Imatinib, 100 mg 30 pcs

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Indications

– Newly diagnosed Philadelphia chromosome positive (Ph+)

Chronic myeloid leukemia (CML) in children and adults;

– Ph+ CML in the chronic phase if prior therapy with interferon alfa has failed, or in the acceleration phase or blast crisis in children and adults;

– newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in adult patients in combination with chemotherapy;

– relapsed or refractory Ph+ ALL in adult patients as monotherapy;

– myelodysplastic/myeloproliferative diseases associated with platelet growth factor receptor gene rearrangements 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 adults with positive or negative abnormal FIP1L1-PDGFR alpha tyrosine kinase;

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

– Adjuvant therapy for gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;

Inoperable, recurrent, and/or metastatic bulging dermatofibrosarcoma in adult patients.

Active ingredient

Composition

Active ingredient:

Imatinib mesylate – 128.56 mg converted to imatinib – 100 mg;

excipients: anhydrous lactose – 350.94 mg, croscarmellose sodium – 10.00 mg, povidone K-30 – 7.50 mg, talc – 3.00 mg, magnesium stearate – 5.00 mg, crospovidone – 15.00 mg.

Shell composition: film coating Insta-Coat – 6.0 mg (polyethylene glycol – 1.2 mg, hypromellose – 2.4 mg, talc – 1.2 mg, titanium dioxide (E 171) – 1.2 mg), iron oxide red (E 172) – 4.00 mg.

How to take, the dosage

Orally, with 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 doses of 400 mg in the morning and in the evening.

Patients who are unable to swallow the whole tablet, such as children, may take the drug diluted; the tablets are diluted with water or apple juice. The desired amount of pills or put in a glass, pour in the fluid (about 100 ml of fluid for 400 mg pills) and stir with a spoon to make a suspension.

The suspension should be taken orally immediately after preparation.

In chronic myeloleukemia (CML), the recommended dose of Imatinib depends on the phase of the disease. In the chronic phase of CML the dose is 400 mg/day; in the acceleration phase and during the blast crisis it is 600 mg/day. The drug should be taken once a day.

The drug is treated as long as the clinical effect persists. In absence of marked side effects and neutropenia or thrombocytopenia unrelated to leukemia, increase of dose from 400 mg to 600 mg or up to 800 mg daily in patients in chronic phase of disease, and from 600 mg to 800 mg in patients in acceleration phase and in blast crisis.

This dose increase may be necessary if CML progresses (at any stage), if there is no satisfactory hematologic response after 3 months of treatment, no cytogenetic response after 12 months of therapy, or if there is a loss of previously achieved hematologic and/or cytogenetic response.

The dosing regimen in children over 2 years of age is based on body surface area. Doses of 340 mg/m2 per day are recommended in children with chronic phase CML and acceleration phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken all at once or divided into 2 equal doses – in the morning and in the evening.

In Ph+acute lymphoblastic leukemia, the recommended dose of Imatinib is 600 mg daily.

In myelodysplastic/myeloproliferative diseases, the recommended dose of Imatinib is 400 mg daily.

In inoperable and/or metastatic malignant gastrointestinal stromal tumors, the recommended dose of Imatinib is 400 mg daily. If there are no side effects of the drug and there is insufficient response, it is possible to increase the daily dose of Imatinib from 400 mg to 600 mg or up to 800 mg.

Imatinib therapy should be stopped if there are signs of disease progression.

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

In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma, the recommended dose of Imatinib is 800 mg daily. For systemic mastocytosis in the absence of a D816V c-Kit mutation, the recommended dose of Imatinib is 400 mg per day. If mutation status is unknown and previous therapy has not been effective enough, the recommended dose is 400 mg daily.

In systemic mastocytosis caused by the abnormal FIP1L1-PDGFR a- tyrosine kinase, resulting from the fusion of the Fip likel and PDGFR genes, the recommended starting dose is 100 mg daily. If efficacy is insufficient and there are no pronounced side effects, it is possible to increase the dose to 400 mg/day.

In hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CHL) in adult patients, the recommended dose is 400 mg/day. In patients with HES/HEL caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended starting dose is 100 mg daily. If efficacy is insufficient and there are no significant side effects, the dose may be increased to 400 mg/day.

Patients with hepatic impairment

As imatinib is metabolized primarily in the liver, in patients with mild, moderate or severe hepatic impairment imatinib should be used in the minimum daily dose of 400 mg. If undesirable toxic effects develop, the drug dose should be reduced. Caution should be exercised when prescribing the drug in patients with severe hepatic impairment.

Patients with impaired renal function

The kidneys do not play a significant role in excretion of imatinib and its metabolites. In patients with impaired renal function or in patients who require systemic hemodialysis, treatment with imatinib should be started at the lowest effective dose of 400 mg once daily, with caution. The starting dose of imatinib may be reduced if intolerant, and increased if it is not effective.

Patients in the elderly

The drug dosing regimen does not need to be adjusted in elderly patients.

Correcting the dosing regimen if non-hematologic side effects of the drug develop

If any serious non-hematologic side effect associated with taking the drug develops, therapy should be interrupted until the situation resolves. Treatment may then be resumed at a dose depending on the severity of the side effect observed.

In case of bilirubin concentration and liver transaminase activity in serum increase 3 and 5 times higher than upper limit of normal (ULN), respectively, treatment with the drug should be temporarily stopped until bilirubin concentration is decreased to values less than 1.5x ULN and activity of “liver” transaminases to values less than 2.5x ULN.

Therapy with imatinib is resumed at a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg daily or from 600 mg to 400 mg daily, or from 800 mg to 600 mg daily; in children, from 340 to 260 mg/m2 daily.

Correcting the dosage regimen in case of serious adverse effects of the hematopoietic system (severe thrombocytopenia, neutropenia)

In case of neutropenia and thrombocytopenia, temporary withdrawal of the drug or reduction of the dose is required, depending on the severity of these adverse events. In systemic mastocytosis (SM) and hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CET/CHL) caused by abnormal FIP1L1-PDGFR a-tyrosine kinase (starting dose of imatinib 100 mg), if absolute neutrophil count <1.0*109/l and/or platelet count <50*109/l decrease is recommended:

1. Discontinue imatinib until the absolute neutrophil and platelet counts are ≥1.5 *109/L and ≥75* 109/L, respectively;

2. Resume treatment with imatinib at the dose used before interruption of therapy.

In chronic phase CML in children and adults, malignant gastrointestinal stromal tumors, myelodysplastic/myeloproliferative diseases, CM and HES/HEL in adult patients (starting dose for adults is 400 mg, for children 340 mg/m2) if absolute neutrophil counts decrease <1.0*109/L and/or platelet count <50* 109/L are recommended:

1. Discontinue imatinib until absolute neutrophil and platelet counts are ≥1.5* 109/L and ≥75* 109/L, respectively;

2. Resume treatment with imatinib at the dose used before interruption of therapy.

If the neutrophil count <1.0* 109/L and/or platelet count <50* 109/L decrease again, repeat steps 1 and then resume treatment with imatinib at a reduced dose of 300 mg (260 mg/m2 in children).

In the phase of acceleration and blast crisis of CML in children and adults and in Ph+ acute lymphoblastic leukemia in adult patients (starting dose for adults is 600 mg, for children 340 mg/m2) if the absolute neutrophil count <0.5*109/L and/or platelet count <1.0*109/L decrease after one or more months of treatment is recommended:

1. Check whether the cytopenia is due to leukemia (bone marrow study);

2. If the cytopenia is not due to leukemia, reduce the imatinib dose to 400 mg (in children 260 mg/m2);

3. If the 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 imatinib until absolute neutrophil and platelet counts are >1*109/L and >20* 109/L, respectively; then resume treatment with imatinib at a dose of 300 mg (260 mg/m2 in children).

In inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma (starting dose of imatinib 800 mg), if absolute neutrophil count <1.0*109/L and/or platelet count <50*109/L decrease is recommended:

1. Discontinue imatinib until the absolute neutrophil and platelet counts are ≥1.5 *109/L and ≥75*109/L, respectively;

2. Resume treatment with imatinib at a dose of 600 mg.

If the neutrophil count <1.0*109/l and/or platelet count <50* 109/l decrease again, repeat steps 1 and then resume treatment with imatinib at a reduced dose of 400 mg.

Interaction

When imatinib is used concomitantly with drugs that inhibit CYP3A4 cytochrome P450 isoenzyme (ketoconazole, itraconazole, erythromycin, clarithromycin, protease inhibitors (indinavir, lopinavir ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, telithromycin), it is possible to slow down the metabolism of imatinib and increase its concentration in blood plasma. Caution is necessary when combining imatinib with drugs – CYP3A4 isoenzyme inhibitors.

On the contrary, concomitant use of drugs that are inducers of CYP3A4 isoenzyme (e.g., rifampicin, dexamethasone, preparations of St. John’s wort, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidone) may lead to accelerated metabolism of imatinib and, consequently, a decrease in its plasma concentration and ineffective therapy. Simultaneous use of imatinib and strong inducers of CYP3A4 isoenzyme should be avoided.

In concomitant use of imatinib and simvastatin there is a 2 and 3.5-fold increase in Stakh and AUC of simvastatin, respectively, which is due to inhibition of CYP3A4 by imatinib.

We recommend caution when using imatinib concomitantly with drugs that are substrates of CYP3A4 isoenzyme and have a narrow range of therapeutic concentration (e.g., cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase serum concentrations of other drugs metabolized by CYP3A4 isoenzyme (triazole-benzodiazepines, dihydropyridine, “slow” calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits CYP2C9 isoenzyme and CYP2C19 isoenzyme in vitro. Prothrombin time prolongation was observed when combining use of imatinib with warfarin. Concomitant use with coumarin derivatives requires short-term monitoring of prothrombin time at the beginning and end of therapy with the drug, as well as when changing imatinib dosing regimen. The use of low molecular weight heparins should be considered as an alternative to warfarin.

When imatinib is combined with chemotherapeutic agents at high doses, transient hepatic toxicity in the form of increased hepatic transaminases and hyperbilirubinemia may develop.

In patients who have undergone thyroidectomy and receive levothyroxine sodium hormone replacement therapy, its plasma concentration may decrease when combined with imatinib.

The question of drug interactions between imatinib and chemotherapy drugs in patients with Ph+ OJIJI is insufficiently studied. Caution should be exercised when using imatinib and chemotherapy drugs together due to the possible increased risk of drug complications, such as hepatotoxicity, myelosuppression, etc.

There have been reports of liver damage when using imatinib and asparaginase together.

When combining imatinib with chemotherapy regimens that have the potential to cause hepatic impairment, hepatic function monitoring should be considered. In vitro, imatinib inhibits the CYP2D6 cytochrome P450 isoenzyme at the same concentrations at which it inhibits the CYP3A4 isoenzyme.

When imatinib is used together with metoprolol, a substrate of the CYP2D6 isoenzyme, there is a moderate decrease in metabolism of metoprolol, accompanied by an increase in Cmax and AUC. Given the moderate increase in the effects of drugs that are substrates of CYP2D6 isoenzyme (e.g., metoprolol), when used together with imatinib, no change in dosing regimen is required. In vitro imatinib inhibits O-glucuronidation of paracetamol/acetaminophen.

Caution should be exercised when using imatinib with paracetamol/acetaminophen because of the possible development of acute hepatic failure with lethal outcome in patients.

Special Instructions

The treatment with imatinib should only be given under the supervision of a physician experienced in working with antitumor drugs.

Handling of the drug should avoid contact with the skin and eyes, and inhaling the drug powder.

There is limited experience with imatinib in children with CML under 2 years of age and limited experience with imatinib for other indications in patients under 18 years of age. Careful growth monitoring in children using imatinib is recommended due to reports of growth retardation.

When using imatinib, regular clinical blood counts and monitoring of liver function (transaminases, bilirubin, alkaline phosphatase) are recommended.

Patients with heart or kidney disease should be monitored closely.

Because marked fluid retention has been noted in 1-2% of cases with imatinib, it is recommended that patients’ body weight be monitored regularly. If there is a rapid, unexpected increase in body weight, the patient should be examined and, if necessary, imatinib therapy should be temporarily stopped and/or diuretics prescribed.

The highest incidence of fluid retention is in elderly patients with comorbid cardiovascular disease. In some cases, severe fluid retention may be fatal.

When using the drug, patients with liver disease should undergo regular clinical blood tests and determine the “activity” of liver enzymes. Since there are reports of hypothyroidism with Imatinib in patients who underwent thyroidectomy and receive levothyroxine sodium replacement therapy, the thyrotropic hormone concentration should be determined regularly in this category of patients.

In patients with hypereosinophilia syndrome and cardiac disease, there have been isolated cases of cardiogenic shock/levan ventricular failure at the start of therapy with Imatinib. These adverse events are managed after administration of systemic glucocorticosteroids, circulatory support measures and temporary withdrawal of Imatinib.

In patients with MDS/MPD and high eosinophil counts, an ECG study should be performed and serum cardiac-specific troponin concentrations should be determined. If abnormalities are detected early in therapy, prophylactic use of systemic glucocorticosteroids (1-2 mg/kg) for 1-2 weeks concurrently with imatinib should be considered.

Bleeding has been observed in both abdominal and hepatic organs, depending on the localization of tumor foci.

Safe contraception should be used during imatinib therapy and for at least 3 months after.

Hepatic transaminases or bilirubin may increase in patients with XMJI, which is controlled by reducing the dose of the drug or temporarily stopping treatment.

Because of the risk of tumor lysis syndrome, clinically significant dehydration and elevated uric acid levels in patients should be corrected as necessary before using imatinib.

Contraindications

– Hypersensitivity to the active substance or any other component of the drug.

– Pregnancy, breast-feeding period.

– Childhood under 2 years of age (efficacy and safety not currently established).

Cautions:

Imatinib should be used with caution in patients with severe hepatic impairment, severe renal impairment (creatinine clearance less than 30 ml/min), cardiovascular disease or if there are risk factors for heart failure, and if regular hemodialysis procedures are performed.

Caution is required when concomitant use of imatinib with drugs that inhibit CYP3A4 isoenzyme, strong inducers of CYP3A4 isoenzyme, with drugs that are substrates of CYP3A4, paracetamol, warfarin (see section “Interaction with other medicinal products”).

Side effects

The evaluation of adverse events (AEs) is difficult in advanced malignancies due to symptoms associated with multiple comorbidities, their progression and various medications.

In long-term daily oral administration in adults and children with CML, Imatinib was generally well tolerated. Most NTs were mild to moderate. Side effects were similar in almost all patients who received imatinib for different indications. 65 years).

Rash and severe skin adverse reactions

A number of patients treated with imatinib experienced generalized erythematous, patchy-papular and pruritic rashes that could resolve on their own despite continued drug treatment. Some patients had itching without a rash; in some cases, erythroderma was present.

Rash occurred in approximately one-third of all patients treated with imatinib for all indications. The rash was often accompanied by itching and usually appeared as erythematous, patchy-papular lesions on the forearm, trunk or face.

While most cases of the rash are mild and go away without treatment, more severe cases may require temporary or complete withdrawal of the drug. As a rule, the severity of the rash decreases after prescription of antihistamines and topical glucocorticosteroids. In some cases, glucocorticosteroids for systemic use are required.

Hepatotoxicity

The drug may have toxic effects on the liver. Impairment of biochemical parameters of liver function usually consists of a slight increase in aminotransferase activity and elevated serum bilirubin concentration.

The toxic effect on the liver is usually manifested within the first two months of treatment, but in some cases it was manifested 6-12 months after the start of treatment. As a rule, after discontinuation of the drug, biochemical indicators of liver function normalize within 1-4 weeks. There have been cases of cytolytic and cholestatic hepatitis and liver failure, in some cases accompanied by lethal outcome.

Incontinence, perforation or ulceration of the stomach or intestine

In a small proportion of patients treated with imatinib, gastrointestinal ulceration has been reported, which in some cases may be due to the local irritant effect of imatinib. Hemorrhagic tumor necrosis as well as gastrointestinal obstruction and perforation were most frequently observed in patients with malignant stromal tumors of the gastrointestinal tract.

In metastatic malignant stromal tumors of the GI tract, tumor necrosis may occur against the background of tumor response, which in rare cases leads to perforation. Gastrointestinal obstruction most often occurred in patients with malignant stromal gastrointestinal tumors, in which its cause may be metastases or adhesions resulting from previously performed GI surgery (in case of using the drug as a means of adjuvant therapy).

Serious respiratory NIHs

Serious (sometimes fatal) NIHs have been reported with imatinib, such as acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. Concomitant cardiovascular or respiratory pathology may exacerbate the severity of NS.

If any of the side effects listed in the instructions worsen, or if the patient notices any other side effects not listed in the instructions, you should tell your doctor.

Overdose

There have been reports of individual cases of imatinib overdose. In one case when imatinib was administered in a dose of 1200-1600 mg for 1-10 days patients showed nausea, vomiting, diarrhea, rash, erythema, edema, swollen face, increased fatigue, muscle cramps, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

When taking the drug in a dose of 1800-3200mg, weakness, myalgia, increased blood creatine phosphokinase activity, bilirubin concentration, and gastrointestinal pain were noted.

In a single dose of 6400 mg (information from the published source) the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, decreased neutrophil count and increased liver transaminase activity. Vomiting and gastrointestinal pain have been reported in a single dose of 8-10mg.

A single dose of 400 mg in children aged 3 years showed vomiting, anorexia, diarrhea, and in a dose of 980 mg – decreased white blood cell count and diarrhea. Treatment: medical observation and symptomatic therapy are recommended. The antidote is unknown.

Pregnancy use

Pregnancy

There are currently no data on the use of imatinib in pregnant women. Animal studies have shown toxic effects on reproductive function, but the potential risk to the fetus is not yet known. Imatinib use is contraindicated during pregnancy. Women of childbearing age should use reliable contraception during imatinib therapy and for at least 3 months after.

Breastfeeding

Imatinib and its metabolites are excreted with breast milk. Because of the lack of data on the effect of imatinib on infants, women taking imatinib should stop breastfeeding.