Safety profile of the preparation Imatinib well studied. Most patients experience certain adverse events (AEs) during the use of the drug. The most frequent AE (> 10%) associated with taking the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, pain in stomach. Most of these AEs were mild or moderately severe.Only 2-5% of patients discontinued drug therapy Imatinib because of the development of AE.
Types of AEs and the frequency of their development are similar when taking the drug Imatinib adults and children with leukemia.
Myelosuppression, AE on the part of the gastrointestinal tract, swelling and rash occur with the use of imatinib 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, occur more often with stromal GI tract. Other serious AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.
It is possible to adjust the dose of the drug depending on the severity of AE, right up to the withdrawal of the drug.
In clinical trials in patients with CML and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract, the followingthe undesirable phenomena listed below in the organs and systems with the frequency of their occurrence: very often (≥1 / 10), often (≥1 / 100 <1/10), infrequently (≥1 / 1000 <1/100), rarely ( ≥1 / 10000 <1/1000), very rarely (<1/10000), including individual messages.
Infectious and parasitic diseases:
infrequently - herpes simple, herpes zoster, nasopharyngitis, pneumonia, sinusitis, inflammation of the subcutaneous tissue, infections of the upper respirationpathways, urinary tract infections, gastroenteritis, sepsis;
rarely - mycoses.
Benign, malignant and unspecified neoplasms (including cysts and polyps):
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, 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.
Disturbances on the part of the organ of sight:
often - eyelid swelling, increased tearing, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision;
infrequent - eye irritation, eye pain, orbital edema, bleeding in the sclera of the eye, 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 - palpitations, chronic heart failure3, pulmonary edema, tachycardia, "hot flashes"4;
rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, increased blood pressure, hematomas.
Vascular disorders:
infrequently - hemorrhages4;
rarely - hematomas, subdural hematomas, cold extremities, lowering of arterial pressure, Raynaud's syndrome.
Disturbances from the respiratory system, chest, mediastinum:
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 oral mucosa, gastrointestinal bleeding7, belching, melena, esophagitis, ascites, stomach ulcer, vomiting of blood, cheilitis, dysphagia, pancreatitis;
rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine.
Disturbances 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, itching, dry skin, erythema, alopecia, night sweats, photosensitivity reactions;
infrequently - pustular rash, petechiae, increased sweating, urticaria, ecchymosis, increased predisposition to education hematoma, hyperpigmentation / hypopigmentation of the skin, exfoliationoily dermatitis, damage nails, folliculitis, psoriasis, purpura, bullous rash;
rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, vesicular rash.
Disturbances from musculoskeletal and connective tissue:
very often - muscle spasms and cramps, musculoskeletal pains, including myalgia, arthralgia, bone pain8;
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:
infrequently - kidney pain, hematuria, acute renal failure, frequent urination.
Violations of the genitals and mammary gland:
infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual irregularities, 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, an increase in the activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase, and serum creatinine;
rarely - increased activity of amylase in the blood plasma.
1Pneumonia was most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract.
2Headache is most common in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors.
3Undesirable cardiac events, including chronic heart failure, were more common in patients with CML in the accelerated phase and with blast crisis compared to patients with CML in the chronic phase (duration of follow-up is 1 year).
4"Tides" was most frequently observed in patients with neoperAbdominal and / or metastatic malignant stromal tumors of the gastrointestinal tract; bleeding (haematomas, hemorrhages) was most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract.
5Pleural effusion was more common in patients with CML in the acceleration phase and in blast crisis compared to patients with CML in the chronic phase (duration of follow-up is 1 year).
6,7Pain in the abdomen and gastrointestinal hemorrhage were most often observed in patients with inoperable and / or metastatic gastrointestinal malignant tumors.
8Musculoskeletal pain including myalgia, arthralgia, bone pain, were more common in patients with CML as compared with patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors.
9Individual cases of hepatic insufficiency and liver necrosis have been reported.
When using the drug Imatinib in clinical practice, as well as in the course of additional clinical studies the following AEs were observed.
Listed below for organs and systems with the frequency of their occurrence: very often (≥1 / 10), often (≥1 / 100 <1/10), infrequently (≥ 1/1000 <1/100), rarely (≥1 / 10000 <1/1000), very rarely (<1/10000), including individual messages. The relationship between drug use and the following AEs is not established (the size of the patient population is unknown).
Disturbances from the nervous system:
infrequently - edema of the brain.
Disturbances on the part of the organ of sight:
rarely - vitreous hemorrhage.
Violations from the heart and blood vessels:
infrequently - thrombosis / embolism;
rarely - pericarditis, cardiac tamponade;
very rarely - anaphylactic shock.
Disturbances from the respiratory system, chest, mediastinum:
infrequent acute respiratory failure1, interstitial pneumonia.
Disorders from the digestive system:
infrequently - ileus (intestinal obstruction), bleeding from the tumor of the digestive 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.
Violations of the genitals and mammary gland:
very rarely - women bleed from the cyst of the yellow body / ovary.
There are some reports of the development of severe acute respiratory failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases.
Individual cases of development of perforations of the gastrointestinal tract with lethal outcome were reported.
Description of individual unwanted drug reactions
Inhibition of hematopoiesis
The frequency of oppression of hematopoiesis and the degree of its expression were maximal in the case of using the drug in high doses and, apparently, depended on the stage of CML.In general, oppression hemopoiesis against the background of the drug Imatinib in patients with CML was reversible and in most cases did not require withdrawal of the drug or a decrease in its dose. 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 patients with CML, in whom the hematopoiesis was suppressed already before the beginning of treatment, during treatment often hemorrhages in the central nervous system or gastrointestinal tract are also noted. In the post-marketing period, separate reports were received on cases of vascular ectasia of the antral stomach (GAVE-syndrome). 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 a generalized erythematous, spotty-papular and itchy rash that could pass independently despite the continued treatment with the drug.Some patients developed 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. In most cases, when the rash occurred, its severity was insignificant, no treatment was required.
However, in rarer severe cases, for example, with Stevens-Johnson syndrome, erythema multiforme or rash with eosinophilia and systemic symptoms (DRESS), it may be necessary to temporarily or completely cancel the drug. As a rule, the severity of the rash decreases after the appointment of antihistamines and glucocorticosteroids for topical application. In some cases, it is required to use glucocorticoid 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,are a slight increase in the activity of aminotransferases and an increase in the 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 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 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 in the abdominal cavity 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) HI were observed against the background of drug administration 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 these instructions side effects are compounded or you notice any other side effects not listed in this leaflet tell your doctor.