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

Excipients: cellulose microcrystalline 141.4 mg, low-substituted giprolose 41.5 mg, povidone K-30 8.5 mg, crospovidone 24.0 mg, silicon dioxide colloid 1.7 mg, magnesium stearate 3.4 mg;

shell: hypromellose 6.9 mg, macrogol 0.7 mg, talc 2.2 mg, iron dye red oxide 0.1 mg, iron oxide dye yellow 1.1 mg.

One tablet, film-coated, 400 mg contains:

active substance: Imatinib mesylate (in terms of imatinib) 478.0 mg (400.0 mg);

Excipients: microcrystalline cellulose 565.6 mg, low-substituted giprolose 166.0 mg, povidone K-30 34.0 mg, crospovidone 96.0 mg, silicon dioxide colloid 6.8 mg, magnesium stearate 13.6 mg;

shell: hypromellose 27.5 mg, macrogol 2.9 mg, talc 8.9 mg, iron dye oxide red 0.3 mg, iron dye oxide yellow 4.4 mg.

Description:

Tablets coated with a film coating, 100 mg: round, biconvex tablets, film-coated from dark yellow to orange-brown, with Risks on one side and engraving "100" on the other side.On the cross section, the core of the tablet is from white to almost white.

Film-coated tablets, 400 mg: oval, biconvex tablets, covered with a film shell from a dark yellow to an orange-brown color, with a risk on one side and an engraving "400" on the other side. On the cross section, the core of the tablet is from white to almost white.

Pharmacotherapeutic group:antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib has a selective inhibitory effect on the enzyme Bcr- Ab1-tyrosine kinase, formed at the fusion of a gene site Bcr (breakpoint cluster region) and proto-oncogene Abl (Abelson), at the cellular level, selectively inhibits proliferation and causes apoptosis of the cell lines expressing Bcr-Abl tyrosine kinase, including immature leukemia cells formed in patients with positive for the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia.

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

Imatinib inhibits proliferation and induces apoptosis of cells of gastrointestinal stromal tumors (GI tract),expressing tyrosine kinase with a mutation c-Kit receptor.

Activation of receptors to platelet or platelet growth factorsb1-tyrosine kinase fragment can cause the development of both myelodysplastic / myeloproliferative diseases and hypereosinophilic syndrome and chronic eosinophilic leukemia and swelling dermatofibrosarcoma. Activation c-Kit receptor tyrosine kinase and receptors for 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 Ab1-tyrosine kinase fragment.

When imatinib was used in patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors, there was a significant increase in the overall survival of patients (48.8 months) and disease-free survival (21 months).

Adjuvant therapy with a drug of gastrointestinal stromal tumors reduces the risk of relapse by 89%, increases the survival rate without symptoms (38 months imatinib compared with 20 months of placebo).Adjuvant therapy with the preparation of gastrointestinal stromal tumors 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 in a dose range of 25 to 1000 mg. Pharmacokinetic profiles were analyzed on the first day of use, as well as on the 7th or 28th day, i.e. after reaching the equilibrium concentration in the plasma.

Absorption

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

When taking the drug with food high in fat, in comparison with receiving on an empty stomach, there is a slight decrease in the degree of absorption (a decrease in C_mOh in blood plasma by 11% and AUC - by 7.4%) and slowing the rate of absorption (an increase in the time to reach the maximum concentration of the drug Imatinib-Alvogen in blood plasma for 1.5 hours).

Distribution

About 95% of the drug 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-detylated piperazine derivative) circulating in the blood stream. In conditions in vitro the pharmacological activity of the metabolite is similar to that of the starting material. Value AUC metabolite is 16% AUC Imatinib, and binding to plasma proteins is similar to that of the starting material.

Excretion

After ingestion of one dose, the drug is excreted from the body for 7 days, mainly in the form of metabolites (68% - intestine, and 13% - kidney). In an unchanged form, about 25% of the dose is excreted (5% by the kidneys and 20% by the intestine). The half-life of imatinib is about 18 hours.

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

Population pharmacokinetics

According to the population pharmacokinetic analysis of patients with CML, the volume of distribution of the drug varies slightly with age (in patients older than 65 years, an increase of 12% was noted).

Effects of body weight: at a body weight of 50 kg, the expected average clearance value is 8.5 l / h; With a body weight of 100 kg, this value rises to 11.8 l / h. However, these differences are not so significant, i.e. correction of the dose is not required depending on the patient's body weight.

The pharmacokinetics of imatinib is independent of sex.

As in adult patients, in children and adolescents under 18 years of age there is a rapid absorption of the drug when ingestion. AUC in this group of patients in a dose range of 260 and 340 mg / m² is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When comparing the values of AUQ in children and adolescents_0-24) on the first and eighth days after taking the drug at 340 mg / m² 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 (CML, Ph + ALL, etc.), 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.The analysis confirmed that the effect of imatinib on children in the dose range of 260 (not above 400 mg) and 340 mg / m² (not more than 600 mg) once a day is similar to that in adult patients who received imatinib in doses of 400 mg or 600 mg once a day.

Pharmacokinetics in specific patient groups

Patients with different degrees liver dysfunction mean values AUC do not increase.

Only a small part of imatinib and its metabolites are excreted by the kidneys. In patients with mild to moderate impaired renal function the concentration of the drug in the blood plasma is about 1.5-2 times higher than in patients with normal renal function, and corresponds to an increase in the concentration of acid alpha-glycoproteins (the main plasma proteins that bind to imatinib). Since the drug is slightly excreted by the kidneys, the clearance of free imatinib in patients with impaired renal function and patients with normal renal function is likely the same.

Indications:

A drug Imatinib-Alvogen is intended for treatment of:

- the first identified positive for the Philadelphia chromosome chronic myeloid leukemia (Ph+ CML) in children and adults;

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

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

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

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

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

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

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

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

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

Contraindications:

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

- children's age (efficacy and safety not established): up to 1 year in patients with Ph+ acute lymphoblastic leukemia; up to 2 years in patients with Ph+ chronic myeloid leukemia; up to 18 years for other indications;

- pregnancy and the period of breastfeeding.

Carefully:

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

Caution is advisable to use Imatinib-Alvogenpacient: with severe hepatic insufficiency, with severe renal dysfunction (including patients in need of regular hemodialysis), cardiovascular disease and / or risk factors for heart failure.

When used simultaneously with preparations inhibiting the isoenzyme CYP3A4, strong inducers of the isoenzyme CYP3A4, preparations that are substrates of the isoenzyme CYP3A4, paracetamol, warfarin (see section "Interaction with other drugs").

Pregnancy and lactation:

Contraindicated the appointment of the drug during pregnancy and during lactation.

Women of reproductive age should take effective contraceptive measures during the entire period of treatment with the drug Imatinib-Alvogen 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:

Inside. 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 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. The required amount of tablets is placed in a beaker, filled with liquid (approximately 50 ml of tablet liquid 100 mg and 100 ml - for 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 chronic myeloid leukemia (CML) recommended dose of the drug Imatinib-Alvogen depends on the phase of the disease. In the chronic phase of CML, the dose is 400 mg per day; in the phase of acceleration and with a blast crisis - 600 mg per 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 an earlier 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 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.

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

When Ph+ acute lymphoblastic leukemia recommended dose of the drug Imatinib-lovogen is 600 mg per day.

When myelodysplastic / myeloproliferative diseases in adults recommended dose of the drug Imatinib-Alvogen is 400 mg per day.

When using the drug Imatinib-Alvogen 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.

When inoperable and / or metastatic malignant GISO recommended dose of the drug Imatinib-Alvogen 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 Imatinib-Alvogen from 400 mg to 600 mg or up to 800 mg is possible.

When there are signs of disease progression drug therapy Imatinib-Alvogen should be discontinued.

When inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma recommended dose of the drug Imatinib-Alvogen is 800 mg per day.

When systemic mastocytosis Without D816V c-Kit mutation or unknown mutational status, or lack of effectiveness of previous therapy, the recommended dose of the drug Imatinib-Alvogen in adults it is 400 mg per day. With systemic mastocytosis due to abnormal FIP1L1-PDGFR α-tyrosine kinase, formed as a result of gene fusion Fip likel 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 per day is possible.

When HEPS and / or chronic eosinophilic leukemia (HAL) in adults, the recommended dose is 400 mg per 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 per day is possible.

With relapsing or refractory Ph+ CFR in adults, the recommended dose is 600 mg per day.

Application of the preparation Imatinib-Alvogen the special patient groups

Patients with impaired hepatic function

Because the imatinib metabolized mainly in the liver, patients with impaired liver function drug Imatinib-Alvogen should be prescribed in a minimum daily dose of 400 mg. With the development of severe undesirable toxic 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, drug treatment Imatinib-Alvogen should start with a minimum effective dose of 400 mg once a day, being careful.

If the drug is intolerant Imatinib-Alvogen 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 using a dose of the drug, the magnitude of which depends on the severity of the observed side effect.

With increasing bilirubin concentration and activity of "hepatic" transaminases in blood serum, respectively 3 and 5 times higher than the upper limit of the norm (VGN), treatment with the drug should be temporarily suspended until the concentration of bilirubin decreases to less than 1.5xVGN and the activity of "hepatic" transaminases up to values less than 2.5хVGN.

Drug therapy Imatinib-Alvogen resume with a reduced daily dose: of adults the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day; the children - from 340 mg / m² up to 260 mg / m² per day.

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

When systemic mastocytosis (SM) and (HES / HAL) caused by abnormal FIP1L1- PDGFR α-tyrosine kinase (initial dose of the drug Imatinib-Alvogen 100 mg), in the case of a decrease in the absolute number of neutrophils in the blood to <1x10⁹/ l and / or the number of platelets in the blood to <50x10⁹/ l it is recommended to cancel the drug Imatinib-Alvogen until the absolute number of neutrophils increases ≥ 1.5x10⁹/ l, and the number of platelets does not increase to ≥75 x10⁹/ l, then resume treatment with the drug Imatinib-Alvogen in the dose used before the interruption of therapy.

When chronic phase of CML the children and adults, GISO in adult patients, myelodysplastic / myeloproliferative diseases, SM and HES / HAL in adult patients (the initial daily intake for adults is 400 mg, for children 340 mg / m²) in the case of a decrease in the absolute number of neutrophils to <1x10⁹/ l and / or the number of platelets to the level 50x10⁹/ l it is recommended to cancel the drug Imatinib-Alvogen until the absolute number of neutrophils increases to ≥ 1.5x10⁹/ l, and the number of platelets does not increase to ≥75 x10⁹/ l, then resume treatment with the drug Imatinib-Alvogen in 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 platelet count to <50x10⁹/ l should repeat the above actions, and then resume treatment with the drug Imatinib-Alvogen in a reduced dose of 300 mg (in children 260 mg / m²).

AT the phase of acceleration and power crisis of CML in children and adults and with Ph+ ALL in adult patients (the initial daily intake for adults is 600 mg, for children 340 mg / m²) in the case of a decrease in the absolute number of neutrophils to a level <0.5x10⁹/ l and / or the number of platelets to a level 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 Imatinib-Alvogen up to 400 mg (in children - 260 mg / m²);

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

4. if cytopenia persists for 4 weeks and its association with leukemia is not confirmed, discontinue the drug Imatinib-Alvogen until the absolute number of neutrophils increases to> 1x10⁹/ l, and the number of platelets does not increase to> 20x10⁹/ l; then resume treatment with the drug Imatinib-Alvogen in a dose of 300 mg (in children - 200 mg / m²).

When inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of the drug Imatinib-Alvogen 800 mg) in the case of a decrease in the absolute number of neutrophils <1x10⁹/ l and / or platelet count <50x10⁹/ l it is recommended to cancel the drug Imatinib-Alvogen until the absolute number of neutrophils increases to ≥ 1,5х10⁹/ l, and the number of platelets does not increase to ≥75 x 10⁹/ l, then resume treatment with the drug Imatinib-Alvogen in a dose of 600 mg.

In the case of a repeated decrease in the number of neutrophils to less than <1x10⁹/ l and / or platelet count to <50x10⁹/ l follows the above actions, repeat, and then resume treatment with the drug Imatinib-Alvogen in a reduced dose of 400 mg.

Side effects:

Safety profile of the preparation Imatinib-Alvogen 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, pain in stomach. Basically, these AEs were mild or moderate, only 2-5% of patients discontinued drug therapy Imatinib-Alvogen because of the development of AE. Myelosuppression, AE from the gastrointestinal tract (GIT), edema and rash occur when imatinib is used in both CML and GISO. In patients with CML, myelosuppression is more common,and in patients with GISO more often there are gastrointestinal and intratumoral bleedings, other disorders from the gastrointestinal tract, such as intestinal obstruction, perforation and ulceration of the mucous membrane. 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 mainly in the periorbital region and lower extremities.

Types of AEs and the frequency of their development are similar when imatinib is taken by adults and children with leukemia.

Concomitant 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" are in some cases capable of reaching serious (including life-threatening ).

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 (<1/10 000), the 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.

On the part of the hematopoiesis system

Often: neutropenia, thrombocytopenia, anemia;

often : pancytopenia, febrile neutropenia;

infrequently: thrombocythemia, lymphopenia, oppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy;

rarely: hemolytic anemia.

From the side of metabolism

often: anorexia;

infrequently: hypokalemia, increased or decreased appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia;

rarely: hyperkalemia, hypomagnesemia.

From the nervous system

Often - headache²;

often: insomnia, dizziness, paresthesia, taste disorder, hypoesthesia;

infrequently: depression, anxiety, decreased libido, migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke;

rarely: confusion, increased intracranial pressure, convulsions, optic neuritis.

From the side of the organ of vision

often: edema of the eyelids, increased lacrimation, conjunctival hemorrhages, 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.

From the side of the hearing organ and labyrinthine disorders

infrequently: vertigo (dizziness), tinnitus, hearing loss.

Heart Disease

infrequently: heart palpitations, chronic heart failure³, pulmonary edema, tachycardia, "hot flashes"⁴;

rarely: arrhythmia, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, increased blood pressure.

Vascular disorders

infrequently: hemorrhage⁴;

rarely: hematoma, subdural hematoma, cold extremities, lowering of arterial pressure, Raynaud's syndrome;

From the respiratory system, organs of the thorax, the mediastinum

often: nosebleeds, shortness of breath, cough;

infrequently: pleural effusion⁵, pain in the pharynx or larynx, pharyngitis;

rarely: pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

From the digestive system

Often: nausea, vomiting, diarrhea, indigestion, abdominal pain⁶;

often: bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis;

infrequently: stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding⁷, belching, melena, esophagitis, ascites, ulceration of the gastric mucosa, vomiting of blood, cheilitis, dysphagia, pancreatitis;

rarely: colitis, paralytic / obturation intestinal obstruction, inflammatory bowel disease.

From the liver and biliary tract

often: increased activity of "liver" transaminases;

infrequently: jaundice, hepatitis, hyperbilirubinemia,

rarely: liver failure⁸, necrosis of the liver⁸.

From the skin

Often: periorbital edema, dermatitis, eczema, skin rash;

often: facial puffiness, itching, erythema, dry skin, erythema, alopecia, night sweats, photosensitivity reactions;

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, petechiae, psoriasis, purpura, bullous rash;

rarely: Acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, erythema multiforme (including Stevens-Johnson syndrome), vesicular rash, leukoclastic vasculitis, acute generalized pustular exanthema.

From the side of 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;

frequency is unknown: growth retardation in children.

From the endocrine system, genital organs and mammary glands

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

General disorders and disorders at the site of administration

Often: fluid retention and swelling, increased fatigue, weight gain;

often: weakness, fever, anasarca, chills, tremors, weight loss;

infrequently: chest pain, general malaise.

Laboratory and instrumental research

Infrequently: increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and creatinine levels in blood plasma;

rarely : increased activity of amylase in blood plasma.

Post-registration application experience

Rarely: vascular ectasia of the antrum of the stomach (GAVE-syndrome).

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

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

3 - Undesirable effects from the heart, including chronic heart failure,were more frequent in patients with CML in the acceleration phase and in blast crisis compared with patients with CML in the chronic phase (duration of follow-up is 1 year).

4 - "Tides" were 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 malignant GIS.

5 - Pleural effusion was more often observed in patients with CML in the accelerated phase and with a blast crisis compared with CML in the chronic phase (duration of follow-up is 1 year).

6/7 - Abdominal pain and gastrointestinal hemorrhage were most often observed in patients with inoperable and / or metastatic GISOs.

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

9 - Musculo-skeletal pains, including myalgia, arthralgia, bone pain, were more common in patients with CML compared to patients with inoperable and / or metastatic GISOs.

During the use of the drug Imatinib-Alvogen were also noted in clinical practice, and in additional clinical studies the following side effects were noted (their relationship between drug use and the following AEs is not established, the size of the patient population is unknown):

From the nervous system

infrequently: cerebral edema.

From the side of the organ of vision

rarely: hemorrhage in the vitreous body.

From the cardiovascular system:

infrequently - thrombosis / embolism;

rarely - pericarditis, cardiac tamponade;

very rarely - anaphylactic shock.

From the respiratory system. organs of the thorax, the mediastinum

infrequently: acute respiratory failure¹, interstitial lung disease.

From the digestive system:

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, vasodilation of the antrum of the stomach.

From the skin and subcutaneous tissues

infrequently: palmar-plantar erythrodisthesis;

rarely: lichenoid keratosis, lichen planus;

rarely: toxic epidermal necrolysis.

frequency is unknown: drug rash with eosinophilia and systemic symptoms.

From the side of musculoskeletal and connective tissue

rarely: avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy;

frequency is unknown: stunted growth in children.

From the genitals

rarely: bleeding from the cyst of the yellow body / ovarian cyst.

Other violations

rarely: tumor lysis syndrome.

Description of individual adverse reactions

Regarding hemorrhages / bleedings: In the postgrade period, separate reports were received on cases of vascular ectasia of the antrum of the stomach (GAVE- a syndrome).

Severe adverse events on the part of the respiratory system:

Severe (sometimes fatal) adverse events were noted with imatinib: 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 the undesirable phenomenon.

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.

If any of these instructions side effects are compounded, or if you notice any side effects not listed in this manual, inform the doctor about it.

Overdose:

Experience with the drug Imatinib-Alvogen in doses exceeding therapeutic, is limited. In spontaneous reports and scientific publications noted isolated cases of drug overdose. In general, the outcome of such cases was favorable.

Antidote to the drug Imatinib-Alvogen is unknown. In case of an overdose, medical supervision and symptomatic therapy are recommended.

Overdose the of adults:

When taking the drug Imatinib-Alvogen in a dose of 1200-1600 mg per day for 10 days were observed nausea, vomiting, diarrhea, rash, erythema, edema, local swelling, fatigue, muscle cramps, 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 use of the drug Imatinib-Alvogen in 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 980 mg in a child at the age of three years, there was a decrease in the number of leukocytes in the blood and diarrhea.

Interaction:

Preparations, which can reduce the concentration of imatinib in the blood plasma (joint application is not recommended):

Simultaneous use of imatinib with drugs 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%.

Preparations, which can increase the concentration of imatinib in the blood plasma:

With the simultaneous use of the preparation imatinib with preparations inhibiting the isoenzyme CYP3A4 cytochrome P450, for example, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir, posaconazole, voriconazole, telithromycin, ketoconazole, itraconazole, erythromycin, clarithromycin), it is possible to slow the metabolism of imatinib and increase its concentration in the blood plasma (C_maxIncreases by 26%, AUC - by 40%).

Care should be taken when combining imatinib with these drugs or other inhibitors CYP3A4.

Preparations, the concentration of which may change when imatinib is administered:

Imatinib is able to inhibit certain cytochrome P isoenzymes₄₅₀. With the joint appointment of imatinib and simvastatin, there is an increase in C_mOh 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, nifedipine 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 having a narrow therapeutic range (eg, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine, ciclosporin and pimozide.) Imatinib also inhibits in vitro isozymes CYP2C9 CYP2C19.

When the drug is used together Imatinib-Alvogen with warfarin, an increase in prothrombin time (PT) 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 an increase in the 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 CYP3A4. When imatinib is used at a dose of 400 mg twice a day, together with metoprolol (substrate isoenzyme CYP2D6), there is an increase in C_mOh and AUC by about 21%, however, taking into account the insignificant increase in the effects of the isoenzyme substrates CYP2D6 when combined with imatinib, there is no need to change the dosage regimen for such drugs.

In vitro imatinib inhibits the O-glucononidation of acetaminophen / paracetamol (inhibition- Ki 58.5 μM). However, the use of the drug Imatinib-Alvogen (400 mg / day for 8 days) with acetaminophen / paracetamol (a single dose of 1000 mg on the eighth day) in patients with CML did not lead to a change in the pharmacokinetics of acetaminophen / paracetamol. The pharmacokinetics of imatinib did not change with a single admission of acetaminophen / paracetamol.Information on the pharmacokinetics or safety of simultaneous application of imatinib in doses> 400 mg / day with acetaminophen / paracetamol or prolonged simultaneous use of acetaminophen / paracetamol and imatinib is not available.

In patients who underwent thyroidectomy and who received levothyroxine sodium replacement therapy, 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.

Care should be taken when using the drug together Imatinib-Alvogen and chemotherapeutic agents in connection with a possible increase in the risk of developing complications such as hepatotoxicity, myelosuppression, etc.

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

Special instructions:

Treatment with imatinib should be done only under the supervision of a doctor who has experience with antitumor drugs. When handling imatinib, avoid contact with skin and eyes, and inhale powder of the drug.

Experience with the drug Imatinib-Alvogen in children with ALL is under 1 year of age, experience with imatinib in children with CML younger than 2 years is limited, experience with imatinib for other indications is limited in patients under 18 years of age.

Long-term effects of prolonged exposure to imatinib for growth in children are not known, but since there are reports of growth retardation, careful growth control is recommended in children receiving imatinib.

When using the drug Imatinib-Alvogen 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.

When imatinib is used in 1-2% of cases, a marked fluid retention is observed, therefore 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 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 symptoms: pleural effusion, congestive heart failure, and renal insufficiency. When imatinib is used in patients with liver diseases, a clinical blood test should be performed regularly and the activity of "liver" enzymes should be determined. Since there are reports of the development of hypothyroidism in the face of imatinib in patients who undergone thyroidectomy and who are receiving substitution treatment with levothyroxine sodium, the concentration of thyroid-stimulating hormone must be regularly measured in this category of patients.

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

In patients with MDS / MPD and high levels of eosinophils, an ECG study should be performed and the concentration of cardiospecific troponin in the blood plasma 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, hemorrhages of various locations were noted. In addition, in the post-marketing period, separate reports were received on cases of vascular ectasia of the antrum of the stomach (GAVE-syndrome), a rare cause of gastrointestinal bleeding, registered in patients with CML, ALL and other diseases.

It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors (abdominal pain, gastrointestinal bleeding, constipation, etc.) at the beginning and throughout the therapy with the drug Imatinib-Alvogen. If necessary, consider the possibility of reversing therapy with the drug.

During therapy with imatinib and at least 3 months after, reliable methods of contraception should be used. A marked increase in the activity of "hepatic" transaminases or bilirubin concentrations was noted in less than 3% of patients with CML and was usually controlled by a decrease in the dose of the drug or a temporary interruption of treatment (the average duration of such episodes was about 1 week). Because of the risk of developing a tumor lysis syndrome, imatinib should be treated with clinically pronounced dehydration and increased uric acid concentrations, if necessary.

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

Some side effects, such as dizziness and blurry vision, can adversely affect the ability to drive vehicles and perform potentially dangerous 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:

Tablets coated with a film coat, 100 mg and 400 mg.

Packaging:

For 10 tablets, film-coated in a blister of Al / PVC / PE / PVDC.

By 3 or 12 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003841

Date of registration:15.09.2016

Expiration Date:15.09.2021

The owner of the registration certificate:Alvogen IPKo S.A.L.Alvogen IPKo S.A.L. Luxembourg

Manufacturer: & nbsp

REMEDICA, Ltd. Cyprus

Representation: & nbspAlvogen Pharma Trading EuropeAlvogen Pharma Trading Europe

Information update date: & nbsp09.11.2017

Illustrated instructions

Instructions

Imatinib-Alvogen ( Imatinib-Alvogen )