Patients with advanced malignant tumors can have many medically aggravated conditions,which make it difficult to assess the causal relationship of the adverse reaction with imatinib due to the presence of a variety of symptoms associated with the ongoing disease, its progression and simultaneous administration of several drugs.
In clinical trials of CML due to adverse reactions, 2.4% of patients with a newly diagnosed disease discontinued treatment. 4% of patients with the disease in the chronic phase with the ineffectiveness of previous therapy with interferon. 4% of patients in the aze of acceleration with ineffectiveness of previous therapy with interferon and 5% of patients in the phase of blast crisis with ineffectiveness of previous therapy with interferon. In clinical studies of imatinib during treatment of GISD due to adverse reactions, 4% of patients stopped taking it.
The profile of adverse reactions differed for two indications. In patients with CML, myelosuppression is more common than in patients with GIS. which is probably due to the presence of the disease itself. In 7 (5%) patients with inoperable and / or metastatic GISO, bleeding at 3/4 was observed in the general toxicity scale: 3 patients with gastrointestinal bleeding.3 patients with intracelach hemorrhage, both types of bleeding were observed in 1 patient. Gastrointestinal swelling can be a source of gastrointestinal bleeding (see section "Special instructions"). Gastrointestinal and intratumoral bleeding can be serious and sometimes fatal. The most frequent adverse events (> 10%) associated with imatinib. in both cases: mild nausea, vomiting, diarrhea, abdominal pain, weakness, myalgia, muscle cramps, rash. A frequent adverse reaction in all studies was superficial edema, mainly described as periorbital edema or edema of the lower limbs. However, these edemas were rarely severe and were eliminated by taking diuretics, and by taking other appropriate measures to eliminate edema or reduce the dose of imatinib.
When taking imatinib in combination with high doses of chemotherapy in patients with Ph+ ALL caused temporary manifestations of hepatotoxicity in the form of increased activity of "hepatic" transaminases and hyperbilirubinemia.
There may be several adverse reactions,described collectively as "fluid retention" in the body: pleural effusion, ascites, pulmonary edema and a rapid increase in body weight with or without superficial edema. These reactions, as a rule, can be eliminated by the temporary cancellation of imatinib, taking diuretics, or taking other appropriate measures to eliminate edema. However, some of the above reactions may be severe or life threatening. There have been reports of fatal cases in patients with blast crisis, who have had a complex of diseases in the history of the disease: pleural effusion, congestive heart insufficiency and renal insufficiency. There were no specific features in the imatinib safety profile for the infant population.
In clinical trials, the following adverse events were noted in the patients listed below in terms of 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), the frequency is unknown (can not be determined from available data).
In each subgroup, unwanted reactions are listed in order of frequency of occurrence, the most common are the first.
Infectious and parasitic diseases: infrequent herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, inflammation of the subcutaneous tissue, upper respiratory infections, influenza, urinary tract infections, gastroenteritis, sepsis: rarely - mycoses.
Benign, malignant and unspecified neoplasms (including polyps and cysts): rarely - tumor lysis syndrome.
From the side 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.
From the side of metabolism and nutrition: often - anorexia; infrequently - hypokalemia. increased appetite, hypophosphatemia. decreased appetite, dehydration, gout, hyperuricemia. hypercalcemia. hyperglycemia. hyponatremia: rarely hyperkalemia, hypomagnesemia.
Disorders of the psyche: often - insomnia; infrequently - depression, decreased libido, anxiety; rarely confusion.
From the nervous system: very often - headache2; often - dizziness, paresthesia, impaired taste,hypoesthesia: infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.
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, bleeding in the sclera of the eye, retinal hemorrhages, blepharitis, macular edema; rarely - cataract, glaucoma, edema of the optic disc.
From the side of the hearing organ and labyrinthine disorders: infrequently - vertigo, noise in the ears, hearing loss.
From the heart: infrequent - palpitations, tachycardia, congestive heart failure3, pulmonary edema: rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.
From the side of the vessels: often - "tides"4, hemorrhage4; infrequently - increase of arterial pressure, hematomas, subdural hematoma, cooling of limbs, lowering of arterial pressure, Raynaud's syndrome.
FROMabout the respiratory system, chest, mediastinum: often shortness of breath, epistaxis, cough: infrequent pleural effusion5, pain in the pharynx or larynx, pharyngitis: rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.
From the digestive system: very often - nausea, diarrhea, vomiting, dyspepsia, abdominal pain6: often - flatulence, bloating, gastroesophageal reflux, constipation, 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.
From the liver and bile ducts: often - increased activity of "liver" transaminases; infrequently hyperbilirubinemia. hepatitis, jaundice; rarely liver failure9, necrosis of the liver9.
From the skin and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often - itchy skin, puffiness of the face, dry skin, erythema, alopecia, night sweats,photosensitivity reaction; infrequent - pustular rash, bruising, increased sweating, urticaria, ecchymosis, increased predisposition to hematoma formation, hypotrichosis, skin hypopigmentation, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, hyperpigmentation of skin, bullous rash; rare - acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, vesicular rash, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, drug rash with eosinophilia and systemic symptoms (DRESS).
From the musculoskeletal system and connective tissue: very often muscle spasms and cramps, musculoskeletal pain (including myalgia, arthralgia, bone pain8); often - swelling of joints: infrequent - stiffness of muscles and joints; rarely - muscular weakness, arthritis, rhabdomyolysis / myopathy; frequency is unknown - growth retardation in children.
From the urinary system: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.
Co side of the reproductive system and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia. violation of the menstrual cycle, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum; rarely bleeding from the cyst of the yellow body / ovary.
General disorders and disorders at the site of administration: very often - fluid retention, swelling, increased fatigue; often - weakness, fever, anasarca, chills, trembling; infrequently - chest pain, general malaise.
From the laboratory indicators: very often - weight gain; often - decreased body weight; infrequently - an increase in serum creatinine, activity of creatine phosphokinase, lactate dehydrogenase, alkaline phosphatase; rarely - increased activity of amylase in 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 gastrointestinal malignant tumors.
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 accelerated 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 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 .
5 - Pleural effusion was more often observed in patients with gastrointestinal and CML stromal tumors in the phase of acceleration and with blast crisis in comparison with patients with CML in the chronic phase.
6/7- Abdominal pain and gastrointestinal hemorrhage were most often observed in patients with inoperable and / or metastatic gastrointestinal malignant tumors.
8 - Musculoskeletal pain and related adverse events (in myalgia of myalgia, arthralgia, bone pain) were more frequent in patients with CML than in patients with inoperable and / or metastatic gastrointestinal malignant tumors.
9 - Fatal cases of hepatic insufficiency and liver necrosis have been reported.
In the application of imatinib in clinical practice, as well as in additional clinical studies, the adverse reactions listed below were noted. Since information on adverse reactions has been obtained in the form of spontaneous reports from patients whose population size is not known accurately, it is not always possible to establish the incidence of adverse reactions or the relationship between imatinib use and these adverse reactions.
Post-registration application experience
Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown - bleeding from the tumor / tumor necrosis.
From the immune system: frequency unknown - anaphylactic shock.
Co side of the nervous system: frequency unknown - edema of the brain.
From the side of the organ of vision: frequency unknown - hemorrhage in the vitreous.
From the heart: frequency is unknown - pericarditis, cardiac tamponade.
From the side of the vessels: frequency unknown - thrombosis / embolism.
From the respiratory, thoracic, mediastinal: frequency unknown - acute respiratory failure1, interstitial lung disease.
From the gastrointestinal tract: rarely - vascular ectasia of the antrum of the stomach (GAVE-syndrome); frequency unknown - paralytic / obstructive intestinal obstruction, perforation of the gastrointestinal tract, diverticulum pt.
From the skin and subcutaneous tissues: frequency unknown - palmar-plantar erythrodysesthesia; lichenoid keratosis, lichen planus; toxic epidermal necrolysis; drug rash with eosinophilia and systemic symptoms (DRESS-cindre).
From the osteomuscular and connective tissue: frequency unknown - Avascular necrosis / necrosis of the head of the femur: growth retardation in children.
1 - 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.
Description of individual adverse reactions
Inhibition of hematopoiesis
In patients with CML, cytopenia was observed in all studies, especially neutropenia and thrombocytopenia, its frequency was higher when taking high doses of imatinib> 750 mg (phase I). However, the frequency of cytopenia also reliably depended on the stage of the disease. Frequency of neutropenia 3 or 4 degrees (absolute number neutrophils <1.0х109/ l) and thrombocytopenia (the number of platelets <50x109/ l) was 4 and 6 times higher in the blast crisis phase and in the acceleration phase (59-64% and 44-63% for neutropenia and thrombocytopenia, respectively) compared with the newly diagnosed CML in the chronic phase (16.7% neutropenia and 8.9% thrombocytopenia). In patients with newly diagnosed CML in the chronic phase of grade 4 neutropenia (absolute number of neutrophils <0.5x109/ l) and thrombocytopenia (number of platelets <10x109/ l) were observed in 3.6% and less than 1% of patients, respectively. The median duration of episodes of neutropenia and thrombocytopenia usually ranged from 2 to 3 weeks and from 3 to 4 weeks, respectively. These undesirable phenomena, as a rule, are stopped by a decrease in the dose of imatinib. or temporary cancellation of his admission, but in rare cases they may require a complete cancellation of imatinib administration or its cancellation for a long time.In children with CML, the most common toxic effect was observed in the form of grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia and anemia. These reactions mainly occurred in the first months of treatment.
In general, oppression of hematopoiesis with imatinib in patients with CML was reversible and in most cases did not require the abolition of imatinib or the reduction of its dose. The abolition of imatinib was required in a small number of cases. Also observed were such phenomena as pancytopenia, lymphopenia and oppression of hematopoiesis.
In studies in patients with inoperable and / or metastatic malignant GISO, anemia of grade 3 and 4 was reported in 5.4% and 0.7% of patients, respectively. This phenomenon, but at least in some patients, may be associated with bleeding in the gastrointestinal tract or intracutaneous hemorrhage. Neutropenia of grade 3 and 4 was observed in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. There were no patients with thrombocytopenia of the 4th degree. The decrease in the number of leukocytes and neutrophils occurred mainly during the first six weeks of therapy, with the establishment of relatively stable values after a given period of time.
Biochemical indicators of blood
A significant increase in the activity of hepatic transaminases (<5%) or an increase in bilirubin concentration (<1%) was observed in patients with CML and, as a rule, these adverse events were resolved after lowering the dose of imatinib or interrupting treatment (the median duration of these adverse events was approximately one week). The treatment was canceled or interrupted for a long time because of a deviation from the norm of laboratory tests of liver function in less than 1% patients with CML. An increase in alanine aminotransferase activity of grade 3 or 4 was observed in 6.8% of patients with GISD, and an increase in activity of aspartate aminotransferase of grade 3 or 4 in 4.8%. The increase in bilirubin concentration was less in 3% of patients.
There have been reports of the development of cytolytic and cholestatic hepatitis and liver failure, in some cases fatal, including the case of a patient taking high doses of paracetamol.
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 and respiratory systems can aggravate the severity of the undesirable phenomenon.