Imvek - instructions for use, dose, side effects, contraindications

capsules hard gelatinous [body and capsule capsule]: titanium dioxide 1.3333%, dye quinoline yellow 0.9197%, dye sunset yellow 0.0044%, gelatin to 100%.

Description:Hard gelatin capsules No. 3 (50 mg dosage) or No. 1 (100 mg dosage) with a yellow body and lid. The contents of the capsules are a granular powder from light yellow to yellow.

Pharmacotherapeutic group:An antitumour agent, a protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib exerts a selective inhibitory effect on the Bcr-ABL tyrosine kinase enzyme formed by the fusion of the Bcr (breakpoint cluster region) and the Abl (Abelson) protooncogene at the cellular level, selectively inhibits proliferation and induces apoptosis of the Bcr-ABL tyrosine kinase expressing cell lines, including immature leukemia cells formed in patients with positive for the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibit Bcr-Abl-positive colonies obtained from the blood of patients with chronic myeloid leukemia.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal tract (GI) stromal tumors 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 overall survival and survival without symptoms.

Adjuvant therapy with imatinib of gastrointestinal stromal tumors within 1 year reduces the risk of relapse by 89%, increases the survival rate without signs of disease. Adjuvant therapy with imatinib of gastrointestinal stromal tumors for 3 years leads to a significant increase in overall survival and survival without signs of disease progression compared to therapy for 1 year.

Pharmacokinetics:

Suction. After oral administration, the bioavailability of imatinib is 98% on average. In the range of doses from 25 mg to 1000 mg, the direct linear dependence of the area under the "concentration time" (AUC) curve 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 the maximum concentration of imatinib in blood plasma by 11%, AUC- by 7.4%) and slowing the rate of absorption concentration of imatinib in blood plasma for 1.5 h).

Distribution. About 95% of imatinib binds to plasma proteins (mainly with 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. After taking one dose imatinib is excreted from the body for 7 days, mainly in the form of metabolites (68% - in the intestine and 13% - in the kidneys). In an unchanged form, about 25% of the dose is excreted (20% by the intestine and 5% by the kidneys). The half-life of imatinib is about 18 hours.

When repeated imatinib once a day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the original concentration by 1.5-2.5 times.

Pharmacokinetics in specific patient groups

In patients older than 65 years, the volume of distribution 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 imatinib dosing depending on the patient's body weight.The pharmacokinetics of imatinib does not depend on sex. Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are insignificant and do not require dose changes. As in adult patients, children and adolescents under the age of 18 have a rapid absorption of imatinib while ingesting. AUC in this group of patients in a dose range of 260 mg / m²and 340 mg / m² is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When comparing the values of AUCq-24 in children and adolescents on days 1 and 8 after re-taking the drug at a dose of 340 mg / m²Once a day, the increase in the value of this indicator is observed 1.7 times, indicating the cumulation of imatinib. Based on the combined population pharmacokinetic analysis in children with hematological diseases, it was shown that the clearance of imatinib is directly proportional to the surface area of the body, other demographic parameters (age, body weight and body mass index) have no clinically significant effect on the imatinib exposure.

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 insufficiency (creatinine clearance more than 30 ml / min), the imatinib exposure in plasma is increased by a factor of 1.5-2, corresponding to an increase in the concentration of acid alpha-glycoproteins (the main plasma proteins binding to Imatinib ). Because the imatinib is slightly excreted by the kidneys, the clearance of free imatinib was the same for healthy volunteers and patients with impaired renal function. Correlation between the exposure of imatinib and the severity of renal impairment was not revealed.

Indications:

- The first identified positive for the Philadelphia chromosome is chronic myeloid leukemia (Ph + XML) in children and adults.

- Ph + XML in the chronic phase in the failure of previous therapy with interferon alpha or in the phase of acceleration, or blast crisis in children and adults.

- For the first time 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 associated with gene rearrangements of the platelet-derived growth factor receptor in adult patients.

- Systemic mastocytosis in adult patients with no D816V c-K.it mutation or with an unknown c-Kit mutation status.

- Hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults with positive or negative abnormal FIP1L1-PDGFR alpha-tyrosine kinase.

- Inoperable and / or metastatic malignant gastrointestinal stromal tumors are positive for c-Kit (CD 117) in adult patients.

- Adjuvant therapy of gastrointestinal stromal tumors positive with c-Kit (CD 117) in adult patients.

- Inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma in adult patients.

Contraindications:Hypersensitivity to imatinib or other components of the drug. Pregnancy and the period of breastfeeding. Children under 2 years of age (safety and efficacy not established).

Carefully:

In patients with severe hepatic insufficiency, renal failure (QC less than 30 ml / min), cardiovascular disease or in the presence of risk factors for heart failure, as well as in the regular procedure of hemodialysis.

When used simultaneously with strong inducers of the isoenzyme CYP3A4, paracetamol, warfarin (see section "Interaction with other medicinal products").

Caution should be exercised when used simultaneously with preparations inhibiting the isoenzyme CYP3A4 and with preparations that are substrates of the isoenzyme CYP3A4.

Pregnancy and lactation:The use of the drug during pregnancy and during breast-feeding is contraindicated. If you need to use the drug during breastfeeding, breastfeeding should be discontinued.

Dosing and Administration:

Inside, with food, washing down with a full glass of water, to reduce the risk of developing gastrointestinal disorders.

Doses of 400 mg and 600 mg per day are 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 can not swallow the whole capsule, for example, children, Imvek can be taken in a diluted form. The contents of the capsules are diluted with water or apple juice. The resulting suspension should be taken orally immediately after preparation.

In chronic myelogenous leukemia (XML) in adults the recommended dose of Imvek depends on the phase of the disease. In the chronic phase of CML the dose is 400 mg per day, during the acceleration phase and with a blast crisis - 600 mg per day. The drug should be taken 1 time per 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 with the progression of XML (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.

In chronic myelogenous leukemia (XML) in children older than 2 years Calculation of the dosing regimen is based on the surface area of the body. Doses of 340 mg / m per day are recommended in children with chronic phase XML and accelerating phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken at a time or divided into 2 equal doses - in the morning and in the evening.

With Ph + acute lymphoblastic leukemia the recommended dose of Imvek is 600 mg per day.

In myelodysplastic / myeloproliferative diseases the recommended dose of Imvek is 400 mg per day.

With inoperable and / or metastatic malignant gastrointestinal stromal tumors the recommended dose of Imvek is 400 mg per day. In the absence of side effects and insufficient response, an increase in the daily dose of Imvek from 400 mg to 600 mg or up to 800 mg is possible. If there are signs of progressing, treatment with Imvek should be discontinued.

When using the drug as an adjuvant therapy in patients with gastrointestinal stromal tumors the recommended dose is 400 mg per day. The minimum duration of treatment is 3 years. Optimal duration Adjuvant therapy is not established.

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma the recommended dose of Imvek is 800 mg per day. With systemic mastocytosis in the absence of D816V c-Kit mutation, the recommended dose of Imvek is 400 mg per day.With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

With systemic mastocytosis due to the abnormal FIP1L1-PDGFR α-tyrosine kinase resulting from the fusion of the Fip like 1 and PDGFR genes, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effect, an increase in the dose to 400 mg per day is possible.

With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose is 400 mg per day. In patients with HES / HAL, caused by abnormal FIP1L1-PDGFR α-tyrosine kinase, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg per day is possible. Treatment with the drug is carried out as long as the clinical effect remains.

Patients with impaired hepatic function

Because the imatinib metabolized mainly in the liver, patients with mild, moderate and severe hepatic insufficiency drug Imvek should be prescribed in a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose of the drug should be reduced.Caution should be given to patients with severe hepatic impairment.

Patients with impaired renal function

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, Imvek should be treated with the lowest effective dose, 400 mg once daily, with caution. If the drug is intolerant, the initial dose can be reduced, with insufficient effectiveness - increased.

Elderly patients

Older patients do not need to adjust the dosage regimen of the drug.

Correction of the dosing regimen in the development of non -hematological adverse reactions

With the development of any serious non-hematologic 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 undesired reaction. With an increase in the concentration of bilirubin and an increase in the activity of liver transaminases in the blood serum 3 and 5 times higher than the upper limit of the norm (VGN)treatment with the drug should be temporarily suspended until the concentration of bilirubin is reduced to less than 1.5xVGN and the activity of "hepatic" transaminases to less than 2.5xVGN.

Therapy with Imvek is resumed with a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day; in children - from 340 mg / m²up to 260 mg / m² per day.

Correction of the dosing regimen with the development of serious side effects from the hematopoiesis system (severe thrombocytopenia, neutropenia)

When neutropenia and thrombocytopenia occur, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these unwanted reactions.

In systemic mastocytosis (CM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / CEL) caused by an abnormal FIP1L1-PDGFR, a tyrosine kinase (the initial dose of Imvek is 100 mg), in the case of a decrease in the absolute number of neutrophils <1x10⁹/ l and / or platelet count <50x10⁹/ l is recommended:

1. cancel the drug until the absolute number of neutrophils becomes ≥ 1.5x10⁹/ l and thrombocytes ≥75x10⁹/ l;

2. the drug should be resumed at the dose used before the interruption of therapy.

In the chronic phase of XML in children and adults (initial dose for adults - 400 mg, for children - 340 mg / m²), malignant gastrointestinal stromal tumors, myelodyspastic / myeloproliferative diseases, SM and HES / HAL in adult patients (the initial dose for adults is 400 mg) in the case of a decrease in the absolute number of neutrophils <1x10⁹/ l and / or platelet count <50X10⁹/ l is recommended:

1. cancel the drug until the absolute number of neutrophils is ≥1.5x10⁹/ l and thrombocytes ≥75x10⁹/ l;

2. to resume treatment with the drug in a dose used before the interruption of therapy;

3. in the case of a repeated decrease in the number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l should repeat the actions specified in paragraph 1, and then resume treatment with the drug in a reduced dose of 300 mg (in children - 260 mg / m²).

In the phase of acceleration and power crisis of CML in children and adults and with Ph + acute lymphoblastic leukemia in adult patients (initial dose for adults - 600 mg, for children - 340 mg / m²) in the case of a decrease in the absolute number of neutrophils <0.5x10⁹/ l and / or the number of platelets <10x10⁹/ l after one or more months of treatment is recommended:

1. check whether the cytopenia is a consequence of leukemia (bone marrow examination);

2. if cytopenia is not associated with leukemia, reduce the dose of the drug to 400 mg (in children - 260 mg / m²);

3. if cytopenia persists for 2 weeks, reduce the dose to 300 mg (in children - 200 mg / m²);

4. if cytopenia persists for 4 weeks and its association with leukemia is not confirmed, discontinue the drug until the absolute number of neutrophils becomes ≥1x10⁹/ l and thrombocytes ≥20x10⁹/ l; then resume treatment with the drug at a dose of 300 mg (in children - 260 mg / m²).

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (the initial dose of Imvek is 800 mg) in the case of a decrease in the absolute number of neutrophils <1x10⁹/ l and / or platelet count <50x10⁹/ l is recommended:

1. cancel the drug until the absolute number of neutrophils becomes ≥ 1.5x10⁹/ l and thrombocytes ≥75x10⁹/ l:

2. to resume treatment with the drug in a dose of 600 mg;

3. in the case of a repeated decrease in the number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l it is necessary to repeat the actions specified in paragraph 1, and then resume treatment with the drug in a reduced dose of 400 mg.

Side effects:

The safety profile of imatinib has been well studied. Most patients with imatinib experience some or other undesirable reactions. The most common adverse reactions (> 10%) associated with imatinib were neutropenia, thrombocytopenia, anemia, headache, neuralgia, edema, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, fatigue, pain in a stomach. In general, these unwanted reactions were mild or moderate. Only 2-5% of patients stopped imatinib therapy because of the development of unwanted reactions. Often peripheral edema was noted mainly in the periorbital region and lower extremities. 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.

Myelosuppression, undesirable reactions of the gastrointestinal tract, edema and rash arise when applying imatinib as in XML, as well as in malignant gastrointestinal stromal tumors.Patients with XML often develop myelosuppression, and patients with malignant stromal tumors of the gastrointestinal tract are more likely to develop gastrointestinal and intrapuinal bleeding.

Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration, occur more often with stromal GI tract.

Other serious adverse reactions with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children. It is possible to correct the dose of the drug, depending on the severity of unwanted reactions, up to the withdrawal of the drug.

In clinical trials in patients with XML and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract, the following adverse reactions listed below for organs and systems with the frequency of their occurrence were noted: 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: infrequent - herpes simple, herpes zoster, nasopharyngitis, pneumonia¹, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycoses.

Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely - tumor lysis syndrome.

Violations from 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.

Impaired 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.

Disorders from the side of the organ of vision: 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 disturbances: infrequently - vertigo, noise in the ears, hearing loss.

Heart Disease: infrequent - sensation of palpitations, chronic³ heart failure, pulmonary edema, tachycardia, "hot flashes"⁴; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, stenocardia, pericardial effusion, increased blood pressure.

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.

Disorders 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, predisposition to the formation of hematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, psoriasis, purpura, bullous rash; rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), discoloration of the nails, angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.

Disturbances from the osteomuscular and connective tissue: very 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; 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 breast: 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, infrequent - 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.

¹ - Pneumonia was most often observed in patients with XML in the phase of acceleration, blast crisis and with inoperable and / or metastatic gastrointestinal malignant tumors.

² - Headache is most common in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors.

³ - Undesirable heart reactions, including chronic heart failure, were more common in patients with XML in the accelerated phase and with blast crises compared to patients with XML in the chronic phase (duration of follow-up is 1 year).

⁴ - "Tides" was most often observed in patients with inoperable and / or metastatic gastrointestinal malignant tumors; bleeding (hematoma, hemorrhage) was most often observed in patients with XML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant gastrointestinal stromal tumors.

⁵ - Pleural effusion was more often observed in patients with XML in the acceleration phase and with blast crises compared to patients with XML 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 malignant tumors.

⁸ - Musculoskeletal pain, including myalgia, arthralgia, bone pain, was more common in patients with XML compared with patients with inoperable and / or metastatic gastrointestinal malignant tumors.

⁹ - Individual cases of hepatic insufficiency and liver necrosis have been reported.

When imatinib was used in the clinical practice of the iostregistration period, as well as during additional clinical studies, the following undesirable reactions listed below for organs and systems were noted, indicating 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. Due to the fact that the size of the patient population is unknown, it is not always possible to reliably estimate the frequency or establish a cause-and-effect relationship with the use of the drug.

Impaired nervous system: infrequently - edema of the brain.

Disorders from the side of the organ of vision: 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.

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.

Disturbances from the osteomuscular and connective tissue: rarely - avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy.

Violations of the genitals: very rarely - women bleed from the cyst of the yellow body / ovary.

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.

² - Individual cases of development of gastrointestinal perforations with a lethal outcome were reported.

Description of individual adverse reactions

Inhibition of hematopoiesis

The frequency of oppression of hematopoiesis and the degree of its expression were maximal when imatinib was administered in high doses and, apparently, depended on the stage of XML. In general, oppression of hematopoiesis with imatinib in patients with XML was reversible and in most cases did not require the drug to be withdrawn or its dose reduced.The abolition of imatinib therapy was required in a small number of cases. Also undesirable reactions were noted, such 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 start of treatment, during treatment often hemorrhages in the brain or GI tract are also noted. 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 imatinib 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 (over 65).

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 had itching, not accompanied by a rash, in some 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 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 it may be necessary to temporarily or completely discontinue 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 glucocorticosteroid preparations for systemic use.

Hepatotoxicity

Imatinib may have toxic effects 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 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 resulting from prior operations on the gastrointestinal tract (in the case of the drug as adjuvant therapy). Heavy undesired reactions with severe respiratory system (sometimes accompanied fatal) adverse reactions were observed atbackground 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 unwanted reactions.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, you should notify the doctor.

Overdose:

The experience with imatinib in doses exceeding the therapeutic dose is limited. In clinical practice, there have been cases of drug overdose. In general, the outcome of cases of imatinib overdose was favorable (there was an improvement in the patients' condition).

Overdose in adults

When taking imatinib in doses of 1200-1600 mg for 1-10 days, nausea, vomiting, diarrhea, rash, erythema, swelling, swelling (mostly facial), increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache pain, loss of appetite.

When imatinib was taken in a dose of 1800-3200 mg (the highest dose was 3200 mg per day for 6 days), weakness, myalgia, increase in the blood activity of creatine phosphokinase, bilirubin concentration, gastrointestinal pain were noted.With imatinib once in a dose of 6400 mg (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, edema of the face, a decrease in the number of neutrophils and an increase in the activity of "liver" transaminases. When taking imatinib in a dose of 8-10 g, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents

In a child at the age of 3 years, when taking Imatinib, 400 mg once, vomiting, diarrhea and anorexia were noted.

In another case, in a child aged 3 years with a single imatinib dose of 980 mg, there was a decrease in the number of leukocytes and diarrhea.

Treatment

In case of an overdose, medical supervision and symptomatic therapy are recommended. Antidote to imatinib is unknown.

Interaction:

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, telithromycin), possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma.Caution should be exercised when Imvek is applied simultaneously with CYP3A4 isozyme inhibitor preparations. Simultaneous use of imatinib and drugs that are inducers of CYP3A4 (for example, rifampicin, dexamethasone, preparations of St. John's wort, peritoneal drugs, carbamazepine, oxcarbazepine, phenytoin, phosphenytoin, phenobarbital, primidon) can lead to an acceleration of imatinib metabolism and, as a result, a decrease in it concentration in blood plasma and inefficiency of therapy. Simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.

With the simultaneous use of imatinib and simvastatin, there was an increase in the maximum plasma concentration and AUC of simvastatin by 2 and 3.5 times, respectively, which is a consequence of the inhibition of CYP3A4 by imatinib. It is advisable to use caution when using Imvek and preparations that are substrates of CYP3A4 and have a narrow range of therapeutic concentration (for example, ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase the serum concentrations of other drugs metabolized by the CYP3A4 isoenzyme (eg, triazolobenzodiazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins). Imatinib also inhibits the isoenzyme CYP2C9 and CYP2C19 in vitro. With the simultaneous use of imatinib with warfarin, prolongation of prothrombin time is observed. With simultaneous application with coumarin derivatives, short-term prothrombin time monitoring at the beginning and the end of therapy with Imvek is needed, as well as with changing the dosage regimen of Imvek. As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

In vitro imatinib inhibits O-glucuronidation of paracetamol, and therefore caution should be exercised when using imatinib with paracetamol (especially when using high doses of paracetamol).

In patients undergoing thyroidectomy and receiving HRT levothyroxine sodium may decrease its plasma concentrations when used with imatinib.

The question of the drug interaction of imatinib and chemotherapy drugs in patients with Rh + ALL has not been adequately studied. Caution should be exercised when using together imatinib and chemotherapeutic drugs in connection with a possible increase in the risk of developing medical complications such as hepatotoxicity, myelosuppression, etc. There are reports of the development of liver damage in the joint use of imatinib and asparaginase.

With the simultaneous use of imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the activity of "hepatic" transaminases and hyperbilirubinemia. With a combination of imatinib and regimens of chemotherapy that can potentially cause liver dysfunction, liver function should be monitored. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme.

When imatinib 400 mg twice a day, together with metoprolol, the substrate of the isoenzyme CYP2D6, there is a moderate decrease in metoprolol metabolism, accompanied by an increase in the maximum plasma concentration and AUC by approximately 21%.Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when they are used simultaneously with Imvek, changes in the dosing regimen are not required.

Special instructions:

Treatment with Imvek should be done only under the supervision of a doctor who has experience working with antitumor drugs.

When handling Imvek, avoid contact with the skin and eyes, and inhale the powder.

Experience with imatinib treatment of children with XML younger than 2 years is limited, experience with imatinib for other indications is limited in patients under 18 years of age. Long-term effects of prolonged exposure to imatinib on growth in children are unknown. But since there are reports of growth retardation with imatinib, careful monitoring of growth in children using Imwec is recommended.

Regular clinical blood tests and liver function monitoring (transamiazy, bilirubin, alkaline phosphatase) are performed.

Care should be taken to monitor patients with heart and kidney disease.

Due to the fact that when imatinib is applied in 1-2% of cases, there is a marked fluid retention, it is recommended to regularly monitor the body weight of patients. In the case of an unexpected rapid increase in body weight, the patient should be examined and, if necessary, temporarily discontinued therapy with Imvek and / or prescribe diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. In some cases, severe fluid retention may have a severe course with a fatal outcome. When imatinib was used, the patient died with a violent crisis and complex symptoms: pleural effusions, congestive cardiac and renal insufficiency.

When Imwec is used, patients with liver disease should be regularly given a clinical blood test and the activity of "liver" enzymes. Since there are reports of the development of hypothyroidism in the face of imatinib in patients who undergone thyroidectomy and who are receiving substitution treatment with levothyroxine sodium, the concentration of thyroid-stimulating hormone must be regularly measured in this category of patients.

In patients with hypereosinophilia syndrome and eosinophilic infiltration of the myocardium, at the beginning of imatinib therapy, cases of cardiogenic shock / left ventricular failure (associated with degranulation of eosinophils) were noted. These undesirable reactions stop after the administration of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary discontinuation of the drug.

In patients with myelodysplastic / myeloproliferative diseases and a high number of eosinophils, ECG testing should be performed and the serum concentration of cardiospecific troponin should be determined. If abnormalities are found, at the beginning of therapy should consider the possibility of preventive use of systemic glucocorticosteroids (1-2 mg / kg) for 1-2 weeks at the same time as Imvek.

In patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors, hemorrhages of various locations were observed, both in the abdominal organs and in the liver, depending on the localization of tumor sites.It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors (abdominal pain, gastrointestinal bleeding, constipation, etc.) throughout the treatment with imatinib.

During therapy with Imvek and at least 3 months after discontinuation of therapy, reliable methods of contraception should be used.

A marked increase in the activity of "hepatic" transaminases or bilirubin was noted in less than 3% of patients with XML and was usually controlled by a decrease in the dose of the drug or a temporary interruption of treatment (the average duration of such episodes was about 1 week).

Due to the risk of development of tumor lysis syndrome, Imvek should, when necessary, correct clinically severe dehydration and elevated uric acid levels in patients.

Effect on the ability to drive transp. cf. and fur:Some side effects of imatinib, such as dizziness and blurred vision, can adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions.In this regard, when applying Imvek, special care must be taken when driving vehicles and performing potentially hazardous activities. If the above undesirable phenomena occur, you should refrain from performing these activities.

Form release / dosage:Capsules 50 mg and 100 mg.

Packaging:

For 10, 12, 20 capsules in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

By 2, 3, 5, 6, 10, 12 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002651

Date of registration:08.10.2014 / 30.07.2015

Expiration Date:08.10.2019

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

EvoFarm Ltd. Russia

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp08.11.2017

Illustrated instructions

Instructions

Imvek (Imvek)