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

Excipients: cellulose microcrystalline 34.85 mg / 139.40 mg, crospovidone 28.00 mg / 112.00 mg, hypromellose 2.50 mg / 10.00 mg, silicon dioxide colloid 1.25 mg / 5.00 mg, magnesium stearate 1, 40 mg / 5.60 mg;

sheath: the main shell-forming mixture is yellow 8.55 mg / 21.375 mg, the main shell-forming mixture is red 0.45 mg / 1.125 mg;

shell-forming yellow mixture contains: Iron Oxide Dye Yellow (C.I. No. 77492, E172) 14.30%, macrogol 4000, 7.15%, talc 7.15%, hypromellose 71.40%; the shell-forming red mixture contains: iron oxide red dye (C.I. No. 77491, E172) 14.30%, macrogol 4000, 7.15%, talc 7.15%, hypromellose 71.40%.

Description:

Dosage of 100 mg: round, biconcave with beveled edges tablets, covered with a film shell from dark yellow to orange-brown color, with engraving "NVR" on one side and "SA" on the other side with a risk between the letters "S" and "A".

Dosage of 400 mg: oval, biconcave with oblique edges of the tablet, covered with a film membrane from a dark yellow to an orange-brown color,with engraving "400" on one side and with a risk between "SL" and "SL" on the other side.

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib is an inhibitor of protein tyrosine kinases, which has a powerful selective effect on activity BCR-ABL tyrosine kinase (TK), as well as some other TK: the receptor of growth factor of mast and stem cells (SCFR or protein tyrosine kinase KIT, Cd 117), the receptors of the domain of discoidin (DDR1 and DDR2), colony-stimulating factor receptor (CSF-1R), platelet derived growth factor receptors (PDGFR-α and PDGFR-β). Imatinib selectively inhibits proliferation and causes apoptosis of the cell lines expressing BCR-ABL, including immature leukemia cells formed in patients with positive for the Philadelphia chromosome (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). In vitro imatinib selectively inhibits BCR-ABL-positive colonies obtained from the blood cells of patients with CML.

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

Activation of receptors of platelet growth factors or ABL- fragment of tyrosine kinase can cause the development of both myelodysplastic / myeloproliferative diseases, and hypereosinophilic syndrome (HES), chronic eosinophilic leukemia and bulging dermatofibrosarcoma. Activation c-Kit receptor tyrosine kinase and receptors of platelet growth factors can underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits signal transmission in cells and cell proliferation resulting from a disruption in the regulation of platelet-derived growth factors and stem cells, c-Kitreceptor and ABL-fragment of tyrosine kinase. When imatinib was used in patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors (GISO), a significant increase in the overall survival of patients (median survival -48.8 months) and disease-free survival (21 months) was noted. Adjuvant therapy with GISO reduces the risk of relapse by 89%, increases the survival rate without symptoms (38 months).Adjuvant therapy imatinib GISO for 1 year reduces the risk of relapse, increases the survival rate without signs of disease. Adjuvant therapy with GISO for 3 years leads to a significant increase in overall survival and survival without signs of disease progression compared with therapy for 1 year.

Pharmacokinetics:

The pharmacokinetic parameters of imatinib were evaluated when the drug was administered in the dose range of 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on day 1, and also when equilibrium concentrations of imatinib in plasma were reached on the 7th or 28th day.

Suction

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

When taking the drug with food high in fat, there is a slight decrease in the degree of absorption (a decrease in the maximum concentration of imatinib in the blood plasma by 11% and the value 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) compared with fasting.

Distribution

About 95% of imatinib binds to blood plasma proteins (mainly albumin and acid α-glycoprotein, to an insignificant degree - with lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver with the formation of the main metabolite (A-demethylated piperazine derivative) circulating in the bloodstream. In vitro the imatinib metabolite has pharmacological activity comparable to the activity of the starting material. AUC metabolite is 16% of AUC imatinib. The binding of a metabolite with plasma proteins is similar to that of imatinib.

Excretion

After a single dose, the drug is excreted from the body for 7 days, mainly in the form of metabolites (68% through the intestine and 13% - by the kidneys). In an unchanged form, about 25% of the dose is excreted (20% through 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, its pharmacokinetic parameters do not change significantly, and the equilibrium concentration of imatinib in the blood plasma exceeds the initial concentration by 1.5-2.5 times.

In patients older than 65 years, the volume of distribution slightly increases (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 dose depending on the patient's body weight. The pharmacokinetics of imatinib does not depend on sex. Changes in the clearance and volume of distribution of imatinib with its simultaneous use with other drugs are insignificant and do not require a change in the dose of the drug.

Children and adolescents: as in adult patients, in children and adolescents under the age of 18 imatinib when ingested quickly and almost completely absorbed. The values AUC in patients of this age group after taking imatinib in doses of 260 and 340 mg / m² similar to those in adults after taking the drug at doses of 400 mg and 600 mg, respectively. When comparing the values of the indicator AUC(0-24) In children and adolescents on the 1 st and 8 th days, when the drug is taken again at a dose of 340 mg / m once a day, the increase in the value of this indicator is observed 1.7 times, indicating the cumulation of imatinib.Based on the combined population pharmacokinetic analysis in children with hematological diseases, it was shown that the clearance of imatinib is directly proportional to the surface area of the body, other demographic parameters (age, body weight and body mass index) have no clinically significant effect on the imatinib exposure.

Impaired liver function: in patients with hepatic dysfunction of various degrees, mean values AUC do not increase.

Impaired renal function: when using imatinib in patients with impaired renal function of mild or moderate degree (creatinine clearance> 30 ml / min), an increase in exposure (effective amount) of the preparation in blood plasma in 1.5-2.0 times, corresponding to an increase in the concentration of acid α-glycoprotein (the main plasma protein binding to imatinib). Since only a small amount of the drug is excreted by the kidneys, the clearance of free imatinib was the same in healthy volunteers and in 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 first detected positive for the Philadelphia chromosome chronic myeloid leukemia (Ph+ CML) in children and adults;

2. Ph+ CML in the chronic phase if previous interferon alpha therapy fails or in the accelerated phase, or blast crisis in children and adults;

3. The positive chromosomal positive for the first time in the Philadelphia (Ph+) acute lymphoblastic leukemia (ALL) in adult patients in combination with chemotherapy;

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

5. myelodysplastic / myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements in adult patients;

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

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

8. inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma in adult patients;

9. Inoperable or metastatic malignant gastrointestinal stromal tumors (GISO), positive for c- Kit (Cd117), in adult patients;

10. adjuvant therapy c-Kit+ (Cd117) GISO in adult patients.

Contraindications:

1. hypersensitivity to imatinib or any other component of the drug;

2. pregnancy and the period of breastfeeding;

3. children's age to 2 years (efficacy and safety of the drug in children of this age have not been established to date).

Carefully:

Severe hepatic impairment, severe renal dysfunction (including patients requiring regular hemodialysis), patients with cardiovascular disease and / or the presence of risk factors for heart failure, while concomitantly using isozyme inhibitory drugs CYP3A4, strong isoenzyme inducers CYP3A4, with preparations that are substrates of isoenzyme CYP3A4, paracetamol, warfarin (see section "Interaction with other medicinal products").

Pregnancy and lactation:

Studies in animals have shown that the drug has reproductive toxicity. There are reports of cases of spontaneous abortion and an increase in the frequency of fetal malformations. For this reason imatinib contraindicated during pregnancy.Women of reproductive age should apply effective contraceptive measures throughout the treatment period and within three months after discontinuation of treatment.

Imatinib and its active metabolites penetrate into breast milk, if you need to use the drug during breastfeeding, you should decide whether to stop breastfeeding.

Dosing and Administration:

The drug should be taken orally, with food, with a full glass of water (to reduce the risk of gastrointestinal disorders).

Doses of 400 and 600 mg per day are taken for 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 tablet, for example children, the drug can be taken in a diluted form, for which the tablets are diluted with water or apple juice.

Necessary number of tablets is placed in a beaker, filled with a liquid (approximately 50 ml of tablet liquid 100 mg and 100 ml - for a 400 mg tablet) and stirred with a spoon to form a slurry. The resulting suspension should be taken immediately after preparation.

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

When CML the recommended dose of Imagliv® 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.

In case of progression of CML (at any stage), in the absence of a satisfactory response to therapy (absence of a complete hematologic response after 3 months of treatment, cytogenetic response after 12 months of therapy or loss of the previously achieved response), if there are no significant side effects and neutropenia / thrombocytopenia, not associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or up to 800 mg per day 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 blast crisis.

Calculation of dosing regimen in children older than 2 years is based on the surface area of the body. Dose 340 mg / m² per day is recommended in children with chronic phase of CML and acceleration phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken simultaneously or divided into 2 equal doses - in the morning and in the evening.

When Ph+ ALL in adults The recommended dose of Imagliv® is 600 mg per day.

When myelodysplastic / myeloproliferative diseases in adults, the recommended dose Imagliv® is 400 mg per day.

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 3 years. Optimum duration Adjuvant therapy is not installed.

When inoperable and / or metastatic malignant GIS the recommended dose of Imagliv® 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 Imagliv® from 400 mg to 600 mg or up to 800 mg is possible.

When there are signs disease progression therapy with Imagliv®should be discontinued.

When inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma The recommended dose of Imagliv® is 800 mg per day.

When systemic mastocytosis Without D816V c-Kit mutation or an unknown mutational status or lack of effectiveness of previous therapy the recommended dose of Imagliv® in adults is 400 mg per day.

When systemic mastocytosis, conditioned by abnormal FIP1L1-PDGFR α-tyrosine kinase, formed as a result of gene fusion Fip like 1 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.

When HES and / or chronic eosinophilic leukemia (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.

When recurrent or refractory Ph+ ALL in adults the recommended dose is 600 mg / day.

Patients with impaired hepatic function

Since imatinib is metabolized mainly in the liver, patients with impaired liver function, Imagliv®should be prescribed in a minimum daily dose of 400 mg.With the development of severe undesirable effects the dose of the drug should be reduced. It is necessary with special caution to prescribe the drug to patients with severe hepatic insufficiency.

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 Imagliv® should be started with a minimum effective dose of 400 mg once a day, observing caution.

If Imagliv® is intolerant, the initial dose of the drug may be reduced, if the efficiency is insufficient, it is increased.

Elderly patients

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

Correction of the dosing regimen in the development of non-hematological 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 using a dose of the drug, the magnitude of which depends on the severity of the observed side effect.With an increase in the concentration of bilirubin and activity "hepatic" transaminases in the serum, respectively, 3 and 5 times higher than the upper limit of the norm (VGN), treatment with the drug should be temporarily to suspend until the concentration of bilirubin is reduced to less than 1.5 × VGN and the activity of "hepatic" transaminase to values less than 2.5 × IV.

Therapy with Imagliv® is resumed with a reduced daily dose: in adults, the dose decrease 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; the children - from 340 to 260 mg / m² per day.

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

When neutropenia and thrombocytopenia occur, a temporary withdrawal of the drug or a decrease in its dose, depending on the severity of these undesirable phenomena.

When systemic mastocytosis (SM) and HES / HAL caused by abnormal FIP1L1-PDGFR α-tyrosine kinase (initial dose of Imagliv®100 mg), in the case of a decrease in the absolute amount neutrophils in the blood to the level of <1x10⁹/ l and / or the number of platelets in the blood to the level <50x10⁹/ l it is recommended to cancel Imagliv® until the absolute number of neutrophils increases to ≥1,5x10⁹/ l, and the number of platelets does not increase to ≥75x10⁹/ l, then resume treatment with Imagliv® at a dose that was used before the interruption of therapy.

When chronic phase of CML in children and adults, GISO in adult patients, myelodysplastic / myeloproliferative diseases, SM and HES / HAL in adult patients (initial daily intake for adults - 400 mg, for children - 340 mg / m²) in the case of a decrease in the absolute amount of neutrophils to a level <1x10⁹/ l and / or platelet count to a <50x10⁹/ l It is recommended to cancel Imagliv® until the absolute amount of neutrophils increases to ≥1,5x10⁹/ l, and the number of platelets is not will increase to ≥75x10⁹/ l, then resume treatment with Imagliv® at the dose used before the interruption of therapy.

In the case of a repeated decrease in the number of neutrophils to a level <1x10⁹/ l and / or the number of platelets to the level <50x10⁹/ l should repeat the above actions, and then resume treatment with Imagliv® at a reduced dose of 300 mg (in children - 260 mg / m²).

In the phase of acceleration and power crisis of CML in children and adults and with Rh+ ALL in adult patients (initial daily dose for adults - 600 mg, for children - 340 mg / m²) in the case of a decrease in the absolute amount neutrophils to levels <0,5x10⁹/ l and / or platelet count to a <10x10⁹/ l after one or more months of treatment 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 Imagliv® 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 imatinib until the absolute number of neutrophils becomes ≥1x10⁹/ l and platelets ≥20x10⁹/ l; then resume treatment with Imagliv at a dose of 300 mg (in children - 200 mg / m²).

When inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma (the initial dose of Imagliv® 800 mg) in the case of a decrease in the absolute amount of neutrophils to a level <1x10⁹/ l and / or platelet count to a <50x10⁹/ l it is recommended to cancel Imagliv® until the absolute number of neutrophils increases to ≥1,5x10⁹/ l, and the number of platelets does not increase to ≥75x10⁹/ l, then resume treatment with Imagliv® in a dose of 600 mg.

In the case of a repeated decrease in the number of neutrophils to a level <1x10⁹/ l and / or platelet count to a <50x10⁹/ l follows the above repeated actions, and then resume treatment with Imagliv® at a reduced dose of 400 mg.

Side effects:

The safety profile of Imagliv® 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 the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. In general, these AEs were mild or moderate, only 2-5% patients discontinued therapy Imagliv® because of the development of AEs.

Myelosuppression, AE from the gastrointestinal tract (GIT), edema and rash occur when imatinib is used in both CML and GISO. In patients with CML more often develops myelosuppression, and in patients with GISO - gastrointestinal and intratumoral bleeding, other disorders of the gastrointestinal tract, such as intestinal obstruction, perforation and ulceration of the mucosa.Other serious AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.

Often peripheral edema was noted in periorbital area and lower extremities.

Types of AEs and the frequency of their development are similar when imatinib is taken by adults and children with leukemia. Combined side effects, such as pleural effusion, ascites, pulmonary edema and a rapid increase in body weight (with or without peripheral edema) that can be classified as "fluid retention", in some cases are capable of reaching serious (including life-threatening) levels.

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 accordance with the recommendations of the World Health Organization (WHO), the undesirable effects are classified according to the frequency of their development as follows: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Infectious and parasitic diseases

infrequently: herpes simplex, herpes zoster, nasopharyngitis, pneumonia¹, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections (including influenza), urinary tract infections, gastroenteritis, sepsis;
rarely: mycosis.
Violations of the blood and lymphatic system
Often: neutropenia, thrombocytopenia, anemia;
often: pancytopenia, febrile neutropenia;
infrequently: thrombocythemia, lymphopenia, severe oppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy;
rarely: hemolytic anemia.
Disorders from the metabolism and nutrition
often: anorexia;
infrequently: hypokalemia, increased or decreased appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia;
rarely: hyperkalemia, hypomagnesemia.
Disturbances from the nervous system
Often: headache²;
often: insomnia, dizziness, paresthesia, taste disorder, hypoesthesia;
infrequently: depression, anxiety, decreased libido, migraine, drowsiness, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke;
rarely: confusion, increased intracranial pressure, convulsions, optic neuritis.
Disturbances on the part of the organ of sight
often: eyelid edema, increased tear, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision;
infrequently: eye irritation, eye pain, orbital edema, bleeding in the sclera of the eye, bleeding in the retina, blepharitis, macular edema;
rarely: cataract, edema of the optic nerve, glaucoma.
Hearing disorders and labyrinthine disorders
infrequently: vertigo (dizziness), tinnitus, hearing loss.
Disorders from the cardiovascular system
often: "tides"³, hemorrhage;
infrequently: a feeling of palpitations, chronic heart failure⁴, pulmonary edema, tachycardia, increase or decrease in blood pressure, hematomas (including subdural hematomas), cold snap extremities, Raynaud's syndrome;
rarely: arrhythmias (including atrial fibrillation, sudden cardiac arrest), myocardial infarction, angina pectoris, pericardial effusion.
Disturbances from the respiratory system, organs of the chest, mediastinum
often: nose bleed, shortness of breath, cough;
infrequently: pleural effusion⁵, pain in the pharynx or larynx, pharyngitis;
rarely: pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.
Disorders from the gastrointestinal tract
Often: nausea, vomiting, diarrhea, dyspepsia, abdominal pain⁶;
often: bloating, flatulence, constipation, gastro-esophageal reflux, dry mouth, gastritis;
infrequently: stomatitis, ulceration mucous membrane of the mouth, gastrointestinal bleeding⁷, belching, melena, esophagitis, ascites, ulceration of the gastric mucosa, vomiting of blood, cheilitis, dysphagia, pancreatitis;
rarely: colitis, paralytic / obturation intestinal obstruction, inflammatory diseases intestines.
Disorders from the liver and bile ducts
often: increased activity "hepatic" transaminases;
infrequently: jaundice, hepatitis, hyperbilirubinemia;
rarely: liver failure, necrosis of the liver⁸.
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, reactions photosensitization;
infrequently: pustular rash, petechiae, increased sweating, urticaria, ecchymosis, increased 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, multiform erythema (including Stevens-Johnson syndrome), vesicular rash, leukoclastic vasculitis, acute generalized pustular exanthema.
Disturbances from musculoskeletal and connective tissue
Often: muscle spasms and cramps, musculoskeletal pain (myalgia, arthralgia, bone pain⁹);
often: swelling of the joints;
infrequently: stiffness of muscles and joints;
rarely: muscle weakness, arthritis.
Disorders from the kidneys and urinary tract
infrequently: pain in the kidney, hematuria, acute renal failure, rapid urination.
Violations of the genitals and mammary glands
infrequently: gynecomastia, erectile dysfunction, menorrhagia, menstrual irregularities, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum.
General disorders and disorders at the site of administration
Often: fluid retention and swelling, increased fatigue, weight gain;
often: weakness, increase body temperature, anasarca, chills, trembling, weight loss;
infrequently: chest pain, general malaise.
Laboratory and instrumental data
infrequently: increased activity alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and creatinine levels in the blood plasma;
rarely: increased activity amylase in the blood plasma.

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

²Headache was most often noted in patients with inoperable and / or metastatic GISO.

³ "Tides" was most often observed in patients with inoperable and / or metastatic GISO; bleeding (hematoma, hemorrhage) was most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic GISO.

⁴Undesirable cardiac events, including chronic heart failure, were more common in patients with CML in the accelerated phase and with a blast crisis in comparison with patients with CML in the chronic phase (duration of follow-up is 1 year).

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

^6/7Abdominal pain and gastrointestinal bleeding were most frequently observed in patients with inoperable and / or metastatic GISS.

⁸Individual cases of hepatic insufficiency and liver necrosis have been reported.

⁹Musculo-skeletal pains, including myalgia, arthralgia, bone pain, were more common in patients with CML in comparison of with patients with Inoperable and / or metastatic GISO.

Post-registration experience applications

During the application of the Imagliv® preparation, the following side effects (their relationship between drug use and the following AEs is not established, the size of the patient population is unknown):

Disturbances from the nervous system

infrequently: swelling of the brain.
Disturbances on the part of the organ of sight
rarely: hemorrhage in the vitreous body.
Disorders from the cardiovascular system
infrequently: thrombosis / embolism;
rarely: pericarditis, cardiac tamponade;
rarely: anaphylactic shock.
Disturbances from the respiratory system, chest organs, the mediastinum
infrequently: acute respiratory failure¹, interstitial lung disease.
Disorders from the gastrointestinal tract
infrequently: paralytic / obturation intestinal obstruction, bleeding from the tumor of the gastrointestinal tract, necrosis of the tumor of the gastrointestinal tract, perforation of the gastrointestinal tract²;
rarely: diverticulitis, vascular ectasia of the antrum of the stomach (GAVE-syndrome)³
Disturbances from the skin and subcutaneous tissues
infrequently: palmar-plantar erythrodysesthesia;
rarely: lichenoid keratosis, red flat lichen;
rarely: toxic epidermal necrolysis;
frequency is unknown: medicinal Rash with eosinophilia and systemic symptoms.
Disturbances from musculoskeletal and connective tissue
rarely: avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy; frequency is unknown: stunted growth in children.
Violations of the genitals and mammary gland
rarely: bleeding from yellow body / ovarian cyst.
Benign, malignant and unspecified neoplasms (including cysts and polyps)
rarely: syndrome of tumor lysis.

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

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

³In the postgrade period, separate reports were received on cases of vascular ectasia of the antrum of the stomach (GAVE-syndrome).

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 Imagliv® in doses exceeding therapeutic limits is limited. In clinical practice, there were isolated cases of drug overdose. In general, the outcome of such cases was favorable.

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

Overdose in adults

When taking Imagliv® at a dosage of 1200-1600 mg / day for 1-10 days, nausea, vomiting, diarrhea, rash, erythema, swelling, local swelling,increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased 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, increased activity of creatine phosphokinase and bilirubin concentration, abdominal pain were noted. With a single application of Imagliv® at a dose of 6400 mg, the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, a decrease in the number of neutrophils and an increase in the activity of "hepatic" transaminases in the serum.

With a single dose of the drug in a dose of 8-10 g, vomiting and abdominal pain were noted.

Overdose in children and adolescents

With a single dose of 400 mg in a three-year-old child, vomiting, diarrhea and anorexia were noted.

With a single dose of Imagliv® at a dose of 980 mg, a decrease in the number of leukocytes in the blood and diarrhea was observed in a child aged 3 years.

Interaction:

Drugs that can reduce the concentration of imatinib in the blood plasma (joint use is not recommended)

Simultaneous application of imatinib with preparations that are isoenzyme inducers CYP3A4 (rifampicin, dexamethasone, preparations from St. John's wort perfumed, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, phosphenytoin, primidon) can lead to an acceleration of the metabolism of imatinib and, as a consequence, to a decrease in its concentration in the blood plasma. According to the results of studies, the concentration of imatinib is reduced by 54-74%.

Drugs that can increase the concentration of imatinib in the blood plasma

With the simultaneous use of imatinib with isozyme inhibitory drugs CYP3A4 cytochrome P450 (eg, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, telithromycin, ketoconazole, itraconazole, erythromycin, clarithromycin), possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma (C_m_Oh increases by 26%, AUC - by 40%). Care should be taken when combining imatinib with these drugs or other inhibitors CYP3A4.

Drugs, the concentration of which may change with the appointment of imatinib

Imatinib is able to inhibit certain cytochrome P450 isoenzymes.When co-administered with imatinib and simvastatin C_m_Oh and AUC simvastatin increases by 2 and 3.5 times, respectively, which is due to inhibition CYP3A4 imatinib.

Imatinib is able to increase concentrations of other drugs metabolized by isoenzyme CYP3A4 (triazolobenzodiazepines, dihydropyridine blockers of "slow" calcium channels (amlodipine, nefidipin, etc.), most of the inhibitors of HMG-CoA reductase (statins).

It is recommended that special care be taken when imatinib and preparations that are substrates of the isoenzyme CYP3A4 and have a narrow therapeutic range (for example, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine, ciclosporin and pimozide). Imatinib also inhibits in vitro isozymes CYP2C9 and CYP2C19.

With the simultaneous use of imatinib with warfarin, prothrombin time (PV) elongation was observed. When used simultaneously with coumarin derivatives, short-term monitoring of PV at the beginning and at the end of therapy with the drug is necessary, as well as when the dosage regimen of imatinib is changed.As an alternative to warfarin, the use of low molecular weight heparins should be considered.

When a combination of imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatotoxicity, manifested by increased activity of "hepatic" transaminases in the blood serum and hyperbilirubinemia. It is necessary to monitor the function of the liver with a combination of imatinib and hepatotoxic regimes of chemotherapy.

In vitro imatinib inhibits isoenzyme CYP2D6 at the same concentrations in which it inhibits the isoenzyme CYP3 A4. When imatinib is used at a dose of 400 mg 2 times a day, together with metoprolol (substrate isoenzyme CYP2D6), there is an increase in C_m_Oh and AUC metoprolol by approximately 21%; however, taking into account the inessential enhancement of the effects of the isoenzyme substrates CYP2D6 when they are used together with imatinib, there is no need to change the dosage regimen of such drugs.

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

In patients who have undergone thyroidectomy and who are receiving replacement therapy with levothyroxine sodium, it is possible to reduce its plasma concentration when combined with imatinib.

The issue of drug interaction between imatinib and chemotherapy drugs in patients with Ph+ ALL.

Caution should be exercised when using imatinib and chemotherapeutic drugs in conjunction with a possible increase in the risk of developing drug complications such as hepatotoxicity and myelosuppression, etc.

There are reports of the development of liver damage in the joint use of imatinib and asparaginase.

Special instructions:

Treatment with Imagliv® should only be carried out under supervision of a physician with experience work with antineoplastic preparations.

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

The experience of treatment with Imagliv® CML in children younger than 2 years old and Ph + ALL in children younger than 1 year is limited. Long-term effects of prolonged exposure to Imagliv® on growth in children are not known, however, since there are reports of cases of growth retardation, it is recommended that careful monitoring of growth in children receiving Imagliv®. It is recommended that caution with the simultaneous use of Imagliv® and preparations that are substrates of the isoenzyme CYP3A4 and have a narrow therapeutic range (see Section "Interaction with other drugs").

Inhibition of hematopoiesis

The frequency of oppression of hematopoiesis and the degree of its expression depend on the stage of CML and the dose of the drug used, they are maximum when the drug is used in high doses. Inhibition of hemopoiesis against the background of the drug Imagliv® in patients with CML is reversible and in most cases does not require withdrawal of the drug or reduction of its dose. There are also cases of lymphopenia. When using Imagliv® is recommended regularly control cell composition of blood and liver function (the activity of "liver" transaminases and alkaline phosphatase, bilirubin concentration).

Swelling and fluid retention

Edema is a frequent side effect of imatinib therapy. The incidence of edema in patients receiving imatinib for all indications, is more than 50%. The frequency and degree of their manifestation, apparently, correlates with the concentration of the drug in the blood plasma. Severe fluid retention (accumulation in the pleural cavity, pulmonary edema, ascites, etc.) is observed in approximately 2.5% patients with CML. Most often there are periorbital edema, with a slightly lower frequency - swelling of the lower extremities. Specific treatment is usually not required. For the timely detection of fluid retention, regular monitoring of body weight of patients is recommended. In the case of an unexpected rapid increase in body weight, a patient should be examined and, if necessary, temporarily discontinued therapy with Imagliv® and / or prescribe diuretics. The highest frequency of development fluid retention is noted in elderly patients with concomitant cardiovascular diseases and renal insufficiency. Care should be taken to monitor patients with heart disease, kidney failure, or risk factors for their development. 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.Most patients with edema and fluid retention are elderly (> 65 years).

In some cases, severe fluid retention may have a severe course with a possible fatal outcome. When the drug is used, the case of the death of a patient with CML in the blast crisis phase and complex symptomatology is described: pleural effusion, development of chronic cardiac and renal insufficiency.

Hepatotoxicity

The drug may have a toxic effect on the liver. Disorders of biochemical parameters of liver function, as a rule, consist 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, however, in some cases, it can manifest 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. A marked increase in the activity of "hepatic" transaminases or bilirubin occurs in less than 3% of patients with CML and usually occurs after a reduction in the dose of the drug or a short-term interruption of treatment (the average duration of such episodes in the studies was about 1 week).When prescribing a drug, patients with liver disease should regularly assess the clinical blood test and determine the activity of "hepatic" enzymes in the blood plasma.

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 GISD, in whom they may be a consequence of the underlying disease (bleeding from the tumor due to its necrosis). In patients with inoperable and / or metastatic GISO in clinical studies of the III phase, bleeding of different locations was noted in 12.9% of cases; in clinical studies of the II phase, gastrointestinal bleeding was observed in 8 patients (5.4%), and bleeding from tumor foci in 4 patients (2.7%). Localization of bleeding depended on the location of tumor sites. In the postgrade period, separate reports were received on cases of vascular ectasia of the antrum, registered in patients with CML and ALL and other diseases. If necessary, consider reversing imatinib therapy.In patients with CML, who had signs of oppression of hematopoies before the start of treatment, hemorrhages in the central nervous system or bleeding from the gastrointestinal tract are often observed. It was found that patients with leukemia with acute development of the disease often have bleeding / hemorrhage caused by thrombocytopenia or thrombocytopathy.

When starting and during therapy with imatinib, one should carefully evaluate the presence of symptoms with hand gastrointestinal tract.

Rash and severe skin undesirable reactions

Skin rash occurs in about a third of all patients receiving imatinib for all indications. She is often accompanied by itching and, like rule, manifests itself in the form erythematous, spotty-papular rashes on the forearms, torso or face. Although In most cases, the rash is mild and without treatment, in more severe cases can a temporary or complete cancellation of the drug. Usually, the severity of the rash decreases after the appointment of antihistamines drugs and local glucocorticosteroids, however, in Some cases require their systemic application.

Intestinal obstruction, perforation or ulceration of the mucous membrane of the stomach or intestine

At a small part of patients on a background of therapy imatinib marked ulcerative lesion Gastrointestinal tract, which in some cases can be a consequence of the local irritating effect of Imatinib. Hemorrhagic necrosis of the tumor and perforation of the gastrointestinal tract are most often observed in patients with GIS. In the case of metastatic GISO, necrosis of the tumor can occur against the background of therapeutic pathomorphosis, which in rare cases leads to perforation. Gastrointestinal obstruction also occurs more often in patients with GIS, its cause may be metastases or adhesions that have arisen as a result of previous surgical treatment.

Hypothyroidism

Against the background of the use of Imagliv® in patients who underwent thyroidectomy and received substitution treatment levothyroxine sodium, there may be cases of development of hypothyroidism. It is necessary to regularly define concentration of thyrotropic hormone in this category of patients.

Hypereosinophilic syndrome

In patients with HES and heart disease (or hidden infiltration of the myocardium by HPP-cells) at the beginning of therapy with imatinib were noted individual cases of development cardiogenic shock / left ventricular failure.These undesirable phenomena are stopped by the introduction systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, temporary cancellation of Imagliv®.

In patients with MDS / MPD and a high number of eosinophils, cardiac function (ECG and serum concentration of cardiospecific troponin) should be monitored. If abnormalities are detected at the beginning of therapy, the possibility of preventive use of systemic glucocorticosteroids (1-2 mg / kg) for 1-2 weeks simultaneously with imatinib.

Tumor lysis syndrome

Due to the risk of developing the syndrome lysis of the tumor, it is necessary to ensure adequate hydration of the patient's body before prescribing Imagliv® monitor the level of uric acid before and during treatment.

Reproductive age

Women of reproductive age during therapy with Imagliv® and at least three months after the end of treatment with the drug should use reliable methods of contraception.

Assessment of the effect of therapy

Molecular monitoring of the response to therapy with Imagliv® in patients with Ph+ CML should be performed routinely every 3 months until a large molecular response is achieved, and then at least every 6 months. Conducting molecular Monitoring is also recommended for changes in therapy. Molecular monitoring allows to evaluate the effectiveness of therapy with tyrosine kinase inhibitors (TEC) in patients with CML, including an inadequate response to therapy or its loss, for example, due to reduced adherence of the patient to treatment (discontinuation of the drug, irregular reception), development of inter-drug interactions, development of resistance to therapy. Real-time polymerase chain reaction (PCR) is the most preferred method monitoring, due to its high sensitivity and minimally invasive nature.

Patients to whom such monitoring is performed every 3-4 months have a higher disease-free Survival rate compared with patients to whom such studies are performed less often. In case of unsatisfactory response to therapy in the absence of factors that reduce its effectiveness (low patient adherence to treatment, inter-drug interaction), it follows that consider changing treatment tactics (for example, the appointment of an alternative drug-tyrosine kinase inhibitor).

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

Some of the side effects of the drug, such as dizziness and blurry vision, can adversely affect the ability to drive vehicles and to perform potentially dangerous species Activities that require increased concentration and speed of psychomotor reactions. If the above undesirable phenomena occur, you should refrain from performing these activities.

Form release / dosage:

Pills, film coated 100 mg, 400 mg.

Packaging:

Dosage of 100 mg: 10 tablets per blister PVC / Al. 2 or 6 blisters together with instructions for use in a cardboard box.

Dosage of 400 mg: 10 tablets per blister PVC / PE / PVDC / Al. For 1 or 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

In a dry place 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:LS-001574

Date of registration:19.11.2012 / 03.02.2016

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

NOVARTIS PHARMA PRODUCTIONS, GmbH Germany

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp15.03.2016

Illustrated instructions

Instructions

Imagliv® (Imagliv®)