Imatib (Capsules) Instructions for Use

Marketing Authorization Holder

Pharma-Sintez, JSC (Russia)

Manufactured By

Pharma-Sintez, JSC (Russia)

Or

Deko Company, LLC (Russia)

Contact Information

PHARM-SINTEZ JSC (Russia)

ATC Code

L01EA01 (Imatinib)

Active Substance

Imatinib (Rec.INN registered by WHO)

Dosage Forms

	Imatib	Capsules 50 mg: 30 pcs.
		Capsules 100 mg: 24, 36, 48, 96, 120 or 180 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size #3, white body, light blue cap; capsule contents – white powder or white powder with a yellowish or brownish tint.

Excipients: microcrystalline cellulose – 48.95 mg, crospovidone – 4 mg, colloidal silicon dioxide – 1.15 mg, magnesium stearate – 1.15 mg.

Capsule body composition: titanium dioxide – 2%, gelatin – q.s. to 100%.
Capsule cap composition: titanium dioxide – 1%, indigo carmine – 0.0161%, gelatin – q.s. to 100%.

10 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Capsules hard gelatin, size #1, white body, dark blue cap; capsule contents – white powder or white powder with a yellowish or brownish tint.

Excipients: microcrystalline cellulose – 97.9 mg, crospovidone – 8 mg, colloidal silicon dioxide – 2.3 mg, magnesium stearate – 2.3 mg.

Capsule body composition: titanium dioxide – 2%, gelatin – to 100%.
Capsule cap composition: titanium dioxide – 1%, indigo carmine – 0.1333%, gelatin – to 100%.

12 pcs. – blister packs (2) – cardboard packs.
12 pcs. – blister packs (3) – cardboard packs.
12 pcs. – blister packs (4) – cardboard packs.
12 pcs. – blister packs (8) – cardboard packs.
12 pcs. – blister packs (10) – cardboard packs.
12 pcs. – blister packs (15) – cardboard packs.
24 pcs. – polymer bottles (1) – cardboard packs.
36 pcs. – polymer bottles (1) – cardboard packs.
48 pcs. – polymer bottles (1) – cardboard packs.
96 pcs. – polymer bottles (1) – cardboard packs.
120 pcs. – polymer bottles (1) – cardboard packs.
180 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein tyrosine kinase inhibitor

Pharmacological Action

Imatinib exerts a selective inhibitory effect on the Bcr-Abl tyrosine kinase enzyme, formed by the fusion of the Bcr (breakpoint cluster region) gene segment and the Abl (Abelson) proto-oncogene, at the cellular level, selectively suppresses proliferation and induces apoptosis of cell lines expressing Bcr-Abl tyrosine kinase, including immature leukemic cells found in patients with Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibits Bcr-Abl-positive colonies derived from blood cells of patients with chronic myeloid leukemia.

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

Activation of platelet-derived growth factor receptors or the Abl fragment of tyrosine kinase can be the cause of both myelodysplastic/myeloproliferative diseases and hypereosinophilic syndrome and chronic eosinophilic leukemia and dermatofibrosarcoma protuberans.

Activation of the c-Kit receptor tyrosine kinase and platelet-derived growth factor receptors may underlie the pathogenesis of systemic mastocytosis.

Imatinib inhibits signal transduction in cells and cell proliferation resulting from dysregulated activity of platelet-derived and stem cell growth factors, the c-Kit receptor, and the Abl fragment of tyrosine kinase.

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

Adjuvant therapy of gastrointestinal stromal tumors with the drug for 1 year reduces the risk of relapse by 89%, increases disease-free survival (38 months for Imatinib compared to 20 months for placebo).

Adjuvant therapy of gastrointestinal stromal tumors with the drug for 3 years leads to a significant increase in overall survival and progression-free survival compared to therapy for 1 year.

Pharmacokinetics

The pharmacokinetic parameters of imatinib were evaluated in the dose range from 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on the first day, as well as upon reaching steady-state plasma concentrations of imatinib on day 7 or 28.

Absorption

After oral administration, the bioavailability of the drug averages 98%. The coefficient of variation for AUC is 40-60%. A direct linear relationship between the AUC value and the dose was noted in the dose range from 25 to 1000 mg.

When taking the drug with a high-fat meal, compared to taking on an empty stomach, a slight decrease in the extent of absorption (decrease in C_max of imatinib in plasma by 11%, AUC – by 7.4%) and a slowdown in the rate of absorption (increase in the time to reach C_max of imatinib in plasma by 1.5 h) are noted.

Distribution

About 95% of imatinib binds to plasma proteins (mainly albumin and acidic alpha-glycoproteins, to a lesser extent – lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver to form the main metabolite (N-demethylated piperazine derivative), circulating in the bloodstream. In vitro, the imatinib metabolite has pharmacological activity similar to that of the parent substance. The AUC value of the metabolite is 16% of the imatinib AUC. The binding of the metabolite to plasma proteins is similar to that of imatinib.

Excretion

It is excreted mainly as metabolites within 7 days after a single dose: 68% – via the intestine and 13% – via the kidneys. About 25% of the administered dose is excreted unchanged (20% – via the intestine and 5% – via the kidneys). T_1/2 of imatinib is about 18 h.

With repeated administration of the drug once/day, the pharmacokinetic parameters do not change, and the steady-state concentration of imatinib exceeds the initial one by 1.5-2.5 times.

Pharmacokinetics in special patient groups

In patients over 65 years of age, V_d increases slightly (by 12%).

For patients weighing 50 kg, the average imatinib clearance is 8.5 L/h, and for patients weighing 100 kg – 11.8 L/h. However, these differences are not significant and do not require adjustment of the drug dosage regimen depending on the patient’s body weight.

The pharmacokinetics of imatinib does not depend on gender.

Changes in imatinib clearance and V_d indicators with simultaneous use with other drugs are insignificant and do not require dose adjustment.

In children and adolescents under 18 years of age, as in adults, rapid absorption of the drug occurs after oral administration. AUC in this group of patients 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 comparing AUC_0-24 values in children and adolescents on the first and eighth days after repeated administration of the drug at 340 mg/m² once/day, an increase in this indicator by 1.7 times is noted, indicating accumulation of imatinib.

In patients with varying degrees of liver dysfunction, the mean AUC values do not increase.

When using imatinib in patients with mild or moderate renal impairment (CrCl >30 ml/min), an increase in drug exposure in plasma by 1.5-2.0 times is observed, corresponding to an increase in the concentration of acidic alpha-glycoproteins (the main plasma proteins that bind to imatinib). Since the drug is minimally excreted by the kidneys, the clearance of free imatinib was the same for healthy volunteers and patients with renal impairment. No correlation was found between drug exposure and the severity of renal impairment.

Indications

• Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in children and adults;
• Philadelphia chromosome-positive (Ph+) CML in the chronic phase after failure of prior interferon alpha therapy or in the accelerated phase, or blast crisis in children and adults;
• Newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adult patients in combination with chemotherapy;
• Relapsed or refractory Ph+ ALL in adult patients as monotherapy;
• Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor gene rearrangements in adult patients;
• Systemic mastocytosis (SM) in adult patients lacking the D816V c-Kit mutation or with an unknown c-Kit mutation status;
• Hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGRF α-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, recurrent and/or metastatic dermatofibrosarcoma protuberans in adult patients.

ICD codes

Dosage Regimen

The drug should be taken orally with a meal, washed down with a full glass of water, to reduce the risk of gastrointestinal disorders.

The drug at a dose of 400 mg/day and 600 mg/day is taken in one dose; the daily dose of 800 mg should be divided into 2 doses – 400 mg in the morning and in the evening.

For patients who are unable to swallow the capsule whole, such as children, the drug can be taken in a diluted form; the contents of the capsules are diluted with water or apple juice. The resulting suspension is taken orally immediately after preparation. After opening the capsules, hands should be washed immediately.

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

For chronic myeloid leukemia (CML) the recommended dose of Imatib depends on the phase of the disease. In the chronic phase of CML, the dose is 400 mg/day; in the accelerated phase and blast crisis – 600 mg/day. The drug should be taken once/day.

In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or 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 blast crisis. Such a dose increase may be necessary in case of CML progression (at any stage), in the absence of a satisfactory hematological response after 3 months of treatment, a cytogenetic response after 12 months of therapy, or loss of a previously achieved hematological and/or cytogenetic response.

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

For Ph+ acute lymphoblastic leukemia the recommended dose of Imatib is 600 mg/day.

For inoperable and/or metastatic malignant gastrointestinal stromal tumors, myelodysplastic/myeloproliferative diseases the recommended dose of Imatib is 400 mg/day. In the absence of drug side effects and insufficient response, it is possible to increase the daily dose of Imatib from 400 mg to 600 mg or to 800 mg.

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

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.

For inoperable, recurrent and/or metastatic dermatofibrosarcoma protuberans the recommended dose of Imatib is 800 mg/day.

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

For systemic mastocytosis caused by abnormal FIP1L1-PDGFR α-tyrosine kinase, formed as a result of the fusion of the Fip like1 and PDGFR genes, the recommended initial dose is 100 mg/day. If the effectiveness is insufficient and there are no severe side effects, it is possible to increase the dose to 400 mg/day.

For hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) in adult patients, the recommended dose is 400 mg/day.

In patients with HES/CEL caused by abnormal FIP1L1-PDGFR α-tyrosine kinase, the recommended initial dose is 100 mg/day. If the effectiveness is insufficient and there are no severe side effects, it is possible to increase the dose to 400 mg/day. Treatment with the drug is carried out as long as the clinical effect persists.

Since Imatinib is metabolized mainly in the liver, patients with mild, moderate or severe liver dysfunction should be prescribed Imatib at a minimum daily dose of 400 mg. If undesirable toxic effects develop, the drug dose should be reduced. The drug should be prescribed with caution to patients with severe liver failure.

The kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with renal impairment or in patients requiring systematic hemodialysis, treatment with Imatib should be started at a minimum effective dose of 400 mg once/day, with caution. If Imatib is not tolerated, the initial dose of the drug may be reduced; if the effectiveness is insufficient, it may be increased.

In elderly patients no adjustment of the drug dosage regimen is required.

Dosage regimen adjustment for the development of non-hematological side effects of the drug

If any serious non-hematological side effect associated with taking the drug develops, therapy should be interrupted until the situation resolves. Then treatment can be resumed at a dose depending on the severity of the observed side effect.

If the concentration of bilirubin and the activity of liver transaminases in the blood serum increase to 3 and 5 times the ULN, respectively, treatment with the drug should be temporarily suspended until the bilirubin concentration decreases to less than 1.5×ULN and the activity of liver transaminases decreases to less than 2.5×ULN.

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

Dosage regimen adjustment for the development of serious side effects from the hematopoietic system (severe thrombocytopenia, neutropenia)

If neutropenia and thrombocytopenia occur, temporary withdrawal of the drug or a reduction in its dose is required, depending on the severity of these adverse events.

For systemic mastocytosis and hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) caused by abnormal FIP1L1-PDGFR α-tyrosine kinase (initial dose of Imatib 100 mg), in case of a decrease in the absolute neutrophil count <1000/µL and/or platelet count <50000/µL, it is recommended

1. Discontinue Imatib until the absolute neutrophil count is ≥1500/µL and platelets are ≥75000/µL;
2. Resume treatment with Imatib at the dose used prior to therapy interruption.

In chronic phase CML in children and adults (initial dose for adults – 400 mg, for children – 340 mg/m²), malignant gastrointestinal stromal tumors, MDS/MPN, SM and HES/CEL in adult patients (initial dose for adults – 400 mg) in case of a decrease in the absolute neutrophil count <1000/µL and/or platelet count <50,000/µL, it is recommended

1. To discontinue Imatib until the absolute neutrophil count is ≥1500/µL and platelets are ≥75,000/µL;
2. Resume treatment with Imatib at the dose used prior to therapy interruption.
3. In case of a repeated decrease in neutrophil count <1000/µL and/or platelet count <50,000/µL, repeat the actions specified in point 1, and then resume treatment with Imatib at a reduced dose of 300 mg (in children – 260 mg/m²).

In the accelerated phase and blast crisis of CML in children and adults and in Ph+ ALL in adult patients (initial dose for adults – 600 mg, for children – 340 mg/m²) in case of a decrease in the absolute neutrophil count <500/µL and/or platelet count <10,000/µL after one or more months of treatment, it is recommended:

1. Check if the cytopenia is a consequence of leukemia (bone marrow examination);
2. If the cytopenia is not related to leukemia, reduce the dose of Imatib to 400 mg (in children – to 260 mg/m²);
3. If cytopenia persists for 2 weeks, reduce the dose to 300 mg (in children – to 200 mg/m²);
4. If cytopenia persists for 4 weeks and its relationship with leukemia is not confirmed, discontinue Imatib until the absolute neutrophil count is >1000/µL and platelets are >20,000/µL; then resume treatment with Imatib at a dose of 300 mg (in children – 260 mg/m²).

In inoperable, recurrent and/or metastatic protuberans dermatofibrosarcoma (initial dose of Imatib 800 mg) in case of a decrease in the absolute neutrophil count <1000/µL and/or platelet count <50,000/µL, it is recommended

1. To discontinue Imatib until the absolute neutrophil count is >1500/µL and platelets are >75,000/µL;
2. Resume treatment with Imatib at a dose of 600 mg.

In case of a repeated decrease in neutrophil count less than 1000/µL and/or platelet count less than 50,000/µL, repeat the actions specified in point 1, and then resume treatment with Imatib at a reduced dose of 400 mg.

Adverse Reactions

The safety profile of imatinib is well studied. Most patients experience some adverse events when using the drug. The most frequent adverse events (>10%) associated with the drug intake were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. Mainly these adverse events were mild or moderate in severity. Only 2-5% of patients discontinued imatinib therapy due to the development of adverse events.

Myelosuppression, gastrointestinal adverse events, edema, and rash occur with imatinib use both in CML and in malignant gastrointestinal stromal tumors. Myelosuppression develops more frequently in patients with CML, while gastrointestinal and intratumoral bleeding occur more frequently in patients with malignant gastrointestinal stromal tumors. Other gastrointestinal disorders, such as gastrointestinal obstruction, perforation, and ulceration, are more common in stromal tumors of the gastrointestinal tract. Other serious adverse events with imatinib use are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome, and growth retardation in children.

Dose adjustment of the drug is possible depending on the severity of adverse events, up to drug discontinuation.

In patients with CML and with inoperable and/or metastatic malignant gastrointestinal stromal tumors, the following adverse events were observed, listed below by organ systems with the frequency of their occurrence: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000, including isolated reports)

Infections and infestations: uncommon – herpes simplex, herpes zoster, nasopharyngitis, pneumonia¹, sinusitis, cellulitis, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rare – mycoses.

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

Blood and lymphatic system disorders: very common – neutropenia, thrombocytopenia, anemia; common – pancytopenia, febrile neutropenia; uncommon – thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy; rare – hemolytic anemia.

Metabolism and nutrition disorders: common – anorexia; uncommon – hypokalemia, increased or decreased appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rare – hyperkalemia, hypomagnesemia.

Psychiatric disorders: common – insomnia; uncommon – depression, anxiety, decreased libido; rare – confusion.

Nervous system disorders very common – headache²; common – dizziness, paresthesia, taste disturbance, hypesthesia; uncommon – migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rare – increased intracranial pressure, convulsions, optic neuritis.

Eye disorders: common – periorbital edema, increased lacrimation, subconjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; uncommon – eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rare – cataract, papilledema, glaucoma.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus, hearing loss.

Cardiac disorders: uncommon – palpitations, chronic³ heart failure, pulmonary edema, tachycardia, flushing⁴; rare – arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, angina pectoris, pericardial effusion, hematomas.

Vascular disorders: uncommon – hemorrhages⁴; rare – hematomas, cold extremities, increased blood pressure, decreased blood pressure, Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders: common – epistaxis, dyspnea, cough; uncommon – pleural effusion⁵, pharyngeal or laryngeal pain, pharyngitis; rare – pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, dyspepsia, abdominal pain⁶; common – abdominal distension, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; uncommon – stomatitis, mouth ulceration, gastrointestinal bleeding⁷, eructation, melena, esophagitis, ascites, gastric ulcer, hematemesis, cheilitis, dysphagia, pancreatitis; rare – colitis, paralytic/obstructive ileus, enterocolitis.

Hepatobiliary disorders: common – increased liver enzymes; uncommon – jaundice, hepatitis, hyperbilirubinemia; rare – hepatic failure⁹, liver necrosis⁹.

Skin and subcutaneous tissue disorders: very common – periorbital edema, dermatitis, eczema, skin rash; common – facial edema, pruritus, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; uncommon – pustular rash, petechiae, hyperhidrosis, urticaria, ecchymosis, increased tendency to bruise, easy bruising, hypotrichosis, skin hyperpigmentation/hypopigmentation, exfoliative dermatitis, nail disorder, folliculitis, psoriasis, purpura, bullous rash; rare – acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioedema, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis.

Musculoskeletal and connective tissue disorders: very common – muscle spasms and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain⁸; common – joint swelling; uncommon – muscle and joint stiffness; rare – muscle weakness, arthritis; frequency unknown – growth retardation in children.

Renal and urinary disorders: uncommon – renal pain, hematuria, acute renal failure, pollakiuria.

Endocrine, reproductive system and breast disorders: uncommon – gynecomastia, erectile dysfunction, menorrhagia, menstrual cycle disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema.

General disorders and administration site conditions: very common – fluid retention and edema, fatigue, weight gain; common – asthenia, pyrexia, anasarca, chills, tremor, weight loss; uncommon – chest pain, malaise.

Investigations: uncommon – increased alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and serum creatinine; rare – increased plasma amylase.

¹ Pneumonia is most frequently observed in patients with CML in accelerated phase, blast crisis and with inoperable and/or metastatic malignant gastrointestinal stromal tumors;

² Headache is most frequently observed in patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors;

³ Cardiac adverse events, including chronic heart failure, were observed more frequently in patients with CML in accelerated phase and blast crisis compared to patients with CML in chronic phase (observation period 1 year);

⁴ Flushing was most frequently observed in patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors; bleeding (hematomas, hemorrhages) are most frequently observed in patients with CML in accelerated phase, blast crisis and with inoperable and/or metastatic malignant gastrointestinal stromal tumors;

⁵ Pleural effusion is observed more frequently in patients with CML in accelerated phase and blast crisis compared to patients with CML in chronic phase (observation period 1 year);

^6/7 Abdominal pain and gastrointestinal bleeding were most frequently observed in patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors;

⁸Musculoskeletal pain, including myalgia, arthralgia, bone pain, were observed more frequently in patients with CML compared to patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors;

⁹Isolated cases of hepatic failure and liver necrosis have been reported.

During the use of imatinib in clinical practice, as well as during additional clinical studies, the following adverse events were observed, listed below by organ systems with the frequency of their occurrence: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated reports).

Nervous system disorders: uncommon – brain edema.

Eye disorders: rare – vitreous hemorrhage.

Cardiac and vascular disorders: uncommon — thrombosis/embolism; rare – pericarditis; cardiac tamponade; very rare – anaphylactic shock.

Respiratory, thoracic and mediastinal disorders: uncommon – acute respiratory failure¹, interstitial pneumonia.

Gastrointestinal disorders: uncommon – ileus (intestinal obstruction), gastrointestinal tumor bleeding, gastrointestinal tumor necrosis, gastrointestinal perforation²; rare —diverticulitis.

Skin and subcutaneous tissue disorders: uncommon – palmar-plantar erythrodysesthesia; rare – lichenoid keratosis, lichen planus; very rare – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: rare avascular necrosis/osteonecrosis of the femoral head, rhabdomyolysis/myopathy.

Reproductive system disorders: uncommon – decreased potency; very rare – in women, bleeding from a corpus luteum/ovarian cyst.

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

²Isolated cases of gastrointestinal perforations with fatal outcome have been reported.

Description of selected adverse reactions

Hematopoietic suppression

The frequency of hematopoietic suppression and its severity were maximal when the drug was used in high doses and, apparently, depended on the stage of CML. In general, hematopoietic suppression during imatinib use in CML patients was reversible and in most cases did not require drug discontinuation or dose reduction. Discontinuation of the drug was required in a small number of cases. Such phenomena as pancytopenia, lymphopenia and bone marrow depression were also noted.

Hemorrhage/bleeding

The most frequent clinically significant bleedings were gastrointestinal bleedings. They occurred most often in patients with late stages of CML and in patients with malignant gastrointestinal stromal tumors, in whom they may be a consequence of the underlying disease (tumor bleeding due to tumor necrosis). In CML patients whose hematopoiesis was already suppressed before the start of treatment, hemorrhages in the CNS or gastrointestinal tract are also often observed during treatment. It is well established that patients with leukemias with acute onset of the disease often experience bleeding/hemorrhage due to thrombocytopenia or thrombocytopathy.

Edema and fluid retention

Edema is a frequent side effect of imatinib. The frequency of edema in patients receiving Imatinib for all indications is more than 50%. The frequency and severity of edema are dose-dependent and apparently correlate with the plasma concentration of the drug. Periorbital edema occurs most often, with slightly less frequency – edema of the lower extremities. Specific treatment is usually not required. In patients with edema and fluid retention, heart failure is rare. In patients with late stages of CML, the frequency of heart failure was higher than in patients of other categories, which can be explained by their generally weakened condition. The same trend was observed regarding renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention were elderly (>65 years).

Rash and severe skin adverse reactions

A number of patients receiving Imatinib experienced generalized erythematous, maculopapular and pruritic rash, which could resolve on its own despite continued treatment with the drug. Some patients experienced pruritus not accompanied by a rash; in some cases, erythroderma was present. Rash was observed in approximately 1/3 of all patients receiving Imatinib for all indications. Often the rash is accompanied by itching and usually manifests as erythematous, maculopapular lesions on the forearm, trunk, or face. Although in most cases the rash is mild and resolves without treatment, in more severe cases temporary or complete discontinuation of the drug may be required. As a rule, the severity of the rash decreases after the appointment of antihistamines and topical corticosteroids. In some cases, systemic corticosteroids are required.

Hepatotoxicity

The drug may have a toxic effect on the liver. Abnormalities in biochemical parameters of liver function usually consist of a slight increase in transaminase activity and an increase in serum bilirubin concentration. The toxic effect on the liver usually manifests within the first 2 months of treatment, but in some cases it manifested 6-12 months after the start of treatment. As a rule, after drug discontinuation, biochemical parameters of liver function normalize within 1-4 weeks.

Cases of cytolytic and cholestatic hepatitis and liver failure have been observed, in some cases with fatal outcome.

Obstruction, perforation or ulcer of the stomach or intestine

A small proportion of patients receiving Imatinib experienced gastrointestinal ulceration, which in some cases may be a consequence of the local irritating effect of imatinib. Hemorrhagic tumor necrosis, as well as gastrointestinal obstruction and perforation, were most frequently observed in patients with malignant gastrointestinal stromal tumors. In the case of metastatic stromal tumors of the gastrointestinal tract, tumor necrosis can occur against the background of tumor response, which in rare cases leads to perforation. Gastrointestinal obstruction most often occurred in patients with malignant gastrointestinal stromal tumors, in whom it can be caused by metastases or adhesions resulting from previous gastrointestinal surgery (when the drug is used as an adjuvant therapy).

Severe adverse events from the respiratory system

Severe (sometimes fatal) adverse events were observed during imatinib intake, namely: acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. Comorbidities of the cardiovascular or respiratory systems may exacerbate the severity of adverse events.

Contraindications

• Children under 2 years of age (efficacy and safety have not been established to date);
• Pregnancy;
• Breastfeeding period;
• Hypersensitivity to imatinib or any other component of the drug.

With caution Imatib should be prescribed to patients with severe hepatic insufficiency, severe renal impairment, cardiovascular diseases or in the presence of risk factors for the development of heart failure, as well as during regular hemodialysis procedure.

Use in Pregnancy and Lactation

The use of imatinib is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Since Imatinib is metabolized mainly in the liver, patients with mild, moderate or severe liver impairment should be prescribed Imatib at a minimum daily dose of 400 mg. If adverse toxic effects develop, the drug dose should be reduced. The drug should be prescribed with caution to patients with severe hepatic insufficiency.

Use in Renal Impairment

The kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with renal impairment or in patients requiring systematic hemodialysis, treatment with Imatib should be started at the minimum effective dose of 400 mg once/day, with caution. If Imatib is not tolerated, the initial dose of the drug may be reduced; if the efficacy is insufficient, it may be increased. Imatib should be prescribed with caution to patients with severe renal impairment.

Pediatric Use

Contraindication: children under 2 years of age (efficacy and safety have not been established to date).

Experience with Imatib in children with CML under 2 years of age is limited; experience with the drug for other indications is limited in patients under 18 years of age. The long-term effects of prolonged exposure to Imatib on growth in children are unknown.

However, since there are reports of growth retardation, careful monitoring of growth is recommended in children taking Imatinib.

Geriatric Use

No dose adjustment of the drug is required in elderly patients.

Special Precautions

Treatment with Imatib should be carried out only under the supervision of a physician experienced in the use of anticancer drugs.

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

Experience with Imatib in children with CML under 2 years of age is limited; experience with the drug for other indications is limited in patients under 18 years of age. The long-term effects of prolonged exposure to Imatib on growth in children are unknown.

However, since there are reports of growth retardation, careful monitoring of growth is recommended in children taking Imatinib.

During treatment with Imatib, it is recommended to regularly perform clinical blood tests and monitor liver function (transaminases, bilirubin, ALP).

Patients with heart and kidney diseases should be carefully monitored.

Since marked fluid retention is observed in 1-2% of cases with the use of Imatib, it is recommended to regularly monitor patients’ body weight.

In case of rapid, unexpected weight gain, the patient should be examined and, if necessary, therapy with Imatib should be temporarily discontinued and/or diuretics prescribed.

The highest frequency of fluid retention is noted in elderly patients with concomitant cardiovascular diseases.

In some cases, marked fluid retention can have a severe course with a fatal outcome. A patient death was reported during drug use in a patient with blast crisis and complex symptomatology: pleural effusion, congestive heart and renal failure.

When using the drug in patients with liver diseases, regular clinical blood tests and determination of liver enzyme activity should be performed.

Since there are reports of hypothyroidism development during imatinib use in patients who have undergone thyroidectomy and are receiving replacement therapy with levothyroxine sodium, regular determination of thyroid-stimulating hormone concentration is necessary in this category of patients.

In patients with hypereosinophilic syndrome and heart diseases, isolated cases of cardiogenic shock/left ventricular failure have been observed at the start of imatinib therapy.

These adverse events are resolved after administration of systemic corticosteroids, measures aimed at maintaining circulation, and temporary withdrawal of Imatib.

In patients with MDS/MPN and a high level of eosinophils, an ECG study and determination of serum cardiac-specific troponin concentration should be performed.

If abnormalities are detected, the possibility of prophylactic use of systemic corticosteroids (1-2 mg/kg) for 1-2 weeks simultaneously with imatinib should be considered at the start of therapy.

In patients with inoperable and/or metastatic malignant gastrointestinal stromal tumors in clinical studies, bleeding of various locations was noted in 12.9% of cases; gastrointestinal bleeding was noted in 8 patients (5.4%), bleeding from tumor foci – in 4 patients (2.7%).

Bleeding was observed both in abdominal organs and in the liver, depending on the location of the tumor foci.

It is necessary to monitor the condition of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors at the start of imatinib therapy.

During therapy with Imatib and for at least 3 months thereafter, reliable methods of contraception should be used.

Marked increase in liver transaminase activity or bilirubin was observed in less than 3% of patients with CML and was usually controlled by dose reduction or temporary interruption of treatment (the average duration of such episodes was about 1 week).

Due to the risk of tumor lysis syndrome, clinically significant dehydration and elevated uric acid levels in patients should be corrected if necessary before prescribing Imatib.

Effect on ability to drive vehicles and operate machinery

Some side effects of the drug, such as dizziness and blurred vision, may negatively affect the ability to drive vehicles and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

In this regard, patients taking Imatib should exercise increased attention and caution when driving vehicles and performing potentially hazardous activities.

Overdose

Experience with Imatib in doses exceeding therapeutic doses is limited. Cases of imatinib overdose have been reported in clinical practice. In general, the outcome of overdose was favorable (improvement in the patients’ condition was noted). An antidote to imatinib is not known. In case of overdose, medical observation and symptomatic therapy are recommended.

Symptoms of overdose in adults

When taking Imatib at a dose of 1200-1600 mg for 1-10 days, nausea, vomiting, diarrhea, rash, erythema, edema, swelling mainly of the face, increased fatigue, muscle spasms, thrombocytopenia, abdominal pain, headache, and decreased appetite were observed.

When taking imatinib at a dose of 1800-3200 mg (the highest dose was 3200 mg/day for 6 days), weakness, myalgia, increased blood activity of CPK, bilirubin concentration, and gastrointestinal pain were noted.

When using imatinib at a single dose of 6400 mg (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, decreased neutrophil count, and increased liver transaminase activity.

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

Symptoms of overdose in children and adolescents

When taking imatinib at a single dose of 400 mg in a 3-year-old child, vomiting, diarrhea, and anorexia were noted. In another case, when taking imatinib at a single dose of 980 mg in a 3-year-old child, diarrhea and a decrease in leukocyte count were observed.

Drug Interactions

With simultaneous use of Imatib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin), slowing of imatinib metabolism and an increase in its plasma concentration are possible. Caution is required when using Imatib concomitantly with drugs that are inhibitors of CYP3A4 isoenzymes.

Conversely, simultaneous use of drugs that are inducers of the CYP3A4 isoenzyme (for example, dexamethasone, rifampicin, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidone, or medicines containing St. John’s wort) may lead to accelerated metabolism of imatinib and, consequently, a decrease in its plasma concentration.

With simultaneous use of imatinib and simvastatin, an increase in C_max and AUC by 2 and 3.5 times, respectively, was noted, which is a consequence of inhibition of the CYP3A4 isoenzyme by imatinib. Caution is recommended when using Imatib concomitantly with drugs that are substrates of the CYP3A4 isoenzyme and have a narrow therapeutic range (for example, cyclosporine and pimozide). Imatib may increase serum concentrations of other drugs metabolized by the CYP3A4 isoenzyme (triazolobenzodiazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the CYP2C9 and CYP2C19 isoenzymes in vitro. When Imatib was used concomitantly with warfarin, prolongation of prothrombin time was observed. With simultaneous use with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of therapy with the drug, as well as when changing the dosing regimen of Imatib. As an alternative to warfarin, the use of low molecular weight heparins should be considered.

When combining Imatib with chemotherapeutic drugs in high doses, transient hepatic toxicity in the form of increased liver transaminase activity and hyperbilirubinemia may develop.

When combining imatinib and chemotherapy regimens that may potentially cause liver function impairment, liver function monitoring should be provided.

In vitro, Imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations at which it inhibits the CYP3A4 isoenzyme. When using Imatib at a dose of 400 mg twice/day concomitantly with metoprolol, a substrate of the CYP2D6 isoenzyme, a moderate decrease in metoprolol metabolism was noted, accompanied by an increase in C_max and AUC by approximately 21%. Given the moderate enhancement of the effects of drugs that are substrates of the CYP2D6 isoenzyme (for example, metoprolol) when used concomitantly with imatinib, no change in dosing regimen is required.

In vitro, Imatinib inhibits the O-glucuronidation of paracetamol. A case of acute liver failure with fatal outcome has been described with simultaneous use of imatinib and paracetamol. Caution should be exercised when using imatinib concomitantly with paracetamol.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.