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

iron oxide yellow oxide, _E 172 0.059 mg / 0.187 mg, iron oxide red oxide, E 172 0.005 mg / 0.017 mg, ferric oxide black oxide, E 172 0.003 mg / -, titanium dioxide, E 171 0.112 mg / 0.384 mg, gelatin * 16.621 mg / 28.212 mg

Cap:

ferric oxide yellow oxide, E172 0.039 mg / 0.125 mg, iron oxide dye

red, E 172 0.003 mg / 0.012 mg, iron dye oxide black, E172 0.002 mg / -, titanium

dioxide, E 171 0.075 mg / 0.256 mg, gelatin * 11.081 mg / 18.808 mg

per 1 capsule 200 mg / 400 mg:

Imatinib, substance-granules 295.00 mg / 590.00 mg

[Active substance of substance-granules:

Imatinib mesylate, 239.00 mg / 478.00 mg. which corresponds to Imatinib 200 mg / 400 mg

Auxiliary substances of granule substance:

radio tape recorder 52,00 mg / 104,00 mg, giprolose 4,00 mg / 8,00 mg]

Auxiliary substances:

talc 3.00 mg / 6.00 mg

Gelatin capsules №1 / №00

Housing:

iron oxide yellow oxide, E 172 0.205 mg / 0.248 mg, iron oxide red dye, E 172 0.214 mg / 0.021 mg, ferric oxide black oxide, E 172 - / 0.014 mg, titanium dioxide, E 171 0.456 mg / 0.472 mg, gelatin * 44.724 mg / 70.045 mg

Cap:

iron oxide yellow oxide, E172 0.137 mg / 0.165 mg, iron oxide red pigment, E 172 0.143 mg / 0.014 mg, ferric oxide black oxide, E172- / 0.009 mg, titanium dioxide, E 171 0.304 mg / 0.315 mg, gelatin * 29.816 mg / 46.697 mg * contains an average of 14.5% water

Description:

Capsules 50 mg. Hard gelatin capsules No. 5 in yellow with a brownish hue (body and lid). The contents of capsules are white or white to yellow granules.

Capsules 100 mg. Hard gelatin capsules №3 of light orange color (body and lid). The contents of capsules are white or white to yellow granules.

Capsules 200 mg. Hard gelatin capsules No. 1 of reddish orange color (body and lid). The contents of capsules are white or white to yellow granules.

Capsules 400 mg. Hard gelatin capsules No. 00 yellow with a brownish tinge (body and lid). The contents of capsules are white or white to yellow granules.

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 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 inhibiting proliferation and

causes apoptosis of the cell lines expressing Bcr-ABL tyrosine kinase, including immature leukemia cells that are formed in patients with chronic myeloid leukemia positive for the Philadelphia chromosome 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 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 the time to reach the maximum concentration of imatinib in the blood plasma by 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 the dose range of 260 mg / m and 340 mg / m is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When the AUCq-24 values were compared for children and adolescents on the 1 st and 8 th days after repeated taking of the drug at a dose of 340 mg / m 2, the increase in the value of this indicator by 1.7 times, indicating the imitation of imatinib, was observed once a day. 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 indicators (age, body weight and body mass index) have no clinically significant effect on 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 (Ph +) chronic myeloid leukemia (XML) in children and adults.

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

- The first diagnosed positive for the Philadelphia chromosome is acute lymphoblastic leukemia (ALL) in children and adult patients in combination with chemotherapy.

- Recurrent or refractory Ph + acute lymphoblastic leukemia in adult patients as monotherapy.

- Myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with gene rearrangements of the platelet-derived growth factor receptor in adult patients.

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

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

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

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

Contraindications:

- Hypersensitivity to imatinib or any other component of the drug.

- Pregnancy and the period of breastfeeding.

- Child age (effectiveness and safety not established):

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

- up to 2 beds in patients with Ph + chronic myeloid leukemia:

- up to 18 years for other indications.

Carefully:Should be used with caution Neopaks® drug in patients with severe liver failure, severe renal impairment, cardiovascular diseases or in the presence of risk factors for heart failure, as well as during regular hemodialysis treatment, while the use of drugs that inhibit isozyme CYP3A4, strong inducers of CYP3A4 izofermenga, with drugs that are substrates of CYP3A4 isoenzyme, acetaminophen, warfarin (see. section "Interaction with other pharmaceuticals ennymi drugs ").

Pregnancy and lactation:

Currently, there is no data on the use of Imatinib in pregnancy. Studies conducted on animals have shown toxic effects on reproductive function, but the potential risk to the fetus is still unknown. The use of the drug Neopox is contraindicated in pregnancy.

At present, it is not known whether imatinib with breast milk. Experimental data indicate that the unchanged drug and / or its metabolites are excreted in significant quantities with breast milk. If Neopox® is needed, breastfeeding should be discontinued.

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 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, the drug 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 immediately after preparation.

Treatment with the drug is carried out as long as the clinical effect remains. With CML, the recommended dose of Neopox® depends on the phase of the disease. In the chronic phase of CML the dose is 400 mg / day, during the acceleration phase 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,it is possible to increase the dose 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 phase of acceleration and with a blast crisis. Such a dose increase may be necessary for the progression of CML (at any stage), in the absence of a satisfactory hematologic response after 3 months of treatment, a cytogenetic response at 12 months of therapy, or loss of a previously hematologic and / or cytogenetic response.

Calculation of the dosing regimen in children over 2 years of age is based on body surface area.

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.

With Ph + ALL, the recommended dose of Neopax is 600 mg per day. Calculation of the 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 adults with relapsed or refractory Ph + ALL, the recommended dose is 600 mg / day.

For MDS / MPD, the recommended dose of Neopax® is 400 mg per day. In HES / HAL 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 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 Neopax® is 400 mg per day. In the absence of side effects of the drug and an insufficient response, an increase in the daily dose of the drug Neopax from 400 mg to 600 mg or up to 800 mg is possible.

If there is evidence of progression of the disease, therapy with Neopox should be discontinued.

When the drug is used as an adjuvant therapy in patients with gastrointestinal stromal tumors, the recommended dose is 400 mg / day. The minimum duration of treatment is 3 years. The optimal duration of adjuvant therapy has not been established.

In the case of inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma, the recommended dose of Neopax is 800 mg per day.

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, in patients with mild, moderate or severe liver function, Neopax 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. 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. In patients with impaired renal function or in patients requiring systematic hemodialysis, treatment with Neopox® should begin at the lowest effective dose, 400 mg once daily, with caution.

With intolerance to the drug Neopox, 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 with the development of non -hematological side effects of the drug

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

With increasing bilirubin concentration and activity of "hepatic" transaminases in blood serum 3 and 5 times higher than the upper limit of normal (VGN), respectively, treatment with Neopax® precursor should be temporarily suspended until the concentration of bilirubin decreases to less than 1.5xVGN and the activity of "hepatic" transaminase to a value less than 2.5 × IV in the blood serum. 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 / m per day.

Correction of the dosing regimen with the development of serious side effects on the part of the hemopoietic system (severe thrombocytopenia, neutropenia). If neutropenia and thrombocytopenia occur, a temporary withdrawal of the Neopax or a dose reduction is required, depending on the severity of these undesirable events.

For HES / HAL caused by an abnormal FIP1L1-PDGFR a-tyrosine kinase (the initial dose of the drug Neopaks8 is 100 mg), in the case of a decrease in the absolute amount of neutrophils <1 x 109 / L and / or platelet count <50x10 / l,

1. cancel the drug Neopox until the absolute number of neutrophils is> 1.5X109 / L and platelets> 75x109 / l;

2. Renew the treatment with Neopax10 in a dose used before the interruption of therapy.

In the chronic phase of CML in children and adults (initial dose for adults - 400 mg, for children - 340 mg / m2), malignant gastrointestinal stromal tumors; MDS / MPH, HES / HAL in adult patients (initial dose for adults - 400 mg) in the case of a decrease in the absolute number of neutrophils <1x10 / l and / or platelet count <50x109 / l is recommended:

1. to cancel the preparation of Neopox until the absolute amount of neutrophils becomes> 1.5x109 / l and platelets> 75x109 / l;

2. to resume treatment with Neopax00 in a dose used before the interruption of therapy;

3. in the case of a repeated decrease in the number of neutrophils <1x10 / l and / or the amount of < 5 (1x109 / L), repeat the actions described in paragraph 1, and then resume treatment with NeoPax at a reduced dose of 300 mg (in children - 260 mg / m).In the phase of acceleration and power crisis of CML in children and adults and in RI + ALL in adults (initial dose for adults is 600 mg, for children - 340 mg / m) in case of absolute neutrophil count decrease <0.5 x 109 / 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 Neopax 130 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, cancel the Neopax preparation until the absolute number of neutrophils becomes> 1x10 / l and platelets> 20x10 / L, then resume treatment with Neopax 300 mg (in children - 200 mg / m2).

In the case of inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (the initial dose of the drug Neopax 800 mg) in the case of a decrease in the absolute number of neutrophils <1x10 / l and / or the number of platelets < 5 3x109 / l / μL is recommended:

1. Abolish the Neopax preparation until the absolute amount of neutrophils becomes> 1.5X109 / L and platelets> 75x10 / L;

2.to resume treatment with a drug Neopax® in a dose of 600 mg.

If the number of neutrophils <1x10 / L and / or the platelet count <50X109 / L is repeatedly reduced, the actions indicated in point I should be repeated and then resumed treatment with a drug of Neopox at 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 undesirable 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: rare - herpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, septicemia; 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.

Mental disorders: often - insomnia; infrequently - depression, anxiety, decreased libido; rarely confusion.

- 2

Violations from the nervous system: very often - headache; 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 eye: often - eyelid edema, increased tearing, conjunctival hemorrhages, 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, tinnitus, hearing loss.

Disorders from the heart: infrequent - a feeling of heartbeat, chronic3 heart failure, pulmonary edema, tachycardia, "hot flashes"; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, stenocardia, pericardial effusion, increased blood pressure.

Vascular disorders: infrequently - hemorrhage4; 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, indigestion, abdominal pain; 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 biliary tract: often - increased activity of "liver" enzymes; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure, 9 liver necrosis.

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 musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain; 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 disorders, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum.

General disorders and disorders at the injection site: 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 studies: infrequently - increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and creatinine levels in the blood serum; 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 was most often observed in patients with inoperable and / or metastatic gastrointestinal malignant 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 (hematomas,hemorrhage) was most often observed in patients with XML in the phase of acceleration, blast crisis and with inoperable and / or metastatic gastrointestinal malignant tumors.

5 - Pleural effusion was 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).

6.7 - Abdominal pain and gastrointestinal bleeding were most frequently 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.

In the application of imatinib in the clinical practice of the gestational 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.

Disorders from the 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: infrequently - 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 digestive tract, perforation 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; frequency unknown - drug rash with eosinophilia and systemic symptoms.

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

Violations from the genitals: very rarely - women have bleeding 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.

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). Severe adverse reactions from the respiratory system Severe (sometimes fatal) adverse reactions were noted with 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 imatinib overdose. In general, the outcome of cases of imatinib overdose was favorable (there was an improvement in the patients' condition).

Antidote to the drug Neopox 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 mostly, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, golubevna pain, 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, increase in serum activity of creatine phosphokinase, bilirubin concentration, gastrointestinal pain were noted. When imatinib was used at 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 imatinib in a dose of 8-10 mg, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents

When taking imatinib at a dose of 400 mg, a 3-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 and diarrhea was observed once in a child at the age of 3 years.

Interaction:

With the simultaneous use of the drug Neopax with drugs that inhibit the isoenzyme CYP3A4 cytochrome P450, - protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), ketoconazole. itraconazole, posaconazole, voriconazole, some macrolides, such as erythromycin, clarithromycin, telithromycin, possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma. Caution is necessary when combined with Neopax® with inhibitors of the isoenzyme CYP3A4. Conversely, the simultaneous use of strong inducers of the isoenzyme CYP3A4 (for example, rifampicin, dexamethasone, St. John's wort, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidon) can lead to an acceleration of the metabolism of imatinib and, as a consequence, a decrease in its concentration in the blood plasma and inefficiency of therapy.Simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.

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 Neopaks and the preparations that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentrations (for example, ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). The drug Neopax may increase serum concentrations of other drugs metabolized by the isoenzyme CYP3A4 (triazolo-benzodiazepines, dihydropyridine, slow calcium channel blockers, most inhibitors of HMG-CoA reductase [statins]). Imatinib also inhibits the isoenzyme CYP2C9 and the isoenzyme CYP2C19 in vitro. When combined with the use of the drug Neopax with the warfarin, prolongation of pro-fombin time was observed. When used simultaneously with coumarin derivatives, short-term monitoring of prothrombin time at the beginning and end of therapy with the drug is necessary,and also with a change in the dosage regimen of the Neopax preparation. As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

With the combination of the drug Neopax with chemospraceptic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the activity of "liver" 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, the preparation Neopax inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme. With the use of the preparation Neopax 400 mg twice a day simultaneously with metoprolol, the substrate of the isoenzyme CYP2D6, there is a moderate decrease in metabolism of metoprolol, accompanied by an increase in Stach 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 the drug Neopax, a change in the dosage regimen is not required.

In vitro imatinib inhibits O-glucuronidation of paracetamol, therefore caution should be exercised when imatinib with paracetamol is used concomitantly (especially when high doses of paracetamol are used). In patients who have undergone thyroidectomy and who receive hormone replacement therapy with levothyroxine sodium, it is possible to reduce its plasma concentration with simultaneous application with imatinib.

The question of the drug interaction of imatinib and chemotherapy drugs in patients with Ph + ALL has not been adequately studied. 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. There are reports of liver damage with simultaneous use of imatinib and asparaginase.

Special instructions:

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

When handling Neopox, avoid contact with the skin and eyes, and inhale the powder of the drug.

Experience with imatinib treatment of children with CML younger than 2 years is limited, experience with imatinib for other indications is limited in patients under 18 years of age, experience with imatinib in children with ALL is under 1 year of age. Long-term effects of prolonged exposure to imatinib on growth in children are unknown. But since there are reports of growth retardation, careful growth control is recommended in children using Neopox.

When using the drug Neopax®, it is recommended to conduct regular blood tests and monitor liver function (transaminase, bilirubin, alkaline phosphatase).

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

Due to the fact that with imatinib 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 Neopox and / or prescribe diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant diseases of the cardiovascular system.

In some cases, severe fluid retention may have a severe course with a fatal outcome. When imatinib was used, the patient died with a blast crisis and complex symptomatology: pleural effusion, congestive cardiac and renal insufficiency.

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 with imatinib in patients who undergone thyroidectomy and who are receiving replacement therapy with levothyroxine sodium, it is necessary to regularly determine the concentration of thyrotropic hormone in the blood plasma in this category of patients. In patients with the syndrome of hypereosinophilia 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 AEs are stopped after the introduction of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary withdrawal of the drug Neopax.

In patients with MDS / MPD and high levels of eosinophils, ECG testing should be performed and the serum concentration of cardiospecific troponin should be determined. 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 trials, 3 phases of bleeding of different locations were noted in 12.9% of cases: in studies 2phgs, gastrointestinal bleeding was seen in 8 patients (5.4%), bleeding from tumor sites - in 4 patients (2.7%).

Bleeding was observed both in the organs of the abdominal cavity and in the liver, depending on the localization of tumor sites. In the postgrade period, separate reports were received on cases of viral ectasia of the antral stomach (GAVE-syndrome), a rare cause of gastrointestinal bleeding, registered in patients with CML and ALL and other diseases. It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignantGastrointestinal stromal tumors (abdominal pain, gastrointestinal bleeding, constipation, etc.) throughout the course of imatinib therapy. If necessary, consider reversing imatinib therapy.

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

A marked increase in the activity of "hepatic" transaminases or bilirubin concentration in blood plasma was observed in less than 3% of patients with CML and was usually controlled by a decrease in imatinib dose 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 prescribing the drug

Neopax should, if necessary, adjust in patients clinically pronounced dehydration and increased concentration of uric acid in the blood plasma.

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 hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions. In connection with this, patients receiving the drug Neopax should show increased attention and caution when driving vehicles and performing potentially hazardous activities. When these AEs are described, you should refrain from performing these activities.

Form release / dosage:Capsules 50 mg, 100 mg, 200 mg, 400 mg.

Packaging:Capsules 50 mg: 30 capsules per container of polypropylene (PP), sealed with a lid of low density polyethylene (LDPE) with control of the first opening.

Capsules 100 mg: For 60 or 120 capsules in a container of polypropylene (PP), capped with a lid of low density polyethylene (LDPE) with control of the first opening.

Capsules 200 mg: For 90 or 120 capsules in a container of polypropylene (PP), sealed with a lid of low density polyethylene (LDPE) with the control of the first opening.

Capsules 400 mg: For 30 or 90 capsules in a container of polypropylene (PP), sealed with a lid of low density polyethylene (LDPE) with the control of the first opening. Each container is placed in a pack of cardboard along with instructions for use.

Storage conditions:At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002019

Date of registration:01.03.2013

The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia

Manufacturer: & nbsp

KRKA-RUS, LLC Russia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp23.08.2013

Illustrated instructions

Instructions

Neopax (Neopax)