Imatinib Foresight - instructions for use, doses, side effects, contraindications

Capsule: gelatin 24.6%, methylparahydroxybenzoate 0.118%, propyl parahydroxybenzoate 0.030%, silicon colloidal dioxide 0.123%, bronopolum 0.012%, sodium lauryl sulfate 0.037%, glycerol 0.025%, titanium dioxide 0.369%, dye brilliant blue 0.061%, water qs up to 100 %.

The body: gelatin 36.6%, methylparahydroxybenzoate 0.176%, propyl parahydroxybenzoate 0.044%, silicon colloidal dioxide 0.183%, bronopolum 0.018%, sodium lauryl sulfate 0.055%, glycerol 0.037%, titanium dioxide 0.549%, dye brilliant blue 0.091%, water qs up to 100 %.

Description:

Hard gelatin capsules No. 2, body and cap of blue color.

The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:An antitumour agent, a protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib selectively inhibits the Bcr-Abl-tyrosine kinase enzyme formed by the fusion of the Bcr (breakpoint cluster region) and the Ablon (Abelson) protooncogene at the cellular level. Imatinib selectively inhibits proliferation and induces apoptosis of the Bcr-Abl tyrosine kinase expressing cell lines, as well as of immature leukemic cells in chronic myeloid leukemia with a positive Philadelphia chromosome and in acute lymphoblastic leukemia. In patients with chronic myelogenous leukemia imatinib selectively inhibits Bcr-Abl-positive colonies.

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

Activation of receptors to platelet growth factors or AAbl 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 AAbl-fragment of tyrosine kinase.

Pharmacokinetics:

Suction. After oral administration, the bioavailability of imatinib is 98% on average. When taking the drug with food high in fat, in comparison with taking on an empty stomach, there is a slight decrease in the degree of absorption and slowing the rate of absorption. Coefficient of variation: for the indicator, the area under the concentration-time curve (AUC) is 40-60%.

Distribution. Binding to plasma proteins is about 95% (mainly with albumin and acid alpha-glycoproteins, to an insignificant degree - with lipoproteins).

Metabolism. Imatinib it is metabolized mainly in the liver. The main metabolite of imatinib circulating in the bloodstream is the N-demethylated piperazine derivative, which in vitro has pharmacological activity similar to that of the parent drug. 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. Imatinib is excreted mainly in the form of metabolites within 7 days after taking one dose (intestine - 68%, kidneys - 13%). 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 doses are administered once a day, the pharmacokinetics of imatinib does not change. The value of the equilibrium concentration exceeds the value of the initial concentration by 1.5 to 2.5 times.

Pharmacokinetics in different groups

In patients older than 65 years, the distribution volume slightly increases (by 12%). The value of clearance of imatinib increases with increasing patient's body weight. However, these changes do not require correction of the dose depending on the body weight and age of the patient.

The pharmacokinetics of imatinib does not depend on sex.

Pharmacokinetics in children

As in adults, children and adolescents under the age of 18 have a rapid absorption of the drug after ingestion. AUC in this group of patients in the dose range of 260 and 340 mg / m is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. Cumulation of the drug after repeated administration is established. 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.

Pharmacokinetics in violation of the function of excretory organs

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 dysfunction (creatinine clearance> 30 ml / min), the drug exposure in plasma is increased by a factor of 1.5 - 2.0, corresponding to an increase in the concentration of acid alpha-glycoproteins (the main plasma proteins , which bind to imatinib). Correlation between the exposure of the drug and the severity of renal impairment is not revealed.

Indications:

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

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

- The first diagnosed positive for the Philadelphia chromosome (Ph +) acute lymphoblastic leukemia in adult patients in combination with chemotherapy.

- Recurrent or refractory acute lymphoblastic leukemia is positive for the Philadelphia chromosome (Ph +) in adult patients as monotherapy.

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

- Systemic mastocytosis in adult patients with no D816V c-Kit mutation or unknown c-Kit mutation status.

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

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

Inoperable and / or metastatic malignant gastrointestinal stromal tumors (GISO) 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.

- Children under 2 years of age (efficacy and safety not established).

- Pregnancy and lactation.

Carefully:

It should be used with caution imatinib in patients with severe hepatic insufficiency,severe impairment of kidney function (QC less than 20 ml / min), cardiovascular disease or in the presence of risk factors for heart failure, as well as regular hemodialysis procedure.

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

Pregnancy and lactation:

Pregnancy

Currently, there are no data on the use of imatinib in pregnant women. Studies conducted on animals have shown toxic effects on reproductive function, but the potential risk to the fetus is still unknown.

Imatinib is contraindicated during pregnancy. Women of childbearing age during therapy with imatinib and at least 3 months after should use reliable methods of contraception.

Lactation

Imatinib and its metabolites are excreted in breast milk. Due to the lack of data on the effects of imatinib on newborns, women receiving imatinib, you should stop breastfeeding.

Dosing and Administration:

Imatinib Foresight should be taken orally, during meals, with a full glass of water.

Doses of 400 and 600 mg per day should be taken in 1 dose; the daily dose of 800 mg should be divided into 2 400 mg in the morning and in the evening.

For patients (including children) who can not swallow the whole capsule, the contents of the capsule 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.

In chronic myelogenous leukemia (XML), the recommended dose of Imatinib Foresit depends on the phase of the disease.

In the chronic phase of XML, the adult dose is 400 mg per day; in the phase of acceleration and with a blast crisis - 600 mg per day. The drug should be taken 1 time per day.

In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, a dose increase 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 accelerated phase and with a blast cry. Such a dose increase may be necessary in the progression of XML (at any stage),in the absence of a satisfactory hematologic response after 3 months of treatment, a cytogenetic response at 12 months of therapy, or loss of a previously hematologic and / or cytogenetic response.

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

Children with chronic phase and accelerated phase of XMJI are recommended to dose 340 mg / m2 per day. 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.

There are no data on the use of the drug in children younger than 2 years.

With Ph + acute lymphoblastic leukemia, the recommended dose of Imatinib Forsythe is 600 mg per day.

In myelodysparastic / myeloproliferative diseases (MDS / MPZ), the recommended dose of Imatinib Foresight is 400 mg per day.

For inoperable and / or metastatic GISS, the recommended dose of Imatinib Foresight 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 Forsyth from 400 mg to 600 mg or up to 800 mg is possible.

When using the drug as an adjuvant therapy in patients with GISO, the recommended dose is 400 mg per day. The minimum duration of treatment is 3 years.The optimal maximum duration of adjuvant therapy has not been established.

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma, the recommended dose of Imatinib Forsyth is 800 mg per day.

With systemic mastocytosis in the absence of D816V c-Kit mutation, the recommended dose of Imatinib Foresight is 400 mg per day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

In systemic mastocytosis caused by an abnormal FIP1L1-PDGFR alpha-tyrosine kinase, resulting from the fusion of the Fip likel and PDGFR genes, the recommended initial dose is 100 mg per day. An increase in the dose from 100 mg to 400 mg can be considered with insufficient effectiveness and no significant side effects.

With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose of Imatinib Foresight is 400 mg per day. In patients with HES / HAL, caused by an abnormal FIP1L1-PDGFR alpha-tyrosine kinase, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the daily dose to 400 mg is possible.Treatment with the drug is carried out as long as the clinical effect remains.

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, patients with mild, moderate or severe impairment of liver function should be used in a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose of the drug should be reduced. In patients with severe hepatic insufficiency, the drug should be used with caution.

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 who require systematic hemodialysis, treatment should begin with a minimum effective dose of 400 mg once a day, taking care.

With intolerance to imatinib therapy, 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

Treatment should be suspended in the development of any serious non-hematologic side effect associated with taking the drug, until the situation is resolved. The treatment can then be resumed at a dose that depends on the severity of the observed serious side effect.

With increasing bilirubin concentration and liver transaminase activity in blood serum 3 and 5 times higher than the upper limit of normal (VGN), respectively, treatment with the drug should be temporarily suspended until the concentration of bilirubin is reduced to less than 1.5 x VGN and the activity of "liver" transaminases up to a value of less than 2.5 x VGN. Therapy with Imatinib Forsyth is resumed in a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day; in children - from 340 to 260 mg / m2 per day. Correction of the dosing regimen with the development of serious side effects on the part of the hemopoietic system (severe thrombocytopenia, neutropenia) When neutropenia and thrombocytopenia occur, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these side effects.

Recommendations for reducing the dose in accordance with the development of neutropenia and thrombocytopenia are presented in the table:

Indications for use	The dynamics of the number of neutrophils and platelets in the blood	Correction of the dosing regimen
Systemic mastocytosis (CM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) caused by abnormal FIP1L1-PDGFR alpha-tyrosine kinase (initial dose of Imatinib Forsyth 100 mg)	Reduction of the absolute number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l.	1. Cancel Imatinib Foresight, until recovery of the absolute number of neutrophils ≥1.5х10⁹/ l and / or platelets ≥75x10⁹/ l. 2. Resumption of treatment with Imatinib Forsyth in a dose applied before the interruption of therapy.
The chronic phase XMJI in children and adults, malignant GISO, myelodysplastic / myeloproliferative diseases, SM and HES / HAL in adult patients (initial dose of Imatinib Forsyte for adults - 400 mg, for children-340 mg / m²).	Reduction of the absolute number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l. In the case of a repeated decrease in the number of neutrophils <1 x 10⁹/ l and / or the number of platelets <50x10⁹/ l.	1. Cancel Imatinib Foresight, until recovery of the absolute number of neutrophils ≥1.5х10⁹ / l, and / or platelets ≥75 x 10⁹/ l. 2. Resumption of treatment with Imatinib Forsyth in a dose applied before the interruption of therapy. Repeat the actions described in paragraph 1 and then resume Imatinib Forsyth's treatment at a reduced dose of 300 mg in adults and 260 mg / m² in children.
The phase of acceleration and blast crisis of CML in children and adults and with RI + acute lymphoblastic leukemia in adult patients (initial dose for adults - 600 mg, for children - 340 mg / m²).	Reduction of the absolute number of neutrophils <0.5x10⁹/ l and / or platelet count <10x10⁹/ l after one or more months of treatment.	1. Check whether cytopenia is due to leukemia (bone marrow examination). 2. If cytopenia is not associated with leukemia, reduce the dose of Imatinib Forsyth 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, it is necessary to cancel Imatinib Forsyth until the absolute number of neutrophils becomes ≥1x10⁹/ l and / or platelets ≥20x10⁹/ l; then resume treatment with Imatinib Forsythe at a dose of 300 mg (in children 260 mg /m²).
Inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma (initial dose of Imatinib Forsyte 800 mg).	Reduction of the absolute number of neutrophils <1x10⁹/ l and / or the number of platelets <50x 10⁹/ l. In the case of a repeated decrease in the number of neutrophils <1x10⁹/ l and / or the number of platelets <50x10⁹/ l.	1. Discard Imatinib Forsyte until the absolute number of neutrophils becomes ≥1.5x10⁹/ l and / or platelets> 75x10⁹/ l; 2. Resume the treatment with Imatinib Forsythe in a dose of 600 mg. Repeat the actions described in paragraph 1, and then resume treatment with Imatinib Forsyth at a reduced dose of 400 mg.

Side effects:

The safety profile of imatinib has been well studied. Most patients with the drug experience some of the undesirable phenomena (AE). The most frequent AE (> 10%) associated with taking the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, pain in stomach. Often there were peripheral edema mainly in the periorbital region and lower limbs. Most of these AEs were mild or moderately severe.Types of AEs and the frequency of their development are similar when imatinib is taken by adults and children with leukemia.

Myelosuppression, AE on the part of the gastrointestinal tract (GIT), edema and rash occur when imatinib is used in both XML and malignant stromal tumors of the gastrointestinal tract. 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 AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.

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.

Side effects are listed below for organs and systems, indicating the frequency of their occurrence.

Frequency determination: very often (> 10%), often (> 1% and <10%), infrequently - (> 0.1% and <1%), rarely (> 0.01% and <0.1% ), very rarely (<0.01%), including individual reports.

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

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

Violations from the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia; often - pancytopenia, febrile neutropenia; infrequently - thrombocythemia, lymphopenia, eosinophilia, lymphadenopathy, oppression of bone marrow hematopoiesis; rarely - hemolytic anemia.

Metabolic and nutritional disorders: often - anorexia; infrequently - hypokalemia, increase or decrease in appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hyponatremia, hypercalcemia, hyperglycemia; rarely - hyperkalemia, hypomagnesemia.

Disorders of the psyche: often - insomnia, infrequently - depression, anxiety, decreased libido; rarely confusion.

Impaired nervous system: very often - headache²; often - dizziness, impaired taste, paresthesia, hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke, cerebral edema; rarely - increased intracranial pressure, convulsions, optic neuritis.

Disorders from the side of the organ of vision: often - eyelid edema, conjunctivitis, increased teardrop, blurred vision, hemorrhage under conjunctiva, dry eye syndrome; infrequent - eye irritation, eye pain, orbital edema, macular edema, retinal hemorrhages, scleral hemorrhage, blepharitis; rarely - cataracts, glaucoma, edema of the optic disc, hemorrhage into the vitreous.

Hearing disorders and labyrinthine disturbances: infrequently - noise in the ears, hearing loss, vertigo.

Heart Disease: infrequent - palpitations, tachycardia, congestive heart failure³, pulmonary edema; rarely - arrhythmia, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, pericarditis, cardiac tamponade.

Vascular disorders: often - "tides" of blood to the face⁴, hemorrhage⁴; infrequently - increase / decrease of blood pressure, violation of capillary permeability, cooling of limbs, Raynaud's syndrome, thrombosis / embolism; rarely - hematomas, subdural hematomas.

Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, dyspnea, cough; infrequently - pleural effusion, pain in the pharynx or larynx, pharyngitis, acute respiratory failure, interstitial pneumonia; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain⁶; often - flatulence, constipation, gastro-esophageal reflux, dry mouth, gastritis; infrequently - stomatitis, ulceration of the oral mucosa, belching, gastrointestinal bleeding⁷, melena, vomiting of blood, cheilitis, esophagitis, ascites, stomach ulcer, dysphagia, pancreatitis, gastrointestinal tract (GIT) necrosis, gastrointestinal perforation, bleeding from the GI tract; rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine, diverticulitis.

Disorders from the liver and bile ducts: often - increased activity of "liver" enzymes; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure⁹, necrosis of the liver⁹.

Disturbances from the skin and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often - puffiness of the face, itching, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequently - petechiae, bruising, increased sweating, urticaria, ecchymosis, increased predisposition to hematoma formation, nail damage, purpura, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, folliculitis, psoriasis, exfoliative dermatitis, bullous rash, palmar-plantar erythrodysesthesia, pustular rash; rarely - acute febrile neutrophilic dermatosis (syndrome, Sweet's), angioneurotic edema, changes in nail color, erythema multiforme, leykoklastichesky vasculitis, Stevens-Johnson syndrome, acute generalized pustular rash, lichenoid keratosis, lichen planus; very rarely - toxic epidermal necrolysis; the frequency is unknown - drug rash with eosinophilia and systemic symptoms.

Disturbances from the osteomuscular and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain⁸; often swelling in the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis, rhabdomyolysis, myopathy, avascular necrosis of the head of the femur, the frequency is unknown - growth retardation in children.

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

Violations of the genitals and breast: infrequently - gynecomastia, enlargement of mammary glands, pain in the nipples, swelling of the scrotum, decreased potency, erectile dysfunction, sexual dysfunction, menorrhagia, menstrual irregularity; very rarely - in women the hemorrhage of the cyst of the yellow body / ovary.

General disorders and disorders at the site of administration: very often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, chills, tremors, anasarca, weight loss; infrequent - general malaise, chest pain; very rarely - anaphylactic shock.

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

¹ Pneumonia is most often observed in patients with XML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant GISOs.

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

³ Side effects from the heart, including congestive heart failure, are more common in patients with XML in the acceleration phase and in blast crisis compared with patients with XML in the chronic phase.

⁴ The "tides" of blood to the face are most often observed in patients with inoperable and / or metastatic malignant GISOs; bleeding (hematoma, hemorrhage) is most often observed in patients with XML in the acceleration phase; blast crisis and with inoperable and / or metastatic malignant GISOs.

⁵ Pleural effusion is more often noted in patients with XMJI in the phase of acceleration and blast crisis compared with patients with XMJI in the chronic phase.

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

⁸ Musculoskeletal pain, including myalgia, arthralgia, bone pain, is more common in patients with inoperable and / or metastatic malignant GISOs.

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

Overdose:

In clinical practice, there have been cases of imatinib overdose. In general, the outcome of the overdose was favorable (there was an improvement in the patients' condition). Antidote to Imatinib is not known. In case of an overdose, medical supervision and symptomatic therapy are recommended.

Overdose in adults

When imatinib was taken in a dose of 1200-1600 mg for 1-10 days, a patient with XML had nausea, vomiting, diarrhea, skin rash, erythema, edema, swelling in the main person, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. When imatinib was taken in a dose of 1800-3200 mg (the highest dose was 3200 mg per day for 6 days), weakness, myalgia, gastrointestinal pain, increased activity of creatine phosphokinase activity and bilirubin concentration were noted.When imatinib was used at a dose of 6400 mg, the patient developed nausea, vomiting, abdominal pain, fever, facial edema, a decrease in the number of neutrophils, and an increase in the activity of "liver" transaminases.

When taking imatinib in a dose of 8-10 g, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents

When taking imatinib 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 diarrhea and a decrease in the number of leukocytes were observed once in a child aged 3 years.

Interaction:

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), ketoconazole, itraconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin) due to the slowing of the metabolism of imatinib, an increase in the concentration of imatinib in the blood plasma is possible. Caution is necessary when combined with imatinib with inhibitor preparations of CYP3A4 isoenzymes.Simultaneous use of imatinib with drugs that are inducers of the isoenzyme CYP3A4 (eg, dexamethasone, rifampicin, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidon or drugs based on St. John's wort) can lead to an acceleration of imatinib metabolism and, as a consequence , to a decrease in its concentration in the blood plasma and inefficiency of therapy. Simultaneous application of imatinib and strong inducers of CYP3 A4 isoenzyme should be avoided.

With the simultaneous use of imatinib and simvastatin, there is an increase in the concentration of simvastatin in the blood, which is a consequence of the inhibition of the isoenzyme CYP3A4 by imatinib. It is advisable to use caution when using imatinib and preparations that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentrations (for example, ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase serum concentrations of other drugs,metabolized by the isoenzyme CYP3A4 (triazolobenzodiazepines, dihydropyridines, blockers of "slow" calcium channels, most inhibitors of HMG-CoA reductase, including statins).

Imatinib inhibits also the isoenzyme CYP2C9 and the isozyme CYP2C19 in vitro. With simultaneous application with warfarin, an increase in prothrombin time is possible. When used simultaneously with coumarin derivatives, short-term prothrombin time monitoring at the beginning and at the end of therapy with imatinib is required, as well as when the imatinib dosage regimen is changed. Alternatively, consideration should be given to the use of low molecular weight heparin derivatives.

When a combination of imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatotoxicity in the form of an increase in the activity of "hepatic" transaminases and hyperbilirubinemia.

With a combination of imatinib and chemotherapy regimens that can potentially have hepatotoxic effects, liver function monitoring should be provided. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme.In applying imatinib 400 mg 2 times a day together with metoprolol, substrate isoenzyme CYP2D6, noted moderate decrease metabolism of metoprolol, accompanied by an increase in Cmax and AUC of approximately 21%. Given a moderate strengthening effect of drugs that are substrates isoenzyme CYP2D6 (e.g., metoprolol), when combined with the use of imatinib not required dosing regime correction. In vitro imatinib inhibits O-glucuronation of paracetamol. A case of a patient of acute liver failure with fatal outcome, while the use of imatinib and paracetamol. Caution must be exercised when applying imatinib together with paracetamol.

In patients undergoing thyroidectomy and receiving HRT levothyroxine sodium may decrease its plasma concentrations when used with imatinib.

Sufficiently studied the question of drug interactions of imatinib and chemotherapy drugs in patients with Ph + OLJI. Be careful when sharing imatinib and chemotherapydrugs in connection with a possible increase in the risk of developing medical 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 Forsyth should be done only under the supervision of a doctor who has experience with antitumor drugs.

It is advisable to use caution when handling the contents of the capsule to avoid contact with the skin, mucous membranes of the eyes, or accidental inhalation of the drug powder. After opening the capsules, wash hands immediately. Efficacy and safety of imatinib in children with CML younger than 2 years has not yet been established. The experience of using the drug for other indications is limited in patients under 18 years of age. Long-term effects of prolonged exposure to imatinib on growth in children are unknown. But since there are reports of growth retardation, careful growth control is recommended in children using imatinib. When using imatinib, it is recommended to conduct regular blood tests and monitor liver function (hepatic activity,transaminase and alkaline phosphatase, bilirubin concentration) especially in patients with liver diseases.

A marked increase in the activity of "hepatic" transaminases or serum bilirubin concentration is observed in less than 3% of patients with XMJ1 and is usually controlled by a decrease in the dose of the drug or temporary interruption of treatment (the average duration of such episodes is about 1 week).

It is recommended to closely monitor patients with heart and kidney disease.

Due to the fact that imatinib shows 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 imatinib and / or prescribe diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. In some cases, severe fluid retention may have a severe course with a fatal outcome.

In patients with malignant gastrointestinal stromal tumors (GISO), gastrointestinal bleeding and bleeding from the tumor are possible.In this case, both intra-abdominal and intrahepatic bleeding are noted, depending on the anatomical location of the tumor. It is necessary to monitor the gastrointestinal tract in patients with metastatic malignant stromal tumors of the gastrointestinal tract (abdominal pain, gastrointestinal bleeding, constipation, etc.) at the beginning and throughout the therapy with imatinib.

In patients with the syndrome of hypereosinophilia and eosinophilic infiltration of the myocardium at the beginning of imatinib therapy, in some cases development of cardiogenic shock of left ventricular failure was associated with degranulation of eosinophils, which was stopped by the introduction of systemic glucocorticosteroids, measures aimed at maintaining blood circulation and temporary abolition of imatinib. In patients with a high level of eosinophils, an ECG study should be performed and the serum concentration of 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.

Patients who underwent thyroidectomy and who received replacement therapy with levothyroxine sodium should regularly be assessed for thyroid-stimulating hormone concentrations, since hypothyroidism may develop with imatinib therapy.

Due to the risk of development of tumor lysis syndrome, imatinib should be corrected, if necessary, for clinically expressed dehydration and elevated uric acid levels in patients.

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

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 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:Capsules 100 mg.

Packaging:

10 capsules per blister of PVC / Al.

3 blisters per pack 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 after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002766

Date of registration:17.12.2014

Expiration Date:17.12.2019

The owner of the registration certificate:Forsythe ZAOForsythe ZAO Russia

Manufacturer: & nbsp

VIVIMED LABS, Ltd. India

Information update date: & nbsp08.11.2017

Illustrated instructions

Instructions

Imatinib Forsyte (Imatinib)