Composition, form of production and packaging
Capsules hard gelatinous, в„–3, the case of white color, a lid of light blue color; the contents of the capsules are white or white powder with a yellowish or brownish hue.
1 caps.
Imatinib mesylate 59.75 mg,
which corresponds to the content of Imatinib 50 mg
Excipients: cellulose microcrystalline - 48.95 mg, crospovidone - 4 mg, silicon colloidal dioxide - 1.15 mg, magnesium stearate - 1.15 mg.
The composition of the capsule body: titanium dioxide - 2%, gelatin - qs up to 100%.
Composition of capsule capsule: titanium dioxide - 1%, indigocarmine - 0.0161%, gelatin - qs up to 100%.
10 pieces. - packings cellular planimetric (3) - packs cardboard.
30 pcs. - vials polymeric (1) - packs cardboard.
Capsules hard gelatinous, в„–1, the case of white color, a lid of dark blue color; the contents of the capsules are white or white powder with a yellowish or brownish hue.
1 caps.
Imatinib mesylate 119.5 mg,
which corresponds to the content of Imatinib 100 mg
Excipients: microcrystalline cellulose - 97.9 mg, crospovidone - 8 mg, silicon dioxide colloid - 2.3 mg, magnesium stearate - 2.3 mg.
The composition of the capsule body: titanium dioxide - 2%, gelatin - up to 100%.
Composition of capsule capsule: titanium dioxide - 1%, indigocarmine - 0.1333%, gelatin - up to 100%.
12 pcs. - packings cellular planimetric (2) - packs cardboard.
12 pcs. - packings cellular planimetric (3) - packs cardboard.
12 pcs. - packings cellular planimetric (4) - packs cardboard.
12 pcs. - packings cellular planimetric (8) - packs cardboard.
12 pcs. - packings cellular planimetric (10) - packs cardboard.
12 pcs. - packings cellular planimetric (15) - packs cardboard.
24 pcs. - vials polymeric (1) - packs cardboard.
36 pcs. - vials polymeric (1) - packs cardboard.
48 pcs. - vials polymeric (1) - packs cardboard.
96 pcs. - vials polymeric (1) - packs cardboard.
120 pcs. - vials polymeric (1) - packs cardboard.
180 pcs. - vials polymeric (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Imatinib exerts a selective inhibitory effect on the Sbl-Abl-tyrosine kinase enzyme formed by the fusion of the breakpoint cluster region and the Abl (Abelson) protooncogene at the cellular level, selectively inhibits proliferation and induces apoptosis of the cell lines expressing the Sbl-Abl tyrosine kinase , including immature leukemia cells formed in patients with positive for the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia.
Imatinib selectively inhibits the Vs-Abl-positive colonies obtained from the blood cells of patients with chronic myelogenous leukemia.
Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal cells expressing tyrosine kinase with a c-Kit receptor mutation.
Activation of receptors to platelet growth factors or Abl fragment of tyrosine kinase may cause the development of both myelodysplastic / myeloproliferative diseases and hypereosinophilic syndrome and chronic eosinophilic leukemia and swelling dermatofibrosarcoma.
Activation of the c-Kit receptor tyrosine kinase and receptors for platelet growth factors may underlie the pathogenesis of systemic mastocytosis.
Imatinib inhibits signaling in cells and cell proliferation resulting from impaired regulation of platelet and stem cell growth factors, the c-Kit receptor, and the tyrosine kinase Abl fragment.
When imatinib was used in patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors, there was a significant increase in the overall survival of patients (48.8 months) and disease-free survival (21 months).
Adjuvant therapy with a drug of gastrointestinal stromal tumors within 1 year reduces the risk of relapse by 89%, increases the survival rate without symptoms (38 months Imatinib compared with 20 months placebo).
Adjuvant therapy with the preparation of gastrointestinal stromal tumors for 3 years leads to a significant increase in overall survival and survival without signs of disease progression compared with therapy for 1 year.
PHARMACOKINETICS
The pharmacokinetic parameters of imatinib were evaluated in the dose range from 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on the first day, as well as when equilibrium concentrations of imatinib in plasma were reached on day 7 or 28.
Suction
After oral administration, the bioavailability of the drug is on average 98%. The variation coefficient for AUC is 40-60%. In the dose range from 25 to 1000 mg, a direct linear dependence of the AUC value on the dose value was observed.
When taking the drug with food high in fat, in comparison with fasting, there is a slight decrease in the degree of absorption (a decrease in Cm of Imatinib in blood plasma by 11%, AUC by 7.4%) and slowing of the rate of absorption (an increase in the time to reach C max imatinib in the blood plasma for 1.5 hours).
Distribution
About 95% of imatinib binds to plasma proteins (mainly albumin and acid alpha-glycoproteins, to a small extent - with lipoproteins).
Metabolism
Imatinib is metabolized mainly in the liver with the formation of the main metabolite (N-demethylated piperazine derivative) circulating in the bloodstream. In vitro imatinib metabolite has pharmacological activity similar to that of the starting material. The AUC value of the metabolite is 16% of the Imatinib AUC. The binding of a metabolite with plasma proteins is similar to that of imatinib.
Excretion
It is excreted mainly in the form of metabolites within 7 days after a single dose: 68% - by the intestine and 13% by the kidneys. In an unchanged form, about 25% of the dose is taken (20% by the intestine and 5% by the kidneys). T 1/2 imatinib is about 18 hours.
With repeated administration of the drug 1 time / day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial concentration by 1.5-2.5 times.
Pharmacokinetics in specific patient groups
In patients older than 65 years, V d increases insignificantly (by 12%).
For patients with a body weight of 50 kg, the average clearance value of imatinib is 8.5 l / h, and for patients with a body weight of 100 kg, 11.8 l / h. However, these differences are not significant and do not require correction of the dosage regimen depending on the patient's body weight.
The pharmacokinetics of imatinib does not depend on sex.
Changes in clearance and V d Imatinib values ​​with simultaneous use with other drugs are unimportant and do not require dose changes.
In children and adolescents under the age of 18, as in adults, there is a rapid absorption of the drug when ingested. AUC in this group of patients in the dose range of 260 and 340 mg / m 2 is similar to that in adults in the dose range of 400 mg and 600 mg, respectively.
When the AUC 0-24 values ​​were compared for children and adolescents on the first and eighth days after repeated taking of the drug at 340 mg / m 2 1 times / day, the value of this indicator increased by 1.7 times, indicating the cumulation of imatinib.
In patients with varying degrees of impaired liver function, the mean AUC values ​​do not increase.
When imatinib is used in patients with mild or moderate renal dysfunction (CK> 30 ml / min), the plasma exposure is increased by a factor of 1.5-2.0, corresponding to an increase in the concentration of acid alpha-glycoproteins (the main plasma proteins that bind imatinib). Since the drug is slightly excreted by the kidneys, the clearance of free imatinib was the same for healthy volunteers and patients with impaired renal function. Correlations between the exposure of the drug and the severity of renal disorders have not been revealed.
INDICATIONS
- the first detected positive for the Philadelphia chromosome chronic myeloid leukemia (Ph + CML) in children and adults;
- positive for the Philadelphia chromosome (Ph +) CML in the chronic phase with failure of previous therapy with interferon alpha or in the phase of acceleration, or blast crisis in children and adults;
- the first diagnosed positive for the Philadelphia chromosome acute lymphoblastic leukemia (Ph + ALL) in adult patients in combination with chemotherapy;
- recurrent or refractory Ph + ALL in adult patients as monotherapy;
- Myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with gene rearrangements of the platelet-derived growth factor receptor in adult patients;
- Systemic mastocytosis (CM) in adult patients with no D816V c-Kit mutation or with an unknown c-Kit mutation status;
- hypereosinophilic syndrome and / or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGRFО±-tyrosine kinase;
- Inoperable and / or metastatic malignant gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;
- adjuvant therapy of gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;
- inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma in adult patients.
DOSING MODE
The drug should be taken orally during meals, with a full glass of water to reduce the risk of developing gastrointestinal disorders.
The drug in a dose of 400 mg / day and 600 mg / day is taken in 1 dose; The daily dose of 800 mg should be divided into 2 doses - 400 mg in the morning and in the evening.
Patients who are not able to swallow the whole capsule, for example children, the drug can be taken in a diluted form; the contents of the capsules are diluted with water or apple juice. The resulting suspension is ingested immediately after preparation. After opening the capsules, wash hands immediately.
Treatment with the drug is carried out as long as the clinical effect remains.
In chronic myelogenous leukemia (CML), the recommended dose of Imatinb depends on the phase of the disease. In the chronic phase of CML the dose is 400 mg / day; in the phase of acceleration and with a blast crisis - 600 mg / day. The drug should be taken 1 time / day.
In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, a dose increase from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease and from 600 mg to 800 mg per day in patients in the accelerated phase and with a blast cry. Such a dose increase may be necessary for the progression of CML (at any stage), in the absence of a satisfactory hematologic response after 3 months of treatment, a cytogenetic response at 12 months of therapy, or loss of a previously hematologic and / or cytogenetic response.
Calculation of the dosing regimen in children over 2 years of age is based on body surface area. Doses of 340 mg / m 2 / day are recommended in children with chronic phase of CML and acceleration phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken simultaneously or divided into 2 equal doses - in the morning and in the evening.
With Ph + acute lymphoblastic leukemia, the recommended dose of Imatin is 600 mg / day.
With inoperable and / or metastatic malignant gastrointestinal stromal tumors, myelodysplastic / myeloproliferative diseases, the recommended dose of Imatinb is 400 mg / day. In the absence of side effects of the drug and an inadequate response, an increase in the daily dose of Imatinb from 400 mg to 600 mg or up to 800 mg is possible.
If signs of disease progression appear, Imatin therapy should be discontinued.
When the drug is used as an adjuvant therapy in patients with gastrointestinal stromal tumors, the recommended dose is 400 mg / day. The minimum duration of treatment is 3 years. The optimal duration of adjuvant therapy is not established.
With inoperable, relapsing and / or metastatic bulging dermatofibrosarcoma, the recommended dose of Imatinb is 800 mg / day.
With systemic mastocytosis, in the absence of D816V c-Kit mutation, the recommended dose of the preparation of ImatinB is 400 mg / day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg / day.
In systemic mastocytosis caused by abnormal FIP1L1-PDGFRО±-tyrosine kinase, resulting from the fusion of the Fip like1 and PDGFR genes, the recommended initial dose is 100 mg / day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.
With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose is 400 mg / day.
In patients with HES / HAL, caused by abnormal FIP1L1-PDGFRО±-tyrosine kinase, the recommended initial dose is 100 mg / day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible. Treatment with the drug is carried out as long as the clinical effect remains.
Since imatinib is metabolized mainly in the liver, patients with mild, moderate or severe impairment of liver function should be prescribed Imatinb in a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose of the drug should be reduced. Caution is advised to prescribe the drug to patients with severe hepatic impairment.
Kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with impaired renal function or in patients requiring systematic hemodialysis, treatment with Imatib should begin with a minimum effective dose of 400 mg 1 time / day, taking care. With intolerance to Imatin, the initial dose of the drug can be reduced, with insufficient effectiveness - increased.
Older patients do not need to adjust the dosage regimen of the drug.
Correction of the dosing regimen with the development of non -hematological side effects of the drug
With the development of any serious non-hematologic side effect associated with taking the drug, therapy should be discontinued until the situation resolves. The treatment can then be resumed at a dose that depends on the severity of the observed side effect.
With an increase in the concentration of bilirubin and the activity of liver transaminases in the blood serum 3 and 5 times higher than the IGN, respectively, treatment with the drug should be temporarily suspended until the concentration of bilirubin decreases to less than 1.5? VGN and the activity of hepatic transaminases to less than 2.5? VGN.
Therapy with ImatinB is resumed with a reduced daily dose: in adults, the dose is reduced from 400 mg / day to 300 mg / day or from 600 mg / day to 400 mg / day, or from 800 mg / day to 600 mg / day; in children from 340 mg / m 2 / day to 260 mg / m 2 / day.
Correction of the dosing regimen with the development of serious side effects from the hematopoiesis system (severe thrombocytopenia, neutropenia)
In the event of neutropenia and thrombocytopenia, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these undesirable phenomena.
In systemic mastoidosis and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / CEL) caused by abnormal FIP1L1-PDGFRО±-tyrosine kinase(initial dose of Imatinb 100 mg), in the case of an absolute decrease in the number of neutrophils <1000 / ОјL and / or the number of platelets <50000 / ОјL is recommended:
1. cancel the preparation of Imatinum until the absolute number of neutrophils is? 1500 / ОјL and platelets? 75,000 / ОјL;
2. Renew the treatment with Imatinb in the dose used before the interruption of therapy.
In the chronic phase of CML in children and adults (initial dose for adults - 400 mg, for children - 340 mg / m 2 ), malignant gastrointestinal stromal tumors, MDS / MPZ, SM and HP / CHL in adult patients (initial dose for adults - 400 mg) in the case of a decrease in the absolute number of neutrophils <1000 / ОјL and / or the platelet count <50000 / ОјL is recommended:
1. cancel the preparation of Imatinum until the absolute number of neutrophils is? 1500 / ОјL and platelets? 75,000 / ОјL;
2. Renew the treatment with Imatinb in the dose used before the interruption of therapy.
3. In the case of a repeated decrease in the number of neutrophils <1000 / ОјL and / or the number of platelets <50000 / ОјL, repeat the actions indicated in paragraph 1, and then resume treatment with Imatinib at a reduced dose of 300 mg (in children - 260 mg / m 2 ).
In the phase of acceleration and blast crisis of CML in children and adults and in Ph + ALL in adult patients (initial dose for adults is 600 mg, for children - 340 mg / m 2 ) in case of absolute number of neutrophils <500 / ОјL and / or number platelets <10,000 / ОјL after one or more months of treatment is recommended:
1. check whether cytopenia is a consequence of leukemia (bone marrow examination);
2. If cytopenia is not associated with leukemia, reduce the dose of Imatin to 400 mg (in children - up to 260 mg / m 2 );
3. If cytopenia persists for 2 weeks, reduce the dose to 300 mg (in children - up to 200 mg / m 2 );
4. If cytopenia persists for 4 weeks and its association with leukemia is not confirmed, discontinue Imatinb until the absolute number of neutrophils is> 1000 / ОјL and platelets> 20,000 / ОјL; then resume treatment with Imatinb in a dose of 300 mg (in children - 260 mg / m 2 ).
In the case of an inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of the preparation of Imatinib 800 mg), in the case of a decrease in the absolute number of neutrophils <1000 / ОјL and / or platelet count <50000 / ОјL, it is recommended:
1. cancel the preparation of Imatinum until the absolute amount of neutrophils is> 1500 / ОјL and platelets> 75,000 / ОјL;
2. resume treatment with Imatinb in a dose of 600 mg.
If the number of neutrophils is less than 1000 / ОјL and / or the number of platelets is less than 50,000 / ОјL, repeat the actions indicated in paragraph 1, and then resume treatment with Imatinib at a reduced dose of 400 mg.
SIDE EFFECT
The safety profile of imatinib has been well studied. Most patients with the use of the drug experience certain adverse events. The most common adverse events (> 10%) associated with drug intake were neutropenia, thrombocytopenia, anemia, headache, neuralgia, edema, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, fatigue, pain in a stomach. Most of these adverse events were mild or moderate in intensity. Only 2-5% of patients discontinued imatinib therapy due to adverse events.
Myelosuppression, undesirable effects from the gastrointestinal tract, edema and rash arise when applying both imatinib in CML and malignant gastrointestinal stromal tumors. In patients with CML usually develops myelosuppression, and in patients with malignant gastrointestinal stromal tumors are more common gastrointestinal bleeding and intratumoral. Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration occur more frequently when stromal tumors of the gastrointestinal tract. Other serious adverse events in the application are imatinib hepatotoxicity, acute renal failure, hypophosphatemia, disorders of the respiratory system, tumor lysis syndrome, growth retardation in children.
A correction dose depending on the severity of adverse events until discontinuation.
In patients with CML with unresectable and / or metastatic malignant gastrointestinal stromal tumors observed following adverse events listed below by organ system and indicating the frequency of occurrence: very common (1/10?), Common (1/100, <1? / 10), uncommon (1/1000, <1/100), rare (1/10000, <1/1000), very rare (<1/10000, including isolated reports):?
Infectious and parasitic disorders: infrequent - herpes simplex, herpes zoster, nasopharyngitis, pneumonia 1 , sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis; rarely - mycoses.
Benign, malignant neoplasms and unspecified (including cysts and polyps): rarely - tumor lysis syndrome.
From hemopoiesis system: very often - neutropenia, thrombocytopenia, and anemia; often - pancytopenia, febrile neutropenia; infrequently - thrombocythemia, lymphopenia, inhibition of bone marrow hematopoiesis, eosinophilia, lymphadenopathy; rarely - hemolytic anemia.
On the part of metabolism and nutrition: often - anorexia; rarely - hypokalemia, increased or decreased appetite, hypophosphataemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely - hyperkalemia, hypomagnesemia.
On the part of the psyche: often - insomnia; rarely - depression, anxiety, decreased libido; rarely confusion.
From the nervous system: very often - headache 2 ; often - dizziness, paraesthesia, taste disturbance, hypoesthesia; rarely - headache, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, a syndrome of "restless" legs, tremors, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.
From a sight organ: often - swelling of the eyelids, increased tearing, bleeding under the conjunctiva, conjunctivitis, a syndrome of "dry" eyes, blurred (blurred vision); infrequently - eye irritation, eye pain, orbital edema, hemorrhages in the sclera of the eye, retinal haemorrhage, blepharitis, macular edema; rarely - cataracts, papilledema, glaucoma.
On the part of the organ of hearing and balance: rare - vertigo, tinnitus, hearing loss.
Of the heart: rarely - palpitations, chronic 3 heart failure, pulmonary edema, tachycardia, "tides" 4 ; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, angina pectoris, pericardial effusion, hematoma.
On the part of the vessels: rarely - a hemorrhage 4 ; rarely - hematoma, cold extremities, increased blood pressure, decreased blood pressure, Raynaud's syndrome.
The respiratory system, thorax, mediastinum: often - nosebleeds, shortness of breath, cough; infrequently - pleural effusion 5, Pain in the throat or larynx, throat; seldom - a chest pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage.
From the digestive system: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain, 6 ; often - bloating, flatulence, constipation, gastro-oesophageal reflux, mucosal dryness of the mouth, gastritis; infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding 7 , belching, melena, esophagitis, ascites, gastric ulcer, vomiting blood, cheilitis, dysphagia, pancreatitis; rarely - colitis, paralytic / obstructive ileus, intestinal inflammation.
Of the liver and biliary tract:often - increase in liver enzymes; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - hepatic insufficiency 9 , hepatic necrosis9 .
Dermatological reactions:very often - periorbital edema, dermatitis, eczema, skin rash; often - swelling of the face, pruritus, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequently - pustular rash, petechiae, increased sweating, urticaria, ecchymosis, increased susceptibility to the formation of haematomas, easy bruising, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, damage nails, folliculitis, psoriasis, purpura, bullous rashes; rarely - acute febrile neutrophilic dermatosis (Sweet's syndrome), nail color change, angioneurotic edema, erythema multiforme, leykoklastichesky vasculitis, Stevens-Johnson syndrome, acute generalized pustular rash.
On the part of the musculoskeletal and connective tissue reference system:very often - muscle spasms and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain 8 ; often - swelling in the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis; the frequency is unknown - slowing of growth in children.
On the part of the kidney and urinary tract: rarely - kidney pain, hematuria, acute renal failure, urinary frequency.
On the part of the endocrine system, reproductive organs and mammary glands: rarely - gynecomastia, erectile dysfunction, menorrhagia, menstrual disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema.
General disorders and the site of injection:very often - fluid retention and edema, fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently - chest pain, malaise.
From the laboratory parameters: rarely - increasing activity of alkaline phosphatase, CPK, LDH and creatinine in blood serum; rarely - increased amylase activity in blood plasma.
1 Pneumonia is the most frequently observed in patients with CML in accelerated phase, and blast crisis with unresectable and / or metastatic malignant gastrointestinal stromal tumors;
2 Headache occur most often in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors;
3Adverse events of the heart, including chronic heart failure, were more common in patients with CML in accelerated phase and blast crisis as compared to patients with CML in chronic phase (duration 1 year of observation);
4 "Tides" most often observed in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors; bleeding (bruising, hemorrhage) is most often observed in patients with CML in accelerated phase, and blast crisis with unresectable and / or metastatic malignant gastrointestinal stromal tumors;
5 Pleural effusion bowl observed in patients with CML in accelerated phase and blast crisis as compared to patients with CML in chronic phase (the duration of observation 1 year);
6/7Abdominal pain and gastrointestinal bleeding occurred most often in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors;
8 Musculoskeletal pain including myalgia, arthralgia, bone pain, were more common in patients with CML than in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors;
9 have been reported some cases of liver failure and liver necrosis.
When applying imatinib in clinical practice, as well as through additional clinical studies the following adverse events were noted, the following organs and systems indicating the frequency of occurrence: very common (1/10?), Common (1/100, <1 /? 10), rare (? 1/1000, <1/100), rarely (? 1/10 000, <1/1000), very rare (<1/10 000, including isolated reports).
From the nervous system: rare - swelling of the brain.
On the part of the organ of vision: rarely - a hemorrhage in the vitreous.
Of the heart and blood vessels: rarely - thrombosis / embolism; rarely - pericarditis; cardiac tamponade; very rarely - anaphylactic shock.
The respiratory system, thorax, mediastinum: rarely - acute respiratory failure 1 , interstitial pneumonia.
From the digestive system: infrequently - ileus (ileus), gastrointestinal bleeding from a tumor, gastrointestinal tumor necrosis, gastrointestinal perforation 2 ; rarely -divertikulit.
Skin and subcutaneous tissue disorders: uncommon - palmar-plantar eritrodizesteziya; rarely - lichenoid keratosis, lichen planus; very seldom - toxic epidermal necrolysis.
On the part of the musculoskeletal system and connective tissue: rare avascular necrosis / necrosis of the femoral head, rhabdomyolysis / myopathy.
On the part of the genitals:infrequently - decreased potency; very rarely - in women bleeding from the corpus luteum cyst / ovary.
1 There are some reports about the development of severe acute respiratory failure with a fatal outcome in patients with severe infections, severe neutropenia and other serious concomitant diseases.
2 have been reported some cases of gastrointestinal perforation with fatal consequences.
Description of individual adverse reactions
myelosuppression
Frequency suppression of hematopoiesis and its degree were highest in case of the drug at high doses and is apparently dependent on the stage of CML. In general, inhibition of blood during treatment with imatinib in CML patients was reversible and generally did not require discontinuation of the drug or reducing its dose. Removal of the drug required in a small number of cases. Also observed phenomena such as pancytopenia, lymphopenia and blood oppression.
Hemorrhage / bleeding
The most common clinically relevant bleeding were bleeding from the gastrointestinal tract. Most often they occur in patients with advanced stage CML and in patients with malignant gastrointestinal stromal tumors in which they may be due to the underlying disease (eg, bleeding from a tumor, tumor necrosis caused). In patients with CML who have been oppressed hematopoiesis even before the initiation of treatment, during treatment and often marked hemorrhage in the central nervous system or gastrointestinal tract. It is well established that patients with acute leukemia disease progression frequently occur bleeding / hemorrhage caused by thrombocytopenia or trombotsitopaty.
Fluid retention and edema
Edema is a common 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 dose-dependent and appears to correlate with the concentration of drug in blood plasma. Often arise periorbital edema, with a somewhat lower rate - lower extremity edema. Specific treatment is usually not required. In patients with edema and fluid retention, heart failure is rare. In patients with advanced CML incidence of heart failure was higher than those of other categories that can be attributed to their debilitated state as a whole. The same trend was observed with respect to renal failure in patients with edema and fluid retention.Most patients with edema and fluid retention were the elderly (> 65 years).
And severe skin rash adverse reactions
A number of patients treated with imatinib, there was a generalized erythematous, maculopapular rash and itching, which could take place independently, despite continued drug treatment. Some patients have itching, is not accompanied by a rash; in some cases present erythroderma. The rash was observed in approximately 1/3 of patients receiving imatinib for all indications. Often the rash is accompanied by itching and usually manifests as erythematous, maculopapular lesions on the forearm, the body or face. Although in most cases the rash is light and goes untreated, more severe cases may require temporary or complete removal of the drug. As a rule, the severity of rash reduced after administration of antihistamines and corticosteroids for topical application.In some cases the use of corticosteroids for systemic use.
Hepatotoxicity
The drug can have toxic effects on the liver. Violations of biochemical parameters of liver function, as a rule, is a slight increase in transaminases and elevated bilirubin serum concentrations. Toxic effects on the liver usually appears within the first 2 months of treatment, but in some cases it is manifested and after 6-12 months after starting treatment. Typically, after the drug liver function normalized for 1-4 weeks.
There have been cases of cytolytic and cholestatic hepatitis and hepatic failure, in some cases accompanied by the death.
Obstruction, or perforation of the stomach or intestine ulcers
A small percentage of patients treated with imatinib, noted gastrointestinal ulceration, which in some cases may be due to local irritation of imatinib. Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract most frequently observed in patients with malignant stromal
tumors of the gastrointestinal tract. In the case of metastatic gastrointestinal stromal tumor necrosis tumor can arise against tumor
