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

Excipients: low substituted giproloza 65.19 mg Povidone 0.285 mg Sodium carboxymethyl starch 21.055 mg colloidal silicon dioxide 1.99 mg magnesium stearate 1.035 mg Opadry yellow (yellow iron oxide colorant, macrogol, talc, hypromellose) 6.84 mg Opadry Red (iron oxide red dye, macrogol, talc, hypromellose) 0.36 mg.

1 tablet, film-coated, 100 mg contains:

active substance: Imatinib mesylate 119.5 mg (in terms of imatinib 100 mg);

Excipients: giproloza low substituted 130.38 mg Povidone 0.57 mg sodium carboxymethylstarch 42.11 mg Colloidal silicon dioxide 3.98 mg magnesium stearate 2.07 mg Opadry yellow (yellow iron oxide colorant, macrogol, talc, hypromellose) 13 68 mg Opadry red (iron oxide red dye, macrogol, talc, hypromellose) 0.72 mg.

Description:

50 mg: Round biconvex tablets, film-coated from dark yellow to brownish-orange, with the engraving "50" on one side.On a cross-section of a tablet of white with a yellowish shade of color.

100 mg: Round biconvex tablets, film-coated from dark yellow to brownish-orange, engraved "100" on one side and the line on the other side. On a cross-section of a tablet of white with a yellowish shade of color.

Pharmacotherapeutic group:antitumor agent, protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib has a selective inhibitory effect on the enzyme Bcr-Abl-tyrosine kinase which is formed at the confluence portion Bcr gene (breakpoint cluster region) and proto-oncogene Abl (Abelson), at the cellular level, selectively inhibits proliferation and induces apoptosis in cell lines expressing WASH-Abl tyrosine kinase, including immature leukemic cells formed in chronic myeloid leukemia patients with Philadelphia chromosome positive (Ph +) 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 in gastrointestinal stromal tumors cells expressing the tyrosine kinase receptor with a mutation c-K.it.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 cell signaling and cell proliferation resulting from impaired regulation of platelet and stem cell growth factors, the c-Kit receptor, and the tyrosine kinase Abl fragment.

Pharmacokinetics:

Suction. After oral administration, the bioavailability of the drug is on average 98%. The coefficient of variation for the area under the curve "concentration-time" (AUC) is 40 - 60%. In the range of doses from 25 to 1000 mg, a direct linear dependence 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 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 (an increase in time until the maximum concentration of imatinib in the blood plasma for 1.5 hours).

Distribution. About 95% of imatinib binds to plasma proteins (mainly albumin and acidic α-glycoproteins, to a small extent - with lipoproteins).

Metabolism. Imatinib metabolized, mainly in the liver with the formation of the main metabolite (N-detylated piperazine derivative) circulating in the systemic circulation. In vitro the imatinib metabolite has pharmacological activity similar to the activity of the starting material. Value AUC metabolite is 16% of AUC imatinib. 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 for 7 days, mainly in the form of metabolites (68% - intestine and 13% - kidney). 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.

With repeated administration of the drug 1 p / day pharmacokinetic parameters do not change, and the concentration of imatinib in the equilibrium state exceeds the original one by 1.5 - 2.5 times.

Pharmacokinetics in special groups of patients. 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 do not appear to be so significant that a dose change is required depending on the patient's body weight. The pharmacokinetics of imatinib does not depend on sex.

In children and adolescents under the age of 18, as in adults, imatinib fast absorbed after ingestion. AUC in the dose range of 260 and 340 mg / m is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When comparing values AUC(o_24) on the 1 st and 8 th days after repeated administration of the drug at a dose of 340 mg / m 1 p / day, there is a 1.7-fold cumulation of imatinib.

In patients with varying degrees of liver function disorder, the mean AUC do not increase.

When imatinib is used in patients with mild to moderate impairment of renal function (creatinine clearance> 30 ml / min), the drug exposure in plasma is increased 1.5-2.0 times, corresponding to an increase in the concentration of acidic α-glycoproteins (basic proteins plasma binding 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:

- The newly identified positive for the Philadelphia chromosome (Ph +)

chronic myelogenous leukemia (XML) in children and adults;

- Ph + XML in the chronic phase with failure of previous therapy

interferon alpha, or in the phase of acceleration, or blast crisis in children and adults;

- The first diagnosed positive for the Philadelphia

chromosome (Ph +) acute lymphoblastic leukemia (ALL) in adult patients in combination with chemotherapy;

- Recurrent or refractory Ph + OLD in adult patients in

quality of monotherapy;

- Myelodysplastic and myeloproliferative diseases (MDS / MPD),

Related to the gene rearrangements of the platelet-derived growth factor receptor in adult patients;

- Hypereosinophilic syndrome and / or chronic eosinophilic leukemia

(HES / HAL) in adult patients with positive or negative abnormal FIP1L1-PDGFR alpha-tyrosine kinase;

- Adjuvant therapy of gastrointestinal stromal tumors

(GIT), positive for c-Kit (CD117) in adult patients;

- Inoperable, relapsing and / or metastatic swelling

dermatofibrosarcoma in adults.

Contraindications:Hypersensitivity to imatinib or any components of the drug, pregnancy, lactation, age under 2 years (safety and efficacy not established).

Carefully:Imatinib should be used with caution in patients with severe hepatic impairment, severe impaired renal function (QC less than 30 ml / min.), cardiovascular disease or in the presence of risk factors for heart failure, and regular hemodialysis.

Pregnancy and lactation:The purpose of the drug is contraindicated. Women of childbearing age during therapy with imatinib and at least 3 months afterwards should use effective methods of contraception.

Dosing and Administration:

Imatinib is taken orally, with food, with a full glass of water. Doses of 400 and 600 mg / day.should be 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 tablet, for example, children, the drug can be taken in a diluted form; pills diluted with water or apple juice. The necessary amount of tablets is placed in a glass, pour liquid (50-100 ml) and stir with a spoon; as a result, a slurry is formed. The resulting suspension should be taken immediately after preparation.

The dosage regimen depends on the diagnosis and the stage of the disease. Imatinib can appoint only doctors who have experience in treating patients with related diseases. Treatment with the drug is carried out as long as the clinical effect remains.

Ph + chronic myelogenous leukemia in adults - The recommended dose of imatinib depends on the phase of the disease. In the chronic phase of XML dose is 400 mg / day, in the phase of XML acceleration and with a blast crisis - 600 mg / day. The drug should be taken 1 time per day. Treatment with the drug is carried out as long as the clinical effect remains. In the absence of severe side effects and neutropenia or thrombocytopenia, not associated with leukemia,It is possible to increase the dose from 400 mg / day to 600 mg / day or up to 800 mg / day in patients in the chronic phase of the disease, and from 600 mg / day to 800 mg / day in patients in the phase of acceleration and blast crisis. Such a dose increase may be necessary in 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.

Ph + chronic myelogenous leukemia in children older than 2 years - the dose is calculated depending on the surface area of the body. In children with chronic phase XML and accelerating phase, a dose of 340 mg / m / day is recommended. 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.

Acute Ph + lymphoblastic leukemia in adults - The recommended dose of imatinib is 600 mg / day.

Myelodysplastic and myeloproliferative diseases in adults - The recommended dose of imatinib is 400 mg / day.

Adjuvant therapy of gastrointestinal stromal tumors in adults - the recommended dose of imatinib is 400 mg / day. The minimum duration of treatment is 3 years.The optimal maximum duration of adjuvant therapy has not been established. If signs of progression appear, therapy with the drug should be discontinued. Inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma adults - the recommended dose is 800 mg / day. Hypereosinophilic syndrome and / or chronic eosinophilic leukemia in adults - the recommended dose is 400 mg / day. In patients with HES / HAL, due to abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended initial dose is 100 mg / day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

Correction of the dosing regimen

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, in patients with mild, moderate or severe hepatic impairment imatinib 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 is advised to prescribe the drug 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, however, in patients with mild to moderate renal impairment, treatment with imatinib should begin with a minimum effective dose of 400 mg / day. Although experience with imatinib has been limited in patients with severe renal dysfunction or with a regular hemodialysis procedure, it is also possible to start therapy with this drug with 400 mg / day, taking care. If the imatinib therapy is poorly tolerated, the initial dose of the drug can be reduced, with insufficient effectiveness - increased.

Elderly patients

Correction of the dosing regimen is not required. Non-hematological side effects

With the development of any serious non-hematologic side effect associated with taking the drug, therapy should be discontinued until the situation resolves. The treatment can then be resumed at a dose that depends on the severity of the observed side effect.

With an increase in the concentration of bilirubin and an increase in the activity of "hepatic" transaminases in the blood serum is 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.

Imatinib therapy is resumed with a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg / day or from 600 mg to 400 mg / day, or from 800 mg to 600 mg / day; in children - from 340 to 260 mg / m / day Hematological side effects

In the event of neutropenia and thrombocytopenia, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these undesirable phenomena.

In the case of hypereosinophilic syndrome and / or chronic eosinophilic leukemia caused by abnormal FIP1L1-PDGFR a-tyrosine kinase (initial dose of imatinib 100 mg), in the case of a decrease in the absolute number of neutrophils <1> <109 / l and / or platelet count <50x109 / l,

- abolish imatinib until the absolute number of neutrophils is> 1.5 x Ю9 / l and platelets> 75x109 / l;

- resume treatment with imatinib at a dose used before the interruption of therapy. In the chronic phase of XMJI in children and adults, gastrointestinal tract stromal tumors (GIST), MDS / MPD and HES / HAL in adults (the initial dose

for adults - 400 mg, for children - 340 mg / m2) in the case of a decrease in the absolute number of neutrophils <1x10 / l and / or platelet count <50x109 / l, it is recommended:

- abolish imatinib until the absolute number of neutrophils is> 1.5x109 / l and platelets> 75 x 109 / L;

- resume treatment with imatinib at a dose used before the interruption of therapy.

In case of a repeated decrease in the number of neutrophils <1x10 / l and / or the number of platelets <50x107l, you should cancel again imatinib until the absolute number of neutrophils is> 1.5x10 / l and platelets> 75x10%, and then resume treatment with imatinib at a reduced dose of 300 mg (in children - 260 mg / m).

In the phase of acceleration and blast crisis of XMJI in children and adults and at (Ph +) - OJIJI in adult patients (initial dose for adults is 600 mg, for children - 340 mg / m) in case of absolute number reduction of neutrophils <0.5x10 / l and / or platelet count <10x10 / L after one or more months of treatment is recommended:

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

- if cytopenia is not associated with leukemia, reduce the dose of imatinib to 400 mg (in children - 260 mg / m);

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

- If cytopenia persists for 4 weeks and its association with leukemia is not confirmed, cancel imatinib until the absolute number of neutrophils is> 1x10 / l and platelets

> 20x10%; then resume treatment with imatinib at a dose of 300 mg (in children - 260 mg / m2). In the case of an inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of imatinib 800 mg), in the case of a decrease in the absolute number of neutrophils <1 x 10 9 / L and / or platelet count <50x10 / l,

- abolish imatinib until the absolute number of neutrophils is> 1.5x10%

and platelets> 75x10%;

- to resume treatment with imatinib at a dose of 600 mg.

In the case of a repeated decrease in the number of neutrophils <1x10 / l and / or the number of platelets <50x 10%, again cancel imatinib until the absolute number of neutrophils is> 1.5x10% and platelets> 75x10%, and then resume treatment with imatinib in a reduced dose of 400 mg.

Side effects:

The safety profile of imatinib has been well studied. Most patients experience certain adverse events (AEs) during the use of the drug. The most frequent AE (> 10%) associated with taking imatinib were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea,myalgia, muscle cramps, rash, weakness, abdominal pain. Most of these AEs were mild or moderately severe. Only 2-5% of patients discontinued imatinib therapy because of the development of AEs. Myelosuppression, AE on the part of the gastrointestinal tract, edema and rash occur when imatinib is used in both XML and malignant stromal tumors of the gastrointestinal tract. In patients with XMJI, myelosuppression often develops, and in patients with malignant stromal tumors of the gastrointestinal tract, gastrointestinal and intratumoral bleeding occurs more often. Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration, occur more often with stromal GI tract. Other serious AEs with 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 depending on the severity of AE, up to the withdrawal of the drug.

Side effects identified in the clinical studies of imatinib in patients with XML and with inoperable and / or metastatic gastrointestinal malignant stromal tumors,(> 1/10), often (> 1/100 <1/10), infrequently (> 1/1000 <1/100), rarely (> 1 / 10 000 <1/1000), very rarely (<1/10 000, including individual reports).

Infectious diseases: infrequent - herpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, inflammation of the subcutaneous tissue, upper respiratory 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.

Impaired nervous system: very often - headache2; often - insomnia, dizziness, paresthesia, a taste disorder, hypoesthesia; infrequently - depression, anxiety, decreased libido, migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - confusion, increased intracranial pressure, convulsions, optic neuritis ,.

Disorders from the side of the organ of vision: often - edema of the eyelids, increased tearing, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; infrequent - eye irritation, eye pain, orbital edema, bleeding in the sclera of the eye, retinal 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 - a feeling of palpitations, chronic heart failure3, pulmonary edema, tachycardia, "hot flashes"; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, increased blood pressure.

Vascular disorders: infrequently - hemorrhage; rarely - hematomas, cold extremities, lowering of blood pressure, Raynaud's syndrome.

Disturbances from the respiratory system, chest, mediastinum: often - nosebleeds, dyspnea, cough; infrequently - pleural effusion, pain in the pharynx or larynx, pharyngitis; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea, indigestion, abdominal pain7; often - bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding, 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" transaminases; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure, necrosis of the liver.

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, petechia, increased sweating, urticaria, ecchymosis, increased predisposition to education 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 musculoskeletal system and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain (including myalgia, arthralgia, pain in the bones1); 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 mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual disorder, 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 - chest pain, general malaise.

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

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

2 Headache was most often noted in patients with inoperable and / or metastatic gastrointestinal stromal tumors.

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

4 "Tides" were most often observed in patients with inoperable and / or metastatic gastrointestinal stromal tumors.

5 Bleeding (hematoma, hemorrhage) was most often observed in patients with XML in the phase of acceleration, blast crisis and with inoperable and / or metastatic gastrointestinal tumors.

6 Pleural effusion was more often observed in patients with XML in the acceleration phase and in blast crisis compared to XML in the chronic phase (duration of follow-up is 1 year).

7 Abdominal pain was most often observed in patients with inoperable and / or metastatic gastrointestinal tumors.

8 Gastrointestinal bleeding was most often observed in patients with inoperable and / or metastatic gastrointestinal tumors.

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

10 Musculo-skeletal pains (including myalgia, arthralgia, bone pain) were more frequent in patients with XML compared with patients with inoperable and / or metastatic gastrointestinal tumors.

When imatinib was used in clinical practice, as well as during additional clinical studies, the following adverse events were noted,listed below for organs and systems with the frequency of their occurrence: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10 000, <1/1000), very rarely (<1/10 000, including individual reports). The relationship between drug use and these adverse events has not been established (the size of the patient population is unknown).

Impaired 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.

Vascular disorders: infrequently - thrombosis / embolism; rarely -

anaphylactic shock.

Disturbances from the respiratory, thoracic, mediastinal: infrequently - acute respiratory failure, interstitial pneumonia.

Disorders from the gastrointestinal tract: infrequently - ileus (intestinal obstruction), bleeding from the tumor of the digestive tract, necrosis of the tumor of the digestive tract, perforation2 of the gastrointestinal tract; rarely - diverticulitis.

Disturbances from the skin and subcutaneous tissues: infrequently - palmar-plantar erythrodysesthesia; rarely - lichenoid keratosis, red flat lichen; very rarely - toxic epidermal necrolysis.

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

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

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

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

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 condition of patients).

Antidote to Imatinib is not known. In case of an overdose, medical supervision and symptomatic therapy are recommended. Overdose in adults

When imatinib was taken in a dose of more than 1200-1600 mg, nausea, vomiting, diarrhea, skin rash, erythema, edema, swelling in the joints, muscle spasms, fatigue, thrombocytopenia, pancytopenia, abdominal pain were observed during 1-10 days. , headache, decreased 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, increased activity of creatine phosphokinase and bilirubin, and gastrointestinal pain were noted.

When imatinib was used at a dose of 6400 mg, the patient developed nausea, vomiting, abdominal pain, fever, facial edema, 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

When taking imatinib in a dose of 400 mg, a three-year-old child experienced vomiting, diarrhea, and anorexia. In another case, when imatinib was taken at a dose of 980 mg, a decrease in the number of leukocytes in the blood and diarrhea was observed once in a child at the age of 3 years.

Interaction:

With the simultaneous use of imatinib with drugs that inhibit the isoenzyme CYP3A4 (incl. ketoconazole, itraconazole, erythromycin, clarithromycin), possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma. Caution is needed when combined with imatinib with CYP3A4 isoenzyme inhibitors.Concomitant use of drugs which are inducers isoenzyme CYP3A4 (e.g., rifampicin, dexamethasone, Hypericum perforatum drugs, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital or primidone), may lead to increased imatinib metabolism and reduce its concentration in plasma.

With simultaneous use of imatinib and simvastatin marked increase in AUC and Cmax of simvastatin 2 and 3.5 times, respectively, which is a consequence of inhibition of CYP3A4 isoenzyme imatinib. It is advisable to use caution when using imatinib and preparations that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentrations (for example, ciclosporin, pimozide). Imatinib may increase serum concentrations of other drugs metabolized isoenzyme CYP3A4 (triazolobenzodiazepiny, dihydropyridine derivatives - Blockers "slow" calcium channel, most inhibitors Z-W-hydroxy-metilglutarilreduktazy coenzyme A (HMG-CoA reductase inhibitors), including statins). Imatinib also inhibits the isoenzymes CYP2C9 and CYP2C19 in vitro. Elongation of prothrombin time was observed when combined with warfarin. When used simultaneously with coumarin derivatives, short-term prothrombin time monitoring at the beginning and at the end of therapy with imatinib is required, as well as when the imatinib dosage regimen is changed. Alternatively, consideration should be given to the use of low molecular weight heparin derivatives.

When a combination 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 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme. When imatinib 400 mg twice a day, along with metoprolol, the substrate of the isoenzyme CYP2D6, there is a moderate decrease in metoprolol metabolism, accompanied by an increase in Cmax and AUC of approximately 21%.Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when combined with imatinib, there is no need to change the dosage regimen. In vitro imatinib inhibits paracetamol O-glucuronidation. A case of development in the patient of acute hepatic insufficiency with a lethal outcome is described with simultaneous application of imatinib and paracetamol. Caution should be exercised when applying imatinib together with paracetamol or preparations of St. John's wort perfumed.

Special instructions:

Treatment with imatinib 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.

Efficacy and safety of imatinib in children with CML younger than 2 years has not yet been established. The experience of imatinib with 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 cases of growth retardation, it is recommended that careful monitoring of growth in children taking imatinib.

Inhibition of hematopoiesis

The frequency of oppression of hematopoiesis and the degree of its expression in the application of imatinb 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 imatinib in patients with CML was reversible and in most cases did not require the drug to be withdrawn or its dose reduced. The abolition of the drug was required in a small number of cases. Also observed were such phenomena as pancytopenia, lymphopenia and oppression of hematopoiesis.

When using imatinib, regular clinical blood testing and monitoring of liver function ("hepatic" transaminases, bilirubin, alkaline phosphatase) are recommended.

Swelling and fluid retention

Edema is a frequent side effect of imatinib. The incidence of edema in patients receiving imatinib by all indications, is more than 50%. The frequency and severity of edema depends on the dose and, apparently, correlates with the concentration of the drug 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. Despite this, careful monitoring of patients with heart disease should be ensured. In patients with advanced stages of XML, 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 highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. 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). For the timely detection of fluid retention, it is recommended to regularly monitor the body weight of patients. In case of a sudden sudden increase in body weight, a patient should be examined and, if necessary, temporarily discontinued therapy with imatinib and / or prescribe diuretics.

In some cases, severe fluid retention may have a severe course with a fatal outcome. When the drug is used, the case of death of a patient with a blast crisis and complexsymptomatology: pleural effusion, chronic cardiac and renal insufficiency.

Hepatotoxicity

The drug may have a toxic effect on the liver. The violation of biochemical indicators of liver function, as a rule, consists in a slight increase in the activity of "liver" transaminases and an increase in the concentration of bilirubin in the blood serum. The toxic effect on the liver usually manifests itself during the first two months of treatment, but in a number of cases it manifests itself 6-12 months after the start of treatment. As a vaccine, after discontinuation of the drug, biochemical parameters of liver function normalize within 1 - 4 weeks. A marked increase in the activity of "hepatic" transaminases or bilirubin was noted in less than 3% of patients with XMJI 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). When using the drug in patients with liver disease should be regularly carried out a clinical blood test and monitoring the liver ("liver" transaminases, bilirubin, alkaline phosphatase).

Hemorrhage / bleeding

The most frequent clinically significant bleeding with imatinib was bleeding from the gastrointestinal tract. Most often they appeared in patients with advanced stages of XMJI and in patients with gastrointestinal malignant stromal tumors, in which they can be a consequence of the underlying disease (tumor bleeding caused by tumor necrosis).

In patients with malignant stromal tumors of the gastrointestinal tract, gastrointestinal bleeding and bleeding from the tumor are possible. In this case, both intra-abdominal and intrahepatic hemorrhages are noted, depending on the anatomical location of the tumor.

In patients with XML, whose hematopoiesis was suppressed already prior to treatment, hemorrhages to the central nervous system or gastrointestinal tract were often observed during treatment. It was found that patients with leukemia with acute development of the disease often have bleeding / hemorrhage caused by thrombocytopenia or thrombocytopathy.

Rash and severe skin undesirable effects

In a number of patients who received imatinib, there was a generalized erythematous, spotty-papular and itchy rash, which could pass independently despite the continued use of 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 and face. 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 corticosteroids for systemic use. 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 locally 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, tumor necrosis may occur against a background of a tumor response, which in rare cases leads to perforation. Obstruction of the gastrointestinal tract was more common in patients with malignant stromal tumors of the gastrointestinal tract, in which it can be caused by metastases or adhesions arising from previous surgery on the digestive tract (in the case of the drug as adjuvant therapy).

Other special instructions

Since there are reports of the development of hypothyroidism with imatinib in patients who undergone thyroidectomy and who are receiving levothyroxine replacement therapy, regular determination of the thyroid-stimulating hormone concentration in this category of patients is necessary.

In patients with hypereosinophilia syndrome and heart disease, individual cases of cardiogenic shock / left ventricular failure were noted at the beginning of imatinib therapy. These undesirable phenomena stop after the introduction of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary withdrawal of imatinib.

In patients with MDS / MPD and high levels of eosinophils, electrocardiography should be performed and the serum concentration of 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 to 2 weeks simultaneously with imatinib.

During therapy with imatinib and at least 3 months after, you should use reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:Some adverse drug reactions, such as dizziness and blurred vision, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions. In this regard, the patient receiving imatinib, care should be taken when driving vehicles and performing potentially hazardous activities.

Form release / dosage:Tablets, film-coated, 50 mg, 100 mg.

Packaging:

For 10 tablets for dosages of 50 mg and 100 mg or 12 tablets for dosing 100 mg into a contour mesh box made of aluminum foil and PVC film.For 3 out-of-round cell packs of 10 tablets for a dosage of 50 mg, for 2 or 6 out-of-round cell packs of 10 tablets for a dosage of 100 mg together with instructions for use in a cardboard pack.

By 2, 3, 4, 8, 10 or 15 contour cell packs of 12 tablets for a dosage of 100 mg together with instructions for use in a pack of cardboard.

Storage conditions:

Keep in dry the dark place at a temperature of no higher than 30 ° 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-002159

Date of registration:26.07.2013

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

Shijiazhuang Yiling Pharmaceutical, Co.Ltd China

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp19.03.2014

Illustrated instructions

Instructions

Imatinib (Imatinib)