their progression and the intake of various medications.
With prolonged daily intake in adults and children with CML imatinib in general, is well tolerated. Most HP were mild or moderate. HP were similar in almost all patients receiving imatinib for various indications. The most frequent HP (> 10%) associated with taking the drug were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, abdominal pain, weakness, myalgia, muscle cramps, skin rash. Total frequency HP varying degrees of severity (with the exception of edema) and the incidence of serious HP were similar in patients taking therapy at a dose of 400 mg and 800 mg per day. In clinical studies, the most common swelling was observed in patients with malignant gastrointestinal stromal tumors who received the drug at a dose of 800 mg per day.
Myelosuppression, AE on the part of the gastrointestinal tract (GIT), edema and skin rash occur when imatinib is used in both CML and malignant stromal tumors of the gastrointestinal tract. In patients with CML, myelosuppression develops more often, and in patients with malignant stromal tumors of the gastrointestinal tract, gastrointestinal and intracutaneous hemorrhages often occur.Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration of the mucosa, occur more often with stromal tumors of the gastrointestinal tract.
Other serious AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.
Combined side effects, such as pleural effusion, ascites, pulmonary edema and a rapid increase in body weight with or without peripheral edema, can be qualified as "fluid retention" and in some cases reach serious (including life-threatening) levels.
The frequency of adverse reactions is classified according to the recommendations of the World Health Organization: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (> 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000), very rarely (<1/10000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).
Infectious and parasitic diseases: infrequent - herpes simple, herpes zoster, nasopharyngitis, pneumonia1, sinusitis, inflammation of the subcutaneous tissue, upper respiratory infections, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycosis.
Benign, malignant and unspecified neoplasms (including polyps and cysts): rarely - tumor lysis syndrome.
Violations of 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.
Disturbances from the nervous system: very often - headache2; often - dizziness, paresthesia, a violation of taste sensations, hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.
Disturbances on the part of the organ of sight: often - swelling 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 disorders: 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, pericardial effusion, increased blood pressure.
Vascular disorders: often - "tides"4, hemorrhage4; rarely - hematoma, subdural hematoma, cold extremities, lowering of arterial 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, gastric ulcer, vomiting of blood, dysphagia, pancreatitis; rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine.
Disorders from the liver and bile ducts: very often - increased activity of "liver" enzymes; infrequently - hyperbilirubinemia, hepatitis, jaundice; 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; infrequent - pustular rash, increased sweating, urticaria, ecchymosis, predisposition to the formation of hematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura,bullous rash; rarely acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, erythema multiforme, leukocytoclastic vasculitis, vesicular rash, Stevens-Johnson syndrome, acute generalized pustular exanthema.
Disturbances from musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain (including myalgia, arthralgia, bone pain)8; often swelling of the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis; frequency is unknown - growth retardation in children.
Disorders from the kidneys and urinary tract: infrequent - pain in the kidney, 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 - Increase in the concentrations of creatinine and activity of alkaline phosphatase (FA), creatine phosphokinase (CK), lactate dehydrogenase; rarely - increased activity of amylase in the blood plasma.
1 - Pneumonia was most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant gastrointestinal stromal tumors of the gastrointestinal tract.
2 - Headache was most often noted in patients with inoperable and / or metastatic gastrointestinal tumors.
3 - Undesirable heart events, including congestive heart failure, were more common in patients with CML in the acceleration phase and with blast crisis compared to patients with CML in the chronic phase (duration of follow-up is 1 year).
4 - "Tides" were most often observed in patients with inoperable and / or metastatic gastrointestinal tumors; bleeding (hematomas, hemorrhages) was most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic gastrointestinal tumors.
5 - Pleural effusion was more often observed in patients with CML in the accelerated phase and with a blast crisis compared with CML in the chronic phase (duration of follow-up is 1 year).
6/7 - Abdominal pain and gastrointestinal hemorrhage were most often observed in patients with inoperable and / or metastatic gastrointestinal tumors.
8 Musculoskeletal pain (including myalgia, arthralgia, pain in the bones) was more often observed in patients with CML compared with patients with inoperable and / or metastatic malignant tumors of the gastrointestinal tract.
9 - Individual cases of hepatic insufficiency and liver necrosis have been reported.
When using Imatinib in clinical practice, as well as in the course of additional clinical studies, the following adverse reactions were reported listed in organs and systems, indicating the frequency of their occurrence: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10,000, <1/1000), very rarely (<1/10 000), including individual messages. The relationship between drug use and these adverse reactions has not been established (the size of the patient population is unknown).
Disturbances from the nervous system: infrequently - edema of the brain.
Vision disorders: rarely - vitreous hemorrhage.
Heart Disease: rarely - pericarditis, cardiac tamponade, very rarely - anaphylactic shock.
Vascular disorders: infrequently - thrombosis / embolism.
Disturbances from the respiratory system, chest and mediastinal organs: infrequent acute respiratory failure1, interstitial pneumonia.
Disorders from the digestive system: infrequently paralytic / obturation intestinal obstruction, bleeding from the tumor of the gastrointestinal tract, necrosis of the tumor of the gastrointestinal tract, perforation of the gastrointestinal tract2; rarely - diverticulitis, vascular ectasia of the antrum of the stomach (GAVE-syndrome).
Disturbances from the skin and subcutaneous tissues: infrequently - palmar-plantar erythrodysesthesia; rarely - lichenoid keratosis, red flat lichen; very rarely - toxic epidermal necrolysis; frequency unknown - drug rash with eosinophilia and systemic symptoms (DRESS).
Disturbances from musculoskeletal and connective tissue: rarely - avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy.
1-Individual reports on the development of severe acute respiratory failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases;
2-There are reports of cases of development of perforations of the gastrointestinal tract with a lethal outcome.
Description of individual unwanted drug reactions
Inhibition of hematopoiesis
The frequency of oppression of hematopoiesis and the degree of its expression were maximal when the drug was used 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 in patients with malignant stromal tumors of the gastrointestinal tract, in which they can be a consequence of the underlying disease (bleeding from the tumor due to tumor necrosis).
In the post-marketing period, separate reports were received on cases of vascular ectasia of the antral stomach (GAVE-syndrome)
In patients with CML, in whom hematopoiesis was suppressed prior to treatment, hemorrhages in the central nervous system or gastrointestinal tract are often observed during treatment. It was found that patients with leukemia with acute development of the disease often have hemorrhages / hemorrhages due to 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 is periorbital edema, with a slightly lower frequency - swelling of the lower extremities. Specific treatment is usually not required. Combined side effects, such as pleural effusion, ascites, pulmonary edema and a rapid increase in body weight with or without peripheral edema, can be qualified as "fluid retention" and in some cases reach serious (including life-threatening) levels.
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 (over 65).
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 be resolved independently, despite 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 or exfoliative lesions on the forearm, trunk or face or in the form of generalized rash with systemic manifestations. Although in most cases the rash is mild and goes away without treatment, in more severe cases (for example,with Stevens-Johnson syndrome, erythema multiforme or rash with eosinophilia and systemic symptoms (DRESS)) may require a temporary or complete withdrawal of the drug. As a rule, the severity of the rash decreases after the appointment of antihistamines and glucocorticosteroids (GCS) for topical application. In some cases, it is required to use GCS drugs for systemic use.
Hepatotoxicity
The drug may have a toxic effect on the liver. Disorders of biochemical indicators of liver function, as a rule, consists in a slight increase in the activity of aminotransferases and an increase in serum bilirubin concentration. The toxic effect on the liver usually manifests itself 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 are normalized 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 intestine
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 occur most often in patients with malignant gastrointestinal stromal tumors in which its cause may be metastasized or adhesions resulting from prior operations on the gastrointestinal tract (in the case of using the drug as adjuvant therapy).
Severe adverse events on the part of the respiratory system
Severe (sometimes fatal) AEs were noted against imatinib, namely: 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 AEs.
If any of the side effects listed in the manual are aggravated, or the patient has noticed any other side effects not listed in the instructions, you should notify the doctor.