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

Active substance: Imatinib mesylate - 119,50 mg in terms of imatinib - 100,0 mg; Excipients: until the mass of the contents of the capsule is 230 mg: microcrystalline cellulose - 92.0 mg, crospovidone (polyplasdone XL-10) 15.0 mg, silicon colloidal dioxide (silicon dioxide colloidal anhydrous) 2.0 mg, magnesium stearate -1.5 mg; Hard gelatin capsules: dye quinoline yellow (E 104) - 0.9197%, dye sunset yellow (E 110) - 0.0044%, titanium dioxide (E 171) - 1.3333%, gelatin - up to 100%.

Description:Hard gelatin capsules No. 1 yellow. The contents of the capsules are white to white-yellow powder.

Pharmacotherapeutic group:antitumor agent, protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib is an antitumor drug that exerts a selective inhibitory effect on the Bcr-Abl tyrosine kinase enzyme formed by the fusion of the breakpoint cluster region and the Ablon (Abelson) protooncogene. At the cellular level, it selectively inhibits proliferation and induces apoptosis of the Bcr-Abl tyrosine kinase expressing cell lines, including immature leukemia cells,formed in patients with a positive in the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia. Imatinib selectively inhibits Bcr-Abl-positive colonies obtained from blood cells of patients with chronic myelogenous leukemia. Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing a tyrosine kinase with a c-Kit receptor mutation. Activation of receptors to platelet growth factors or Abl fragment of tyrosine kinase may cause the development of both myelodysplastic / myeloproliferative diseases (MDS / MPZ) and hypereosinophilic syndrome and chronic eosinophilic leukemia and swelling dermatofibrosarcoma. Activation of the c-Kit receptor tyrosine kinase and receptors for platelet growth factors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits cell signaling and cell proliferation resulting from impaired regulation of platelet and stem cell growth factors, c-Kit receptor, and tyrosine kinase Abl.

When imatinib is used in patients with inoperable and / or metastatic malignanciesGastrointestinal stromal tumors showed a significant increase in overall survival of patients and survival without signs of disease. Adjuvant therapy with a drug of gastrointestinal stromal tumors significantly reduces the risk of relapse, increases the survival rate without signs of disease.

Pharmacokinetics:

After ingestion, the drug is well absorbed, bioavailability averages 98%. The maximum concentration of C max in blood plasma is reached after 2-3 hours and is 0.6-1.2 μg / ml. In the dose range of 25 to 1000 mg, the area under the concentration-time curve (AUC) increases in proportion to the dose increase. When taking the drug with food high in fat, in comparison with fasting, there is a slight decrease in the degree of absorption (a decrease of Cmax of imatinib in blood plasma by 11%, AUC - by 7.4%) and a slowing of the rate of absorption (an increase in plasma IgM in plasma blood for 1.5 hours).

The connection with blood plasma proteins, mainly with albumin and alpha 1-acid glycoprotein is 95%. To a small extent, the drug binds to lipoproteins.

Metabolized in the liver to form the main active metabolite - N-demethylated piperazine derivative. 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. With repeated administration of the drug once a day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial concentration by 1.5-2.5 times. After taking one dose, the drug is excreted for 7 days mainly in the form of metabolites: 68% - intestine, 13% - kidney; in unchanged form - 25% (5% - kidneys, 20% - intestines). The average clearance value of imatinib in patients under 50 years and a body weight of 50 kg is 8.5 l / h. The half-life of imatinib is about 18 hours. In patients older than 65 years, the volume of distribution increases insignificantly (by 12%). For patients with a body weight of 50 to 100 kg, the average clearance values of imatinib differ insignificantly and do not require correction of the dosing of the drug. The pharmacokinetics of imatinib does not depend on sex. Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are not significant and do not require dose changes.

In children and adolescents under the age of 18, the AUC in the 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 the AUC (0-24) values were compared for children and adolescents on the 1st and 8th days after repeated intake of 340 mg / m2 once a day, the value of this indicator increased by 1.7 times, indicating a cumulation of imatinib.

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 impairment of renal function (creatinine clearance> 30 ml / min), the drug exposure in plasma is increased by 1.5-2.0 times. Since the drug is slightly excreted by the kidneys, the clearance of free imatinib was the same for healthy volunteers and patients with impaired renal function. Correlations between the exposure of the drug and the severity of renal disorders have not been revealed.

Indications:

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

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

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

- recurrent or refractory Ph + OLD in adult patients as 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 an unknown c-Kit mutation status;

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

- Inoperable and / or metastatic malignant gastrointestinal stromal tumors, positive for c-Kit (CD 117), in adult patients;

- adjuvant therapy of gastrointestinal stromal tumors, positive for c-Kit (CD 117) in adult patients;

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

Contraindications:Hypersensitivity to imatinib or any other component of the drug, pregnancy,the period of breastfeeding, children under 2 years of age (safety and efficacy have not been established).

Carefully:in patients with severe hepatic insufficiency (possibly increasing the effect of imatinib), in patients on hemodialysis (no data on use), in patients with severe renal dysfunction, in patients with cardiovascular disease or in the presence of risk factors for heart failure.

Pregnancy and lactation:The drug is contraindicated during pregnancy and breastfeeding.

Dosing and Administration:

Inside, with food, drinking a full glass of water. Patients who are not able to swallow the whole capsule, for example children, the drug can be taken in a diluted form; the contents of the capsules are diluted with water or apple juice (50-100 ml), stirring with a spoon. The resulting suspension is taken orally immediately after preparation. Doses of 400 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.

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

In adults, the recommended daily dose to the stage of remission is 400 mg, during the acceleration phase and with a blast crisis - 600 mg. Treatment with the drug is carried out as long as the clinical effect remains.

If the disease progresses, if there is no hematologic effect after 3 months of therapy, a cytogenetic effect after 12 months of treatment or if a previously hematologic and / or cytogenetic effect is lost and no side effects occur, a dose increase may be possible: to the remission stage from 400 to 600 mg / day or up to 800 mg / day, during the acceleration phase and with a blast crisis - from 600 to 800 mg / day (400 mg twice a day). Treatment is long, with the aim of achieving and maintaining clinical and hematologic remission.

In children older than 2 years, the calculation of the dose is based on the surface area of the body. Doses of 340 mg / m per day are 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.

With Ph + acute lymphoblastic leukemia (ALL), the recommended dose of imatinib is 600 mg per day.

In myelodysplastic / myeloproliferative diseases, the recommended dose is 400 mg per day.

With inoperable and / or metastatic malignant gastrointestinal stromal tumors, the recommended dose is 400 mg per day.

In the absence of side effects and insufficient effect, an increase in the daily dose from 400 mg to 600 mg or up to 800 mg is possible.

If signs of disease progression appear, therapy with the drug should be discontinued.

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

With inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma of adult patients, the recommended dose is 800 mg per day. In systemic mastocytosis (CM) in adult patients with no D816V c-Kit mutation or with an unknown c-Kit mutation status in the absence of the D816V c-Kit mutation, as in the case of an unknown mutation status and the lack of effectiveness of previous therapy,the recommended dose is 400 mg, with systemic mastocytosis caused by 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. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose is 400 mg / 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 dose to 400 mg / day is possible. If signs of disease progression appear, imatinib therapy should be discontinued.

Therapy in special patient groups

When the liver function of all severity imatinib prescribe a minimum daily dose of 400 mg. In severe hepatic insufficiency, the drug is administered with caution. With an increase in the concentration of bilirubin by 3 times in comparison with the upper limit of the norm (VGN),activity of "liver" transaminases - 5 times the treatment is temporarily suspended until the concentration of bilirubin decreases to less than 1.5> <VNG and the activity of "liver" transaminases is less than 2.5> <VGN. In this case, the treatment is resumed, reducing the dose from 400 to 300 mg and from 600 to 400 mg or from 800 mg to 600 mg per day; in children from 340 mg to 260 mg / m2 per day.

In patients with mild to moderate renal dysfunction, treatment should begin with a minimum effective dose of 400 mg once daily. Kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with severe renal dysfunction or with a regular hemodialysis procedure, the drug can also be started with 400 mg once a day. If the drug is intolerant, the initial dose of the drug can be reduced, with insufficient effectiveness - increased. Older patients do not need a dosage adjustment. With the development of any serious non-hematologic side effect associated with taking the drug, therapy should be discontinued until the situation resolves. The treatment can then be resumed at a dose that depends on the severity of the observed side effect.

Correction of the dosing regimen with the development of serious side effects from the hematopoiesis system

When systemic mastocytosis (SM), and hypereosinophilic syndrome and / or chronic eozinofilnom leukemia (HES / CEL) caused abnormal FIP1L1-PDGFR tyrosine kinase alpha (initial dose of 100 mg of the drug), by decreasing the absolute number of neutrophils to 1 x 109 / l (one thousand / ml.), platelet - 50 x 109 / l (. 50 thousand / ml) is recommended to cancel the drug to normalize the respective indices (neutrophil - not less than 1.5 x 109 / l (1.5 thousand /. μl), platelets - not less than 75 × 109 / L (75 thousand / μL), resume taking the drug at a dose used before the interruption of therapy. When chronic XMJI phase in children and adults, malignant gastrointestinal stromalnyh tumors, myelodysplastic / myeloproliferative diseases, SM and HES / CEL in adults in the case of occurrence of neutropenia and thrombocytopenia, decrease of neutrophils to 1 x 10% (one thousand. / l) platelet - to 50 x 109 / l (. 50 thousand / ml) treatment is stopped until the normalization of indicators (neutrophil - not less than 1.5 x 109 / l (1.5 thousand / ml) platelet -. at least 75 x YU9 / l (75 thousand / mkl) treatment is resumed in the former regime (400 mg / day,in children - 340 mg / m2); if the indicators decrease again below the limit of acceptable values, the treatment is resumed after a break (needed to restore blood counts) at a reduced dose of 300 mg / day, in children - 260 mg / m).

In the phase of acceleration and power crisis of XML in children and adults and at Ph + OLE in adult patients (initial dose for adults is -600 mg, for children - 340 mg / m2) in case of neutrophil decrease less than 0.5 x 10 / L (500 / μL) , platelets - less than 10 x 109 / l (10 thousand / μl) after one or more months of treatment, it is recommended:

- to check whether the cytopenia is a consequence of leukemia (a bone marrow biopsy is performed); if cytopenia is not associated with leukemia, imatinib dose is reduced to 400 mg, in children - 260 mg / m2; if the cytopenia persists for the next 2 weeks, the dose is reduced to 300 mg, in children 200 mg / m; if the cytopenia persists for 4 weeks, the treatment is stopped until the recovery of blood counts (neutrophils - not less than 1 x 109 / l (1 thousand / μl), platelets

- not less than 20 x 109 / l (20 thousand / μl), and then renewed at a reduced dose of 300 mg / day, in children

- 260 mg / m2.

In the case of inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma (initial dose of 800 mg), in the case of a decrease in the number of neutrophils less than 1 x 109 / L (1000 / μL) and / or platelet counts below 50 x 109 / L (50tys / μL) cancel the taking of the drug,until the absolute number of neutrophils reaches normal levels (neutrophils - at least 1.5 x 10%, (1.5 thousand / μL), platelets - at least 75 x 109 / L (75 thousand / μL), resume treatment in In case of repeated decrease in the number of neutrophils less than 1 x 10 / l (1000 / μl) and / or platelet count less than 50 × 10% (50 thousand / mkl), the drug should be withdrawn until the neutrophil and platelet counts normalize, then resume treatment in a reduced dose of 400 mg.

Side effects:

With prolonged daily intake of patients with XML imatinib is transferred well. The most common adverse events associated with taking the drug were transient mild nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, neutropenia, thrombocytopenia, anemia, headache, abdominal pain. All these phenomena were easily stopped. Other adverse events that occur with imatinib include lysis of the tumor, acute generalized pustular exanthema (rarely), and growth retardation in children (the frequency is unknown). The most common edema is noted in patients with malignant gastrointestinal stromal tumors receiving imatinib in a dose of 800 mg / day.

In patients with XML and with inoperable / or metastatic malignant gastrointestinal stromal tumors, the following AEs were listed, indicating the frequency of their occurrence: very often (> 1/10), often (> 1/100 - <1/10), infrequently (> 1/1000 - <1/100), rarely (> 1/10000 - <1/1000), very rarely (<1/10000), including individual messages:

Infectious and parasitic diseases: infrequent - herpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycoses.

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

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

Disorders from the metabolism and nutrition: often - anorexia, infrequently - hypokalemia,increased or decreased appetite, hypophosphataemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia, rarely - hyperkalemia, hypomagnesemia.

Disorders of the psyche: often - insomnia, rarely - depression, anxiety, loss of libido, seldom - confusion.

Impaired nervous system: very often - headache, often - dizziness, paraesthesia, taste disturbance, hypoesthesia, rarely - headache, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, a syndrome of "restless" legs, tremors, hemorrhagic stroke, rarely - increased intracranial pressure, convulsions, optic neuritis.

Disorders from the side of the organ of vision: often - swelling of the eyelids, increased lacrimation, conjunctival hemorrhage, vitreous hemorrhage, conjunctivitis, a syndrome of "dry" eyes, blurred vision, rarely - eye irritation, eye pain, orbital edema, hemorrhages in the sclera of the eye, retinal haemorrhage, blepharitis, macular edema, rarely - cataract, edema of the optic nerve, glaucoma.

Hearing disorders and labyrinthine disturbances: infrequently - vertigo, tinnitus, hearing loss

Heart Disease: infrequently - palpitation, congestive heart failure, pulmonary edema, tachycardia, "hot flashes", rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, pericarditis.

Vascular disorders: infrequently - hemorrhage; rarely - hematomas, cold extremities, increase or decrease in blood pressure, Raynaud's syndrome.

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

Disorders from the digestive system: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain, often - bloating, flatulence, constipation, gastroesophageal reflux, dryness of the oral mucosa, gastritis, infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding, belching, melena, esophagitis, ascites, stomach ulcer, vomiting of blood, cheilitis, dysphagia,pancreatitis, rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine.

Disorders from the liver and bile ducts: often - increased activity of "liver" enzymes, infrequently - jaundice, hepatitis, hyperbilirubinemia, hepatic insufficiency, liver necrosis.

Dermatological reactions: very often - periorbital edema, dermatitis, eczema, skin rash, often - puffiness of the face, itching, erythema, dry skin, alopecia, night sweats, photosensitivity reactions, infrequently - pustular rash, bruises, sweating, urticaria, ecchymosis, increased predisposition to formation of hematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash, rarely - febrile neutrophilic dermatosis (Sweet syndrome), discoloration of nails , angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.

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

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

Disorders from the endocrine system, genital organs and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema, very rarely - in women bleeding from the corpus luteum cyst / ovary.

General disorders and disorders at the site of administration: very often - fluid retention and edema, fatigue, weight gain, often - weakness, fever, anasarca, chills, trembling, weight loss, infrequently - chest pain, malaise.

Laboratory and instrumental research: infrequently, an increase in creatinine and alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase in the blood plasma, and rarely an increase in amylase activity in blood plasma.

In the application of imatinib in clinical practice, as well as in the course of additional studies, the following AEs were listed listed with the frequency of their occurrence: very often (> 1/10), often (> 1/100 - <1/10), infrequently (> 1/1000 - <1/100), rarely (> 1/10000 - <1/1000), very rarely (<1/10000), including individual messages:

Disorders from the nervous system: infrequently - edema of the brain.

Disorders from the side of the organ of vision: rarely - vitreous hemorrhage.

Disorders from the heart and blood vessels: infrequently - thrombosis / embolism, rarely - pericarditis, cardiac tamponade, very rarely - anaphylactic shock.

Disturbances from the respiratory system, chest, mediastinum: infrequently - acute respiratory failure, interstitial pneumonia.

Disorders from the digestive system: infrequently - paralytic / obturation intestinal obstruction, bleeding from the gastrointestinal tumor, necrosis of the gastrointestinal tumor, perforation of the gastrointestinal tumor, rarely - diverticulitis.

Dermatological reactions: infrequent - palmar-plantar erythrodysesthesia, rarely - lichenoid keratosis, red flat lichen, toxic epidermal necrolysis.

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

Overdose:

There are reports of individual cases of imatinib overdose. In one case, imatinib in a dose of 1200-1600 mg for 1-10 days was observed in patients: nausea, vomiting, diarrhea, rash, erythema, swelling, swelling of the face, increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain , headache, decreased appetite. When taking the drug at a dose of 1800-3200 mg, weakness, myalgia, an increase in the activity of creatine phosphokinase activity, bilirubin concentration, and gastrointestinal pain were noted.

When using the drug at a dose of 6400 mg once (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, a decrease in the number of neutrophils and an increase in the activity of "liver" transaminases. When taking the drug at a dose of 8-10 mg, vomiting and gastrointestinal pain were noted once.

When taking the drug at a dose of 400 mg, once in children aged 3 years, vomiting, anorexia, diarrhea, and a dose of 980 mg - a decrease in the number of leukocytes and diarrhea. Treatment: medical supervision and symptomatic therapy are recommended.The antidote is unknown.

Interaction:

Increasing concentrations of Imatinib plasma possible while the use of drugs that inhibit cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin) due to a slowing of the metabolism of imatinib. Caution is needed when combined with imatinib with inhibitor preparations of the CYP3A4 isoenzyme.

On the contrary, the simultaneous use of drugs which are inducers isoenzyme CYP3A4 (e.g., dexamethasone, rifampicin, preparations from Hypericum perforatum, antiepileptic drugs: phenobarbital, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, primidone) can lead to increased imatinib metabolism, and, consequently, reduce its concentration in the blood plasma.

With simultaneous use of imatinib and simvastatin marked increase in AUC and Cmax of simvastatin 2 and 3.5 times, respectively, which is a consequence of inhibition of CYP3A4 isoenzyme imatinib. Caution is recommended while the use of imatinib and drugs that are substrates for CYP3A4 isozyme and having a narrow range of therapeutic concentrations (e.g. ciclosporin and pimozide). Imatinib can increase serum concentrations of other drugs metabolized by the isoenzyme CYP3A4 (triazolo-benzodiazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the isoenzymes CYP2C9 and CYP2C19 in vitro. Elongation of prothrombin time was observed when combined with warfarin. With simultaneous administration with coumarin derivatives, a short-term monitoring of prothrombin time at the beginning and end of imatinib therapy is necessary, as well as a change in the dosage regimen of the drug. As an alternative to warfarin, consideration should be given to the use of low molecular weight heparin derivatives. When a combination of imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the concentration of "liver" transaminases and hyperbilirubinemia.

With a combination of the drug and regimens of chemotherapy that can potentially cause impaired liver function, liver function should be monitored. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme. When imatinib was used at a dose of 400 mg twice a day, along with metoprolol, the substrate of the CYP2D6 isoenzyme, there was a moderate decrease in metoprolol metabolism, accompanied by an increase in Cmax and AUC of approximately 21%. Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when combined with Histamel, changes in the dosing regimen are not required.

Special instructions:

Treatment with the drug is carried out only under the supervision of a doctor who has experience working with antitumor drugs.

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

Efficacy and safety of imatinib in children with CML younger than 2 years has not yet been established. It is recommended to carry out a careful growth control in children using imatinib, in connection with the available reports of a delay in their growth. Care should be taken to monitor patients with heart disease.

Due to the fact that the drug causes fluid retention in the body, patients need to regularly monitor body weight.In the case of a rapid sudden increase in body weight, it is necessary to temporarily stop therapy and prescribe diuretics. The highest frequency of fluid retention is observed in elderly patients suffering from cardiovascular diseases. In some cases, severe fluid retention may have a severe course with a fatal outcome. When the drug was used, the death of a patient with a blast crisis and complex symptoms was noted: pleural effusion, congestive cardiac and renal insufficiency.

Imatinib can cause irritation of the digestive tract, so it is recommended to take it with food and drink a full glass of water.

During therapy, it is necessary to regularly monitor clinical blood tests and liver function (transaminase, bilirubin, alkaline phosphatase). A marked increase in the activity of "hepatic" transaminases or bilirubin concentrations is possible in patients with XMJT and is usually controlled by a decrease in the dose of the drug or temporary interruption of treatment.

In patients who underwent thyroidectomy and who received levothyroxine sodium replacement therapy with imatinib, regular monitoring of the thyroid-stimulating hormone concentration should be made to avoid the development of hypothyroidism.In patients with hypereosinophilic syndrome and heart disease, at the beginning of imatinib therapy, cases of cardiogenic shock / left ventricular failure were noted. These undesirable phenomena are stopped by the use of systemic glucocorticosteroids, temporary withdrawal of the drug and the adoption of measures to maintain blood circulation.

In patients with MDS / MPD and high levels of eosinophils, ECG testing should be performed and the serum concentration of cardiospecific troponin should be determined. If abnormalities are found, the possibility of prophylactic use of systemic glucocorticosteroids (1-2 mg / kg) should be considered for 1-2 weeks simultaneously with imatinib.

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

In patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors in clinical studies, 3 phases of hemorrhage of different localizations were noted in 12.9% of cases; in studies of 2 phases, gastrointestinal bleeding was noted in 8 patients (5.4%), bleeding from puffy foci in 4 patients (2.7%).Bleeding was observed both in the organs of the abdominal cavity and in the liver, depending on the localization of tumor sites. It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors at the beginning of imatinib therapy. Increased activity of "liver" transaminases or bilirubin

was observed in less than 3% of patients with XMJ1 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).

A small proportion of patients who received imatinib, ulceration of the gastrointestinal tract was noted, which in some cases may be a consequence of the local irritating effect of imatinib. Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract, were most often observed in patients with malignant stromal tumors of the gastrointestinal tract. In the case of metastatic malignant stromal tumors of the gastrointestinal tract, necrosis of the tumor in rare cases can lead to perforation. Gastrointestinal obstruction may occur in patients with malignant stromal tumors of the digestive tract, in which its cause may be metastases or adhesions,arising from a previous operation on the digestive tract (if imatinib is used as an adjuvant therapy).

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

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

Some undesirable effects of the drug, such as dizziness, fatigue, blurred vision can negatively affect the ability to concentrate and the speed of psychomotor reactions.

In this regard, patients receiving the drug Histamel, should show increased attention and caution in the management of transport and employment in these activities.

Form release / dosage:Capsules of 100 mg.

Packaging:

For 10 or 12 capsules in a planar cell package. For 12, 60 or 120 capsules in a plastic can. Each jar or 6 or 12 contour packs of 10 capsules, or 5 or 10 contour squares of 12 capsules, together with instructions for use in a pack of cardboard.

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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002066

Date of registration:13.05.2013

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp13.05.2013

Illustrated instructions

Instructions

Histamel (Gistamel)