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

Excipients: cellulose microcrystalline 46.00 mg, 92.00 mg, crospovidone 7.50 mg, 15.00 mg, silica colloidal dioxide 1.00 mg, 2.00 mg, magnesium stearate 0.75 mg, 1.50 mg, titanium dioxide 0 , 38 mg, 0.60 mg, gelatin 47.51 mg, 74.81 mg, ferric iron oxide, yellow 0.11 mg, 0.03 mg.

Capsules of 100 mg also contain a ferric oxide red oxide - 0.56 mg.

Composition of ink: shellac, iron dye red oxide (E172), propylene glycol, potassium hydroxide.

Description:

Dosage 50 mg: from light yellow to orange-yellow color opaque capsules No. 3, marked "NVR SH" in red ink. The contents of the capsules are a white powder with a yellowish hue of color.

Dosage of 100 mg: from orange to orange with a grayish shade of color, opaque capsules No. 1, marked "NVR SI" in red ink. The contents of the capsules are a white powder with a yellowish hue of color.

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

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

Imatinib selectively inhibits Vsr-Abl-positive colonies obtained from the blood cells of patients with chronic myelogenous leukemia.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing tyrosine kinase with a mutation c-Kit receptor.

Activation of receptors to platelet or platelet growth factorsbl-fragment of tyrosine kinase can cause the development of both myelodysplastic / myeloproliferative diseases, and hypereosinophilic syndrome and chronic eosinophilic leukemia and bulging dermatofibrosarcoma. Activation c-Kit receptor tyrosine kinase and receptors to platelet growth factors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits signaling in cells and cell proliferation resulting from disturbance of regulation activity of platelet growth factors and stem cells, c-Kitreceptor and Abl-fragment of tyrosine kinase.

When imatinib is used in patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors showed a significant increase in 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 in comparison with 20 months. placebo). Adjuvant therapy with a drug of gastrointestinal stromal tumors for 3 years leads to a significant increase in overall survival and survival without signs of progression disease compared with therapy for 1 year.

Pharmacokinetics:

Pharmacokinetic parameters Imatinib were evaluated in a dose range of 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on the first day, and also when equilibrium concentrations of imatinib in the plasma reached 7 or 28 days.

Absorption

After oral administration, the bioavailability of the drug is on average 98%. The coefficient of variation for the indicator area under the "concentration-time" curve (AUC) is 40-60%. In the dose range from 25 to 1000 mg, a direct linear relationship of the value AUC of the dose value.

When taking the drug with food high in fat, in comparison with reception on an empty stomach, there is a slight decrease degree of absorption (decrease maximum concentration of imatinib in blood plasma by 11%, AUC - by 7.4%) and slowing of suction speed (increasing the time to achieve maximum concentration of imatinib in blood plasma for 1.5 hours).

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 the imatinib metabolite has pharmacological activity similar to the activity 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, the drug is excreted from the body within 7 days, mainly in the form of metabolites (68% - intestine and 13% - kidney). Unchanged about 25% of the dose is withdrawn (20% by the intestine and 5% by the kidneys). The half-life of imatinib is about 18 hours.

With repeated administration of the drug 1 time per day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial concentration by 1.5-2.5 times.

In patients older than 65 years, the volume of distribution increases slightly (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 of the drug 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 years have a rapid absorption of the drug when ingested. AUC in this group of patients in a dose range of 260 and 340 mg / m² is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When compared in children and adolescent values AUC(0-24) on the first and eighth days after repeated taking of the drug at 340 mg / m once a day, the increase in the value of this indicator is 1.7 times, indicating a cumulation of imatinib.

Based on the combined Population pharmacokinetic analysis in children with hematological diseases (CML, Ph + ALL, etc.), it was shown that the clearance of Imatinib is directly proportional to the area body surface, others Demographic indicators (age, body weight and body mass index) have no clinically significant effect on imatinib exposure. Analysis confirmed that the effect of imatinib on children in the dose range of 260 (not above 400 mg) and 340 mg / m² (not higher than 600 mg) once a day is similar to in adult patients who received imatinib in doses of 400 mg or 600 mg once a day. In patients with varying degrees of liver function disorder, the mean AUC do not increase.

When imatinib is used in patients with mild or moderate renal impairment (creatinine clearance> 30 ml / min), the drug exposure in plasma is increased by a factor of 1.5-2.0, corresponding to an increase in the concentration of acidic alpha-glycoproteins (the main plasma proteins that bind to 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:

1. The newly identified positive for the Philadelphia chromosome (Ph+) chronic myeloid leukemia (CML) in children and adults.

2. Ph+ CML 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.

3. The first diagnosed positive for the Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) in children and adult patients in combination with chemotherapy;

4. recurrent or refractory Ph+ ALL in adults as a monotherapy;

5. myelodysplastic / myeloproliferative diseases associated with gene rearrangements of the growth factor receptor thrombocytes, in adults patients;

6. systemic mastocytosis in adult patients with no D816V from-Kit mutation or with an unknown c-Kit mutational status;

7. hypereosinophilic syndrome and / or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1- PDGRF alpha-tyrosine kinase.

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

9. Adjuvant therapy of gastrointestinal stromal tumors c-Kit (Cd 117) in adult patients;

10. Inoperable, relapsing and / or metastatic bulging dermatofibrosarcoma in adult patients.

Contraindications:

Hypersensitivity to imatinib or any other component of the drug.

Pregnancy and lactation.

Child age (effectiveness and safety not established):

- up to 1 year in patients with Ph+ acute lymphoblastic leukemia;

- up to 2 years in patients with Ph+ chronic myeloid leukemia;

- up to 18 years for other indications.

Carefully:

If you have any of the listed diseases before taking the drug, be sure to consult a doctor.

Caution should be exercised use Glivec® preparation:

1. in patients with impaired liver function of severe severity;

2. in patients with impaired kidney function severe severity;

3. in patients with diseases of cardio-vascular system or in the presence of risk factors for heart failure;

4. with a regular hemodialysis procedure;

5. when used simultaneously with preparations inhibiting the isoenzyme CYP3A4, strong isoenzyme inducers CYP3A4, preparations that are substrates of isoenzyme CYP3A4;

6. when used simultaneously with paracetamol, warfarin (see section "Interaction with other drugs").

Dosing and Administration:

The drug should be taken with food, washed down with a full glass of water to reduce the risk of developing gastrointestinal disorders.

Doses of 400 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 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.Treatment with the drug is carried out as long as the clinical effect remains.

Routine monitoring of response to those cases should be performed in patients with Ph+ chronic myeloid leukemia, either during the use of the drug or in the event of a change in therapy, in order to identify a suboptimal response to treatment, loss of response, insufficient adherence of the patient to treatment (compliance) or possible drug interactions.

Correction therapy should conduct, based on results of monitoring.

In chronic myeloid leukemia (CML) the recommended dose of Glivec® 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 per day.

In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, a dose increase is possible:

- from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease;

- from 600 mg to 800 mg per day in patients in the phase of acceleration and with a blast crisis.

Such a dose increase may be necessary in 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 dosing regimen in children older than 2 years is based on the surface area of the body. The recommended daily dose is 340 mg / m². 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.

When Ph+ acute lymphoblastic leukemia the recommended dose of Glivec® is 600 mg per day.

Calculation of dosing regimen in children older than 1 year is based on the surface area of the body. The recommended daily dose is 340 mg / m². The total daily dose in children should not exceed 600 mg. The daily dose of the drug is recommended to be taken simultaneously.

In adult patients with recurrent or refractory Ph+ acute lymphoblastic leukemia the recommended dose is 600 mg / day.

When myelodysplastic / myeloproliferative the recommended dose of Glivec® is 400 mg per day.

When systemic mastocytosis Without D816V c-Kit mutation, the recommended dose of Glivec® is 400 mg per day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day. In the presence of anomalous FIP1L1-PDGFR α-tyrosine kinase, which results from the fusion of genes Fip like1 and PDGFR, 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 / 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, due to 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 / day is possible. Treatment with the drug is carried out as long as the clinical effect remains.

When inoperable and / or metastatic malignant gastrointestinal stromal tumors the recommended dose of Glivec® is 400 mg per day.In the absence of side effects of the drug and an inadequate response, an increase in the daily dose of Glivec® c 400 mg to 600 mg or up to 800 mg.

If signs of disease progression appear, Glivec® therapy should be discontinued.

When the drug is used as a 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 has not been established. With inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma the recommended dose of Glivec® is 800 mg per day.

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, in patients with impaired liver function of mild, moderate and severe severity, Glivec® should be used at a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose of the drug should be reduced. It should be used with caution in patients with impaired liver function of severe severity.

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, treatment with Glivec® should be started at the lowest effective dose, 400 mg once daily, with caution. If Glivec® is intolerant, the initial dose of the drug 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 development of non-hematological side effects of the drug

In the development of any serious non-hematological by-product effect associated with taking the drug, therapy should be discontinued until the situation is resolved. 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 "hepatic" transaminases in the serum 3 and 5 times higher than the upper limit of the norm (VGN), respectively,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 Glivec® 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 to 260 mg / m² per day.

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

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.

With systemic mastocytosis (CM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) caused by abnormal FIP1L1-PDGFR α-tyrosine kinase (the initial dose of Glivec® is 100 mg), in the case of a decrease in the absolute number of neutrophils <1 × 10⁹/ l and / or the number of platelets <50x10⁹/ l is recommended:

1. abolish the Glivec® preparation until the absolute amount of neutrophils increases to ≥ 1.5x10⁹/ l and platelets ≥75x10⁹/ l;

2. resume treatment with Glivec® at a dose interruption of therapy.

In the chronic phase of CML in children and adults (initial dose for adults - 400 mg, for children - 340 mg / m²), malignant gastrointestinal stromal tumors, myelodysplastic / myeloproliferative diseases, SM and HES / HAL in adult patients (initial dose for adults - 400 mg) in case of absolute absolute neutrophil count decrease <1x10⁹/ l and / or the number of platelets <50 * 10⁹/ l is recommended:

1. abolish the Glivec® preparation until the absolute amount of neutrophils increases to ≥ 1.5x10⁹/ l and platelets ≥75x10⁹/ l;

2. resume treatment with Glivec® in a dose used before the interruption of therapy.
3. In case of a repeated decrease in the number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l, repeat the actions described in paragraph 1, and then resume treatment with Glivec® at a reduced dose of 300 mg (in children, 260 mg / m²).

In the phase of acceleration and blast crista CML in children and adults and with Rh+ 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. to ascertain whether cytopenia is a consequence of leukemia (bone marrow examination);

2. if cytopenia is not associated with leukemia, reduce the dose of Glivec® 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 Glivec® until the absolute quantity neutrophils are not will increase to ≥1x10⁹/ l and platelets ≥20x10⁹/ l; then resume treatment with Glivec® at a dose of 300 mg (in children - 260 mg / m²).

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of Glivec® 800 mg) at case of declining absolute quantities neutrophils <1x10⁹/ l and / or quantities platelets <50x10⁹/ l recommended:

1. abolish Glivec® until the absolute quantity neutrophils are not will increase to ≥1.5х1-⁹/ l and thrombocytes ≥75x10⁹/ l;

2. resume treatment with Glivec® in a dose of 600 mg.

In case of a repeated decrease quantities neutrophils less than 1х10⁹/ l and / or quantities less than thrombocytes 50x10⁹/ l repeat the actions described in paragraph 1 and then resume treatment with Glivec® at a reduced dose of 400 mg.

Side effects:

PThe safety profile of the Glivec® preparation is well known. Most patients experience certain adverse events (AEs) during the use of the drug. The most frequent AE (> 10%) associated with taking the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, pain in stomach. Often peripheral edema was noted at periorbital area and swelling of the lower extremities.

Most of these AEs were mild or moderately severe. Only 2-5% of patients discontinued therapy with Glivec® because of the development of AEs. Types of adverse events and their incidence are similar when taking Glivec® with adults and children with leukemia.

Myelosuppression, AE on the part of the gastrointestinal tract (GIT), edema and rash occur when imatinib is used as indicated by CML, and also for malignant stromal tumors of the gastrointestinal tract. In patients with CML, myelosuppression is more common,and in patients with malignant stromal tumors of the gastrointestinal tract, gastrointestinal and intracutaneous hemorrhages often occur. Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration, occur more often with stromal GI tract. Other serious AEs when using imatinib are hepatotoxicity. acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children. It is possible to adjust the dose of the drug depending on the severity of AE, right up to the withdrawal of the drug.

In clinical trials in patients with CML and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract, the following undesirable phenomena listed below are listed below but to the organs and systems with the frequency of their occurrence: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (<1/10000), including individual messages.

Infectious and parasitic diseases: infrequent - herpes simple, herpes zoster, nasopharyngitis, pneumonia¹, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycosis.

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

Violations from the blood and lymphatic system: 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 - swelling of the eyelids, increased tear, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; infrequent eye irritation, pain in the eyes, orbital edema, hemorrhage in the sclera, retinal hemorrhage, blepharitis, macular edema; rarely - cataract, edema of the optic nerve, glaucoma.

Hearing disorders and labyrinthine disturbances: infrequent vertigo, tinnitus, hearing loss.

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

Vascular disorders: infrequently - hemorrhage⁴; rarely - hematoma, subdural hematoma, cooling of limbs, lowering of arterial pressure, Raynaud's syndrome.

Disturbances from the respiratory system, chest and mediastinal organs: 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, pain in a stomach⁶, often - bloating, flatulence, constipation, gastro-esophageal reflux, dry mouth, gastritis; infrequently - stomatitis, ulceration of the mucous membrane of the oral cavity, gastrointestinal bleeding⁷, eructation, 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 "hepatic" enzymes; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely liver failure⁹, necrosis of the liver⁹.

Disturbances from the skin and subcutaneous tissues: 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, petechiae, psoriasis, purpura, bullous rash; rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), discoloration of the nails, angioedema, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.

Disturbances from the musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain⁸; often swelling of the joints; infrequent - stiffness of the mouse and joints, rarely - muscle weakness, arthritis; frequency is unknown - growth retardation in children.

Disorders from the kidneys and urinary tract: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.

Violations of the genitals and mammary glands: infrequently gynecomastia, erectile dysfunction, menorrhagia, violation of menstrual cycle, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum.

General disorders and disorders at the site of administration: very often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently pain in the chest, general malaise.

Laboratory and instrumental research: infrequently - increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and concentrations serum creatinine; rarely - increased activity of amylase in the blood plasma.

¹Pneumonia is the most frequently observed in patients with CML in accelerated phase, the power crisis and with unresectable and / or metastatic malignant stromal tumors of the gastrointestinal tract.

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

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

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

⁵Pleural effusion was more common in patients with CML in accelerated and blasted crisis compared to patients with CML in the chronic phase (duration of follow-up was 1 year).

^6/7 Abdominal pain and gastrointestinal bleeding were most often observed in patients with inoperable and / or metastatic gastrointestinal malignant tumors.

⁸Musculoskeletal pain, including myalgia, arthralgia, bone pain, was more often observed in patients with CML compared with patients with inoperable and / or metastatic gastrointestinal malignant tumors.

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

With the use of Glivec ® in clinical practice, as well as during additional clinical trials, the following AEs 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. The relationship between drug use and the following AEs is not established (the size of the patient population is unknown).

Violations from the nervous system: infrequently - edema of the brain.

Disorders from the side of the organ of vision: rarely - vitreous hemorrhage.

Heart Disease: rarely - pericarditis, cardiac tamponade; very rarely - anaphylactic shock.

Vascular disorders: infrequently - thrombosis / embolism.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently acute respiratory insufficiency¹, interstitial pneumonia.

Infringements from digestive system: infrequently - paralytic / obturative intestinal obstruction, bleeding from a tumor of the digestive tract, necrosis of the tumor of the gastrointestinal tract, perforation of the gastrointestinal tract²; rarely diverticulitis, vascular ectasia antrum (GAVE- syndrome).

Disturbances from the skin and subcutaneous tissues: infrequently - palmar dysfunction erythrodysesthesia; rarely - lichenoid keratosis, red flat lichen; very rarely - toxic epidermal necrolysis; frequency unknown - drug rash with eosinophilia and systemic symptoms (DRESS).

Breaches from the side of the bone-muscular and connective tissue: rarely - avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy.

Violations of the genitals and breast: very rarely - bleeding from yellow cyst body / ovary.

¹There are some reports of the development of severe acute respiratory insufficiency with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases.

²Individual cases of development of perforations of the gastrointestinal tract with lethal outcome were reported.

Description of individual unwanted drug reactions

Inhibition of hematopoiesis

The frequency of oppression of hematopoiesis and the degree of its expression were maximal when the drug was used in high doses and, apparently, depended on the stage of CML. In general, the oppression of hematopoiesis against the background of the Glivec® preparation in patients with CML was reversible and in most cases, ns required the drug to be withdrawn or reduced. The withdrawal of the drug was required in a small number of cases. Also observed were such phenomena as pancytopenia, lymphopenia and oppression of hematopoiesis.

Hemorrhage / bleeding

The most frequent clinically significant bleeding were bleeding from the gastrointestinal tract.Most often they appeared in patients with advanced stages of CML and in patients with malignant stromal tumors of the gastrointestinal tract, in which they can be a consequence of the underlying disease (bleeding from the tumor, caused by its necrosis). In the post-registration period separate reports were received on cases of vascular ectasia of the antrum 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 are often observed during treatment. It was established that in patients with leukemia with acute development of the disease, bleeding / hemorrhage due to thrombocytopenia or thrombocytopathy.

Swelling and fluid retention

Edema is a frequent side effect of imatinib. Frequency of edema in patients receiving imatinib on all readings is more than 50%. Frequency and severity of edema depends on the dose and, apparently, correlates with the concentration of the drug in the blood plasma. More often a periorbital edema, with a slightly lower frequency - edema of the lower extremities. Specific treatment is usually not required. 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.

In patients with edema and fluid retention, heart failure is rare. In patients with advanced stages of CML, the incidence of heart failure was higher than in patients of other categories, which can be explained by their weakened state as a whole. The same trend was observed with regard to renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention were elderly (> 65 years).

Rash and severe skin undesirable reactions

In a number of patients who received imatinib, there was a generalized erythematous, spotty-papular and itchy rash that could resolve independently, despite continuing treatment with the drug. Some patients developed itching, not accompanied by a rash; in a number of cases, there was erythroderma.A rash was noted in about a third of all patients who received imatinib for all indications. Often the rash is accompanied by itching and, as a rule, manifests itself in the form of erythematous, spotty-papular or exfoliative lesions on forearm, trunk or face or in the form of generalized rash with systemic manifestations. AT Most cases when the rash occurred, its severity was insignificant, no treatment was required. However, in rarer severe cases, for example, with Stevens-Johnson syndrome, erythema multiforme or rash with eosinophilia and systemic symptoms (DRESS), may require a temporary or complete discontinuation of the drug. 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 with glucocorticosteroid drugs.

Hepatotoxicity

The drug may have a toxic effect 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, there was ulceration of the LCG, 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 is most often were 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 most often occurred in patients with malignant stromal tumors of the gastrointestinal tract,in which its cause may be metastasis or adhesion process in the abdominal cavity, resulting from a previous operation on the digestive tract (in the case of the drug as an adjuvant therapy).

Severe adverse events on the part of the respiratory system

Severe (sometimes fatal) AEs were noted during the administration of Glivec®, namely acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. The concomitant pathology of the cardiovascular or respiratory systems can aggravate the severity of AEs.

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

Overdose:

The experience of using Glivec® in doses exceeding therapeutic limits is limited. In clinical practice, there have been cases of drug overdose. In general, the outcome of cases of overdose with Glivec® was favorable (improvement in the condition of patients was noted).

The antidote to Glivec® is not known.In case of an overdose, medical supervision and symptomatic therapy are recommended.

Overdose in adults

Nausea, vomiting, diarrhea, rash, erythema, swelling, swelling in the face, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache pain, loss of appetite.

When taking the drug at 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 the use of Glivec® in a dose of 6400 mg once (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, a decrease in the number of neutrophils and an increase in the activity of "liver" transaminases.

When taking the drug at a dose of 8-10 mg, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents

When taking the drug at a dose of 400 mg, a 3-year-old child experienced vomiting, diarrhea, and anorexia. In another case, with the administration of Glivec® in a dose of 980 mg, a decrease in the number of white blood cells and diarrhea was observed once in a child at the age of 3 years.

Interaction:

With the simultaneous use of Glivec® with isozyme inhibitory drugs CYP3A4 cytochrome P450, for example, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), antifungal agents of the azole group (incl. ketoconazole, itraconazole, posaconazole, voriconazole), some antibiotics-macrolides (erythromycin, clarithromycin, telithromycin), possibly deceleration metabolism of imatinib and increase in its concentration in the blood plasma. Caution is needed when using Glivec® together with isozyme inhibitor preparations CYP3A4.

On the contrary, the simultaneous use of drugs that are inducers of isoenzyme CYP3A4 (E.g., rifampicin, dexamethasone, Hypericum perforatum drugs, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidone) may accelerate metabolism of imatinib and, as a consequence, reduction of its plasma concentration and treatment failure. Simultaneous use of imatinib and strong isoenzyme inducers should be avoided CYP3A4.

With the simultaneous use of imatinib and simvastatin, there is an increase in C_m_Oh and AUC simvastatin in 2 and 3.5 times, respectively, which is a consequence of inhibition of the isoenzyme CYP3A4 imatinib. It is advisable to use caution when using Glivec® and preparations that are substrates of the isoenzyme CYP3A4 and having a narrow range of therapeutic concentration (e.g., ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine).

Glivec® can increase serum concentrations blood other drugs metabolized by isoenzyme CYP3A4 (triazolo-benzodiazepines, dihydropyridine, blockers of "slow" calcium channels, most of the inhibitors of HMG-CoA reductase, incl. statins).

Imatinib also inhibits isoenzyme CYP2C9 and isoenzyme CYP2C19 in vitro. With the simultaneous use of Glivec® with warfarin, increased prothrombin time. With simultaneous application from coumarin derivatives require short-term monitoring prothrombin time at the beginning and end of therapy with the drug, as well as when changing the dosage regimen of Glivec®.As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins. Insufficiently studied question Imatinib medication and chemotherapy drugs in patients with Ph+ ALL. Caution should be exercised when imatinib and chemotherapeutic agents are used concomitantly with the possible increase in the risk of developing drug complications such as hepatotoxicity, myelosuppression, etc. When combining imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in form of increased 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 isoenzyme CYP2D6 cytochrome P450 at the same concentrations in which it inhibits the isoenzyme CYP3A4. When imatinib is used at a dose of 400 mg 2 times a day, together with metoprolol, an isoenzyme substrate CYP2D6, there is a moderate slowdown in metabolism metoprolol, followed by increase in C_m_Oh and AUC approximately 21%. Given the moderate increase in the effects of drugs that are substrates of isoenzyme CYP2D6 (for example, metoprolol), with their simultaneous application with imatinib, a change in the dosage regimen is not required.

In vitro imatinib inhibits O-glucuronidation acetaminophen / paracetamol (inhibition constant-Ki 58.5 μm). However, the use of Glivec® (400 mg / day for 8 days) with acetaminophen / paracetamol (single dose of 1000 mg on the eighth day) in patients with CML did not lead to a change in pharmacokinetics acetaminophen / paracetamol. The pharmacokinetics of imatinib did not change with a single admission of acetaminophen / paracetamol. Information on the pharmacokinetics or safety of simultaneous application of imatinib in doses> 400 mg / day with acetaminophen / paracetamol or long-term simultaneous applications acetaminophen / paracetamol and Imatinib are absent.

In patients after thyroidectomy receiving a substitution hormonal therapy with levothyroxine sodium, it is possible to reduce its concentration in blood plasma with simultaneous application with imatinib. Reported development messages lesions of the liver with simultaneous application of imatinib and asparaginase.

Special instructions:

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

When handling the drug, avoid contact with the skin and eyes, as well as inhaling the powder of the drug.

Experience with Glivec® treatment of children with CML younger than 2 years is limited, the experience of using the drug for other indications is limited in patients under 18 years of age, the experience of using the drug in children with ALL is less than one year. Long-term effects The long-term effects of Glivec® on growth in children are not known, but since there are reports of growth retardation, careful growth control is recommended in children receiving Glivec®. When using Glivec® it is recommended that blood tests and liver function tests be performed on a regular basis (transaminases, bilirubin, alkaline phosphatase).

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

In connection with the fact that with Glivec® 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, a patient should be examined and, if necessary, temporarily discontinued therapy with Glivec® and / or diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant and cardiovascular diseases.

In some cases, severe fluid retention may have a severe course with a fatal outcome. When the drug was used, the patient died with a blast crisis and complex symptomatology: pleural effusion, congestive heart failure and kidney failure.

When using the drug in patients with liver disease should be regularly carried out a clinical blood test and determine the activity of "liver" enzymes.

Since there are reports of the development of hypothyroidism during treatment with Glivec drug in patients who have undergone thyroidectomy and receiving replacement therapy with levothyroxine sodium, it is necessary to regularly definition the concentration of thyroid-stimulating hormone in this category of patients.

Have patients with hypereosinophilia syndrome (SGE) and eosinophilic infiltration of the myocardium at the beginning of imatinib therapy, there were isolated cases of development of cardiogenic shock / left ventricular failure (associated with degranulation of eosinophils). These undesirable phenomena stop after additions to therapy systemic glucocorticosteroids, taking measures aimed at maintaining blood circulation, and temporary withdrawal of Glivec®.

In patients with MDS / MPD and high levels of eosinophils, ECG testing should be performed and the concentration of cardiospecific troponin in the blood serum. When detecting abnormality of the start of therapy should be considered a prophylactic use of systemic glucocorticoids (1-2 mg / kg) for 1-2 weeks, concurrently with imatinib.

In patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors in clinical studies, 3 phases of hemorrhage of different localizations were noted in 12.9% of cases; in studies of 2 phases, gastrointestinal bleeding was noted in 8 patients (5.4%), bleeding from tumor sites in 4 patients (2.7%).

Bleeding was observed as from abdominal cavity, both and liver, depending on the location of tumor lesions. In addition, in the post-marketing period, separate reports were received on cases of vascular ectasia of the antrum of the stomach (GAVE-syndrome), a rare cause of gastrointestinal bleeding, registered in patients with CML and ALL and others diseases.

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.) at the beginning and throughout the therapy with imatinib. If necessary, consider the possibility of reversing therapy with the drug.

During therapy with Glivec® and at least 3 months afterwards, reliable methods of contraception should be used.

A marked increase in the activity of "hepatic" transaminases or bilirubin concentrations was noted in less than 3% of patients with CML 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 before the use of Glivec®, it should, if necessary, be adjusted clinically pronounced dehydration and increased concentration of uric acid.

Effect on the ability to drive transp. cf. and fur:

Some side effects of the drug, such as dizziness and blurred vision, can adversely affect the ability to drive vehicles and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. In this regard, patients receiving Glivec® should show increased attention and caution when managing vehicles and performing potentially hazardous activities. When these undesirable phenomena appear, one should refrain from performing these activities.

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

Packaging:

Capsules 50 mg, 10 pcs. in a blister of PVC / PE / PVDC. 3 blisters together with the instruction in a cardboard bundle.

Capsules 100 mg, 12 pcs. in a blister of PVC / PE / PVDC. 2, 3, 4, 8, 10 and 15 blisters together with the instruction in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 30 ° C.

The drug should be stored out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013241 / 01

Date of registration:07.11.2011 / 08.04.2014

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

FARMSTANDART-UFAVITA, JSC Russia

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp11.03.2016

Illustrated instructions

Instructions

Glivec® (Glivec®)