The safety profile of imatinib has been well studied. Most patients may experience certain adverse events (AEs) when using the drug.
The most frequent AE (> 10%) associated with taking the drug are: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, pain in stomach. Often marked peripheral edema mainly in the periorbital area and swelling of the lower extremities. Most of these AEs are mild or moderate.
The types of adverse events and the frequency of their development are similar when imatinib is taken by adults and children with leukemia.
When imatinib is used both for CML and for malignant GISO, myelosuppression, AE on the part of the gastrointestinal tract (GIT), edema and rash may occur.However, myelosuppression is more likely to develop in patients with CML, and patients with malignant GISOs are more likely to develop gastrointestinal and intrapulmonary hemorrhages.
Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration, are more common in GISO. Other serious AEs with imatinib may include hepatotoxicity, acute renal failure, hypophosphataemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children. It is possible to correct the dose of imatinib depending on the severity of AE, up to the withdrawal of the drug.
Unwanted reactions, recorded more often than single observations, are listed below for organs and systems, indicating the frequency of their occurrence. Frequency definition: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), very rarely (<1/10000), including individual messages, the frequency is unknown (the frequency can not be calculated from the available data).
Infectious and parasitic diseases: infrequently - Herpes simplex, herpes zoster, pneumonia1, upper respiratory tract infection, nasopharyngitis, sinusitis, subcutaneous tissue inflammation, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycosis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely - syndrome of tumor lysis.
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, gout, hypophosphatemia, dehydration, hyperuricemia, hyponatremia, hypercalcemia, hyperglycemia; 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, impaired taste, paresthesia, hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke, cerebral edema; rarely - increased intracranial pressure, convulsions, optic neuritis.
Disturbances on the part of the organ of sight: often - eyelid edema, conjunctivitis, increased tearing, blurred vision, conjunctival hemorrhages, dry eye syndrome; infrequent - eye irritation, eye pain, orbital edema, macular edema, bleeding in the sclera of the eye, retinal hemorrhages, blepharitis; rarely - cataracts, glaucoma, edema of the optic nerve, hemorrhage in the vitreous.
Hearing disorders and labyrinthine disorders: infrequently - noise in the ears, vertigo, hearing loss.
Heart Disease: infrequently - heart palpitations, chronic heart failure3, pulmonary edema, tachycardia, "hot flashes"4; rarely - arrhythmia, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, pericarditis, cardiac tamponade, increased blood pressure.
Vascular disorders: infrequently - hemorrhage4, thrombosis / embolism; rarely - hematoma, cold extremities, Reynaud's syndrome, subdural hematoma, lowering of blood pressure; very rarely - anaphylactic shock.
Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, dyspnea, cough; infrequently - pleural effusion5, pain in the pharynx or larynx, pharyngitis, acute respiratory failure10, interstitial pneumonia; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.
Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain6; often - bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; infrequent - ulceration of the oral mucosa, stomatitis, belching, gastrointestinal bleeding7, bleeding from a tumor of the digestive tract, necrosis of the tumor of the digestive tract, cheilitis, ascites, gastric ulcer, dysphagia, melena, pancreatitis, esophagitis, vomiting of blood, perforation of the gastrointestinal tract11, paralytic / obstructive intestinal obstruction; rarely - colitis, inflammation of the intestine, diverticulitis, vascular ectasia of the antral part of the stomach (GAVE-syndrome).
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, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequently - pustular rash, petechiae, increased sweating, urticaria, ecchymosis, predisposition to hematoma formation, nail damage, purpura, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, folliculitis, psoriasis, exfoliative dermatitis, bullous rash, palmar-plantar erythrodysesthesia; rarely acute febrile neutrophilic dermatosis (Sweet syndrome), angioedema, color change of nails, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, 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: Often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain8; often - swelling of the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis, rhabdomyolysis / myopathy, avascular necrosis / necrosis of the head of the femur; frequency is unknown - growth retardation in children.
Disorders from the kidneys and urinary tract: infrequently - pain in the kidney, frequent urination, hematuria, acute renal failure.
Violations of the genitals and mammary gland: infrequently - gynecomastia, breast enlargement, nipple pain, scrotum edema, erectile dysfunction, sexual dysfunction, menorrhagia, menstrual cycle disorder; rarely - bleeding from the cyst of the yellow body / ovary.
General disorders and disorders at the site of administration: Often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, chills, tremors, anasarca, weight loss; infrequently - general malaise, chest pain.
Laboratory and instrumental data: 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 is most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant GISOs.
2 Headache is most often noted in patients with inoperable and / or metastatic malignant GISOs.
3 Undesirable heart events, including chronic heart failure, are more common in patients with CML in the accelerated phase and with blast crisis compared to patients with CML in the chronic phase.
4 "Tides" are most often observed in patients with inoperable and / or metastatic malignant GISOs; bleeding (hematoma, hemorrhage) is most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant GIS.
5 Pleural effusion is more common in patients with CML in the acceleration phase and in blast crisis compared to patients with CML in the chronic phase.
6/7 Abdominal pain and gastrointestinal bleeding are most often observed in patients with inoperable and / or metastatic malignant GISOs.
8 Musculo-skeletal pains, including myalgia, arthralgia, bone pain,are more frequent in patients with CML compared to patients with inoperable and / or metastatic malignant GIS.
9 There are data on individual cases of development of hepatic insufficiency and liver necrosis when imatinib is used.
10 There are data on the occurrence of severe acute respiratory failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases with imatinib.
11 There are data on cases of development of perforations of the gastrointestinal tract with a lethal outcome when imatinib is used.
Description of individual adverse reactions
Inhibition of hematopoiesis
The frequency of oppression of hematopoiesis and the degree of its expression are maximal when imatinib is used in high doses and depends on the stage of CML. In general, the oppression of hematopoiesis with imatinib in patients with CML is reversible and in most cases does not require withdrawal of the drug or a reduction in its dose. Also noted are such phenomena as pancytopenia, lymphopenia and oppression of hematopoiesis.
Hemorrhage / bleeding
The most frequent clinically significant bleeding are bleeding from the digestive tract. Most often, they may occur in patients with advanced stages of CML and in patients with GISS, in whom they may be a consequence of the underlying disease (bleeding from the tumor due to its necrosis).
There are separate reports on cases of vascular ectasia of the antral part of the stomach (GAVE-syndrome).
In patients with CML, in whom hematopoiesis was suppressed prior to treatment, hemorrhages in the central nervous system or gastrointestinal tract may also occur during treatment.
Patients with leukemia with acute development of the disease may experience hemorrhage / hemorrhage due to thrombocytopenia or thrombocytopathy.
Swelling and fluid retention
Edema is a frequent undesirable reaction 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 correlates with the concentration of imatinib in the blood plasma. Most often, periorbital swelling may occur, with a slightly lower frequency - swelling of the lower extremities. Specific treatment is usually not required.
Concomitant adverse reactions, 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". In some cases, these phenomena can reach the degree of serious (including life-threatening).
In patients with edema and fluid retention, heart failure is rare. In patients with advanced stages of CML, the incidence of heart failure is higher than in patients of other categories, which can be explained by their weakened state as a whole. The same trend is observed with regard to renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention are elderly (> 65 years).
Rash and severe skin undesirable reactions
In patients receiving imatinib, there may be a generalized erythematous, spotty-papular and itchy rash, which can be resolved independently, despite continued treatment with imatinib, as well as an itching that is not accompanied by a rash; in some cases, there may be erythroderma.
A rash occurs in about a third of all patients receiving 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 occurs, its severity is negligible, no treatment is required. However, in rarer severe cases, for example, with Stevens-Johnson syndrome, erythema multiforme or rash with eosinophilia and systemic symptoms (DRESS), a temporary or complete cancellation of imatinib may be required. As a rule, the severity of the rash decreases after the use of antihistamines and glucocorticosteroids for topical application. In some cases, there may be a need for systemic therapy of glucocorticosteroids.
Hepatotoxicity
The drug may have a toxic effect on the liver. Disorders of biochemical parameters of liver function, as a rule, consist in a slight increase in the activity of aminotransferases and an increase in the concentration of bilirubin in the blood plasma.Toxic effects on the liver can usually occur during the first two months of treatment, but in a number of cases it may occur 6-12 months after the start of treatment. As a rule, after the abolition of imatinib, the biochemical parameters of liver function normalize within 1-4 weeks.
There are reports of cases of development 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
In patients receiving imatinib, ulceration of the gastrointestinal tract, which in some cases may be a consequence of the local irritating effect of imatinib, may be noted.
Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract, most often occur in patients with malignant GISOs.
In the case of metastatic GISO, necrosis of the tumor can occur against a background of a tumor response, which in rare cases leads to perforation.
Gastrointestinal obstruction most often can occur in patients with malignant GISOs, in whom its cause may be metastases or adhesions in the abdominal cavity,the result of previous surgery on the digestive tract (in the case of imatinib as a means of adjuvant therapy).
Severe adverse reactions from the respiratory system
Severe (sometimes fatal) AE can occur 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.