Imatinib grindex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMATINIB GRINDEKS (IMATINIB GRINDEKS)

Composition:

Active substance: imatinib (imatinib);

Each hard capsule contains 100 mg of imatinib (as imatinib mesylate);

Excipients: Prosolv (microcrystalline cellulose, colloidal anhydrous silicon dioxide), crospovidone, talc, magnesium stearate;

Capsule shell (body and cap): iron oxide red (E 172), iron oxide yellow (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: Hard gelatin capsules of brown-orange color. The capsule contents are a powder ranging from white to light yellow or yellowish-brown.

Pharmacotherapeutic group. Antineoplastic agents, tyrosine kinase inhibitors BCR-ABL. ATC code L01E A01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Imatinib is a low-molecular-weight inhibitor of protein tyrosine kinases that strongly inhibits Bcr-Abl tyrosine kinase (TK), as well as several receptor tyrosine kinases: Kit, stem cell factor receptor (SCF - Stem Cell Factor), encoded by the c-Kit proto-oncogene, discoidin domain receptors (DDR1 and DDR2), colony-stimulating factor-1 receptor (CSF-1R), and alpha- and beta-platelet-derived growth factor receptors (alpha-PDGFR and beta-PDGFR). Imatinib may also inhibit cellular processes mediated by activation of these receptor kinases.

Pharmacodynamic Effects

Imatinib is a protein tyrosine kinase inhibitor that potently inhibits Bcr-Abl tyrosine kinase activity in vitro at the cellular level and in vivo. This compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl-positive cell lines, as well as in freshly isolated leukemic cells from patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+) and acute lymphoblastic leukemia.

In vivo, the compound demonstrates antitumor activity as monotherapy in animal models of Bcr-Abl-positive tumor cells.

Additionally, imatinib is a potent inhibitor of the tyrosine kinase receptor for platelet-derived growth factor (PDGF) (Platelet-derived Growth Factor - PDGF), PDGF-R, and stem cell factor (SCF) receptor c-Kit, and it inhibits PDGF- and SCF-mediated cellular changes. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells that express an activating kit mutation.

Constitutive activation of the PDGF receptor or Bcr-Abl protein tyrosine kinase results from chromosomal translocations or overproduction of PDGF and has been implicated in the pathogenesis of myelodysplastic/myeloproliferative diseases (MDS/MPD), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and dermatofibrosarcoma protuberans (DFSP). Imatinib inhibits aberrant signal transduction and cellular proliferation caused by dysregulated activity of PDGFR and Abl kinases, including de-regulated PDGFR signaling and Bcr-Abl tyrosine kinase activity.

The efficacy of the drug is based on standard hematological and cytogenetic response rates and progression-free survival in chronic myeloid leukemia (CML), standard hematological and cytogenetic response rates in Ph+ ALL (acute lymphoblastic leukemia), MDS/MPD (myelodysplastic/myeloproliferative disorders), and objective responses in GIST and unresectable DFSP (dermatofibrosarcoma protuberans).

Pharmacokinetics

The effects of imatinib were studied following administration in doses ranging from 25 to 1000 mg. Pharmacokinetic profiles were analyzed on Day 1 and on Day 7 or Day 28, when steady-state plasma concentrations of imatinib were achieved.

Absorption

The mean absolute bioavailability of the drug is 98%.

The coefficient of variation for imatinib plasma AUC varies among patients after oral administration.

When administered with a high-fat meal compared to fasting conditions, there is a slight reduction in the extent of absorption (an 11% decrease in Cmax and a 1.5-hour prolongation of tmax, with a minor 7.4% reduction in AUC).

The effect of prior gastrointestinal surgery on the absorption of the drug has not been studied.

Distribution

In vitro studies indicate that at clinically relevant concentrations, approximately 95% of imatinib is bound to plasma proteins (primarily to albumin and alpha-1 acid glycoprotein, to a lesser extent to lipoproteins).

Metabolism

The major circulating metabolite of imatinib is the N-demethylated piperazine derivative, which demonstrates in vitro potency similar to that of the parent compound. The plasma AUC of this metabolite is only 16% of the AUC for imatinib. Plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.

Imatinib and its N-demethylated metabolite together account for approximately 65% of circulating radioactivity (AUC (0–48)). The remainder of circulating radioactivity consists of numerous minor metabolites.

In vitro studies have shown that CYP3A4 is the primary human P450 enzyme responsible for the biotransformation of imatinib. Among potential concomitant medications (acetaminophen, acyclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V), only erythromycin (IC50 50 μM) and fluconazole (IC50 118 μM) demonstrated inhibitory effects on imatinib metabolism that may have clinical significance.

In vitro, imatinib has been shown to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6, and CYP3A4/5. The Ki values in human liver microsomes were 27, 7.5, and 7.9 μmol/L, respectively. The maximum plasma concentration of imatinib in patients is 2–4 μmol/L; therefore, inhibition of CYP2D6 and/or CYP3A4/5 metabolism of concomitantly administered drugs is possible. Imatinib does not interfere with the biotransformation of 5-fluorouracil but inhibits the metabolism of paclitaxel due to competitive inhibition of CYP2C8 (Ki = 34.7 μM). This Ki value is significantly higher than the expected plasma concentration of imatinib in patients; therefore, no interaction is anticipated when 5-fluorouracil or paclitaxel is co-administered with imatinib.

Elimination

Following oral administration of 14C-labeled imatinib, approximately 81% of the dose is eliminated within 7 days, with 68% excreted in feces and 13% in urine. About 25% of the dose is excreted unchanged (5% in urine, 20% in feces). The remainder is eliminated as metabolites.

Plasma Pharmacokinetics

The elimination half-life (t1/2) of imatinib in healthy volunteers is approximately 18 hours, supporting the feasibility of once-daily dosing. Over the dose range of 25 to 1000 mg, there is a direct linear relationship between AUC and dose. With repeated once-daily dosing, the pharmacokinetics of imatinib remain unchanged, and accumulation at steady state is 1.5 to 2.5 times the initial value.

Pharmacokinetics in Patients with Gastrointestinal Stromal Tumors (GIST)

In patients with GIST, exposure to imatinib is 1.5 times higher than in patients with CML when the same dose (400 mg) is administered. Preliminary pharmacokinetic analysis in GIST patients identified three variables (albumin, white blood cell count, and bilirubin) statistically associated with imatinib pharmacokinetics. Decreased albumin levels lead to reduced clearance (CL/F), as does a higher white blood cell count, resulting in reduced CL/F. However, these factors are not considered clinically significant enough to warrant dose adjustments. In this patient group, liver metastases may potentially lead to hepatic insufficiency and reduced metabolism.

Population Pharmacokinetics

Pharmacokinetic data in patients with CML show a minor effect of age on volume of distribution (a 12% increase in patients aged 65 years and older). This change is not considered clinically significant. There is a slight effect of body weight on imatinib clearance: for patients weighing 50 kg, the average clearance is 8.5 L/h, increasing to 11.8 L/h for patients weighing 100 kg. These changes are not sufficient to justify body weight-based dose adjustments. Imatinib pharmacokinetics are not influenced by gender.

Pharmacokinetics in Children

As in adults, imatinib is rapidly absorbed after oral administration in children in both phases of clinical trials. Doses of 260 and 340 mg/m²/day in children achieve plasma exposure comparable to 400 mg and 600 mg doses in adults, respectively. Comparison of AUC(0–24) on Day 8 versus Day 1 at a dose of 340 mg/m²/day showed a 1.7-fold accumulation after repeated once-daily dosing.

Based on a population pharmacokinetic analysis in children with hematologic disorders (CML, Ph+ ALL, or other hematologic disorders treated with imatinib), imatinib clearance increases with increasing body surface area. After adjusting for body surface area, other demographic factors such as age, body weight, and body mass index do not have clinically significant effects on imatinib exposure. The analysis confirms that imatinib exposure in children receiving 260 mg/m² once daily (without exceeding 400 mg once daily) or 340 mg/m² (without exceeding 600 mg once daily) is similar to that in adults receiving 400 mg or 600 mg once daily.

Patients with Organ Impairment

Imatinib and its metabolites are not significantly excreted by the kidneys. Patients with mild to moderate renal impairment have higher plasma exposure than those with normal renal function. The increase is approximately 1.5 to 2-fold, corresponding to a 1.5-fold increase in plasma alpha-1 acid glycoprotein levels, to which imatinib is highly bound. The clearance of free drug for imatinib is likely similar in patients with renal impairment and those with normal renal function, as renal excretion is a minor elimination pathway for imatinib.

Although pharmacokinetic analyses showed considerable inter-individual variability, mean imatinib exposure was not increased in patients with various degrees of hepatic impairment compared to patients with normal liver function.

Clinical characteristics.

Indications.

Imatinib Grynidex is indicated for:

• treatment of patients (adults and children) with newly diagnosed Philadelphia chromosome-positive (Ph+) (with bcr-abl in leukocytes) chronic myeloid leukemia (CML), for whom bone marrow transplantation is not considered as first-line therapy;
• treatment of patients (adults and children) with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in the accelerated phase, or in blast crisis;
• in combination chemotherapy for patients (adults and children) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with presence of the Philadelphia chromosome in leukocytes;
• as monotherapy in adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL);
• treatment of adults with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangement;
• treatment of adults with progressive hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα gene rearrangement;
• treatment of adult patients with Kit (CD117)-positive, inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST);
• adjuvant therapy in adult patients who are at high risk of recurrence of Kit (CD117)-positive malignant gastrointestinal stromal tumors (GIST) after resection (patients at low or minimal risk may not require adjuvant therapy);
• treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) that cannot be surgically removed.

The effect of imatinib on the outcome of bone marrow transplantation has not been established.

In adults and children, the efficacy of imatinib is based on data regarding the rates of overall hematologic and cytogenetic response and progression-free survival in CML, rates of hematologic and cytogenetic response in Ph+ ALL, MDS/MPD, rates of hematologic response in HES/CEL, and rates of objective response in adult patients with inoperable and/or metastatic GIST and DFSP, as well as progression-free survival in adjuvant therapy of GIST patients. Experience with imatinib in patients with MDS/MPD associated with PDGFR gene rearrangement is very limited. Except for newly diagnosed CML in chronic phase, controlled studies demonstrating clinical benefit or increased survival have not been conducted for these conditions.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.

Medicinal products that may increase imatinib plasma concentrations

Substances that inhibit the activity of CYP3A4 isoenzyme of cytochrome P450 (e.g., protease inhibitors such as indinavir, lopinavir/ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungal agents including ketoconazole, itraconazole, posaconazole, voriconazole; macrolides such as erythromycin, clarithromycin, telithromycin) may reduce metabolism and increase imatinib plasma concentrations. A significant increase in imatinib concentration (mean Cmax and AUC increased by 26% and 40%, respectively) was observed in healthy volunteers when the drug was administered concomitantly with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be exercised when prescribing imatinib concomitantly with CYP3A4 inhibitors.

Medicinal products that may decrease imatinib plasma concentrations

Substances that are inducers of CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, or Hypericum perforatum, also known as St. John's wort) may significantly reduce imatinib plasma concentrations, potentially increasing the risk of treatment failure.

When multiple doses of rifampicin (600 mg) were administered prior to a single dose of imatinib 400 mg, a reduction in maximum concentration (Cmax) and area under the concentration-time curve from 0 to ∞ (AUC0-∞) by 54% and 74%, respectively, was observed compared to values without rifampicin administration. Similar results were observed in patients with malignant glioma receiving imatinib while taking enzyme-inducing antiepileptic drugs such as carbamazepine, oxcarbazepine, and phenytoin. The AUC of imatinib in plasma was reduced by 73% compared to patients not taking enzyme-inducing antiepileptic drugs. Concomitant use of rifampicin or other potent CYP3A4 inducers with imatinib should be avoided.

Medicinal products whose concentrations may be altered by imatinib

Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2-fold and 3.5-fold, respectively, indicating CYP3A4 inhibition by imatinib. Therefore, caution is advised when co-administering imatinib with CYP3A4 substrates that have a narrow therapeutic index (such as cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase plasma concentrations of other medicinal products metabolized by CYP3A4 (triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors such as statins, etc.).

Due to the known increased risk of bleeding associated with imatinib use (e.g., hemorrhage), patients requiring anticoagulants should receive low molecular weight heparin or standard heparin rather than coumarin derivatives such as warfarin.

In vitro, imatinib inhibits the activity of CYP2D6 isoenzyme of cytochrome P450 at concentrations similar to those affecting CYP3A4 activity. Imatinib at a dose of 400 mg twice daily exerts an inhibitory effect on CYP2D6-mediated metabolism of metoprolol, increasing the Cmax and AUC of metoprolol by approximately 23% (90% CI [1.16–1.30]). Dose adjustment is apparently not required when imatinib is co-administered with CYP2D6 substrates, but caution is recommended with CYP2D6 substrates having a narrow therapeutic range, such as metoprolol. For patients taking metoprolol, clinical monitoring should be considered.

In vitro, imatinib inhibits O-glucuronidation of paracetamol (Ki value 58.5 µmol/L). This inhibition was not observed in vivo after administration of 400 mg imatinib and 1000 mg paracetamol. High doses of imatinib and paracetamol have not been studied.

Therefore, caution is required when administering high doses of imatinib concomitantly with paracetamol.

In patients after thyroidectomy taking levothyroxine, plasma exposure to levothyroxine may be reduced when imatinib is co-administered. Caution is recommended in such cases. However, the mechanism of this interaction is currently unknown.

There is clinical experience with concomitant use of imatinib and chemotherapy in patients with Ph+ ALL, but the interaction characteristics between imatinib and chemotherapy regimens are not fully defined. Adverse effects of imatinib may be intensified, particularly hepatotoxicity, myelosuppression, or others; concomitant use of L-asparaginase has also been reported to enhance liver toxicity. Therefore, the use of imatinib in combination regimens requires precautionary measures.

Special precautions for use.

There is a potential for interaction when imatinib is prescribed concomitantly with other medicinal products. Caution should be exercised when using imatinib with protease inhibitors, azole antifungal agents, certain macrolides (see section "Interaction with other medicinal products and other forms of interaction"), substrates of CYP3A4 with a narrow therapeutic range (such as cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine), or warfarin and other coumarin derivatives.

When imatinib is administered concomitantly with medicinal products that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or St. John's wort), exposure to imatinib may be significantly reduced, potentially increasing the risk of treatment failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided.

Hypothyroidism

Clinical cases of hypothyroidism have been reported in patients following thyroidectomy who were receiving levothyroxine replacement therapy during imatinib treatment. In such patients, thyroid-stimulating hormone (TSH) levels should be carefully monitored.

Hepatotoxicity

Imatinib is primarily metabolized in the liver, with only 13% metabolized by the kidneys. Patients with hepatic dysfunction (mild, moderate, or severe) should be closely monitored for peripheral blood counts and liver enzymes. It should be noted that patients with GIST may have liver metastases, which could lead to hepatic insufficiency.

Hepatic injury, including hepatic failure and liver necrosis, has been observed.

Severe liver function abnormalities have been observed during combined therapy with imatinib and high-dose chemotherapy agents. Liver function should be carefully monitored, as imatinib in combination with chemotherapy may lead to hepatic dysfunction.

Fluid retention

Cases of pronounced fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial edema) have been reported in approximately 2.5% of patients with newly diagnosed CML who received imatinib. Therefore, regular monitoring of patients' body weight is recommended. In case of sudden rapid weight gain, a thorough patient evaluation should be performed, and appropriate supportive and therapeutic measures initiated if necessary. During clinical trials, increased frequency of such events was observed in elderly patients and patients with a history of cardiovascular disease. Therefore, caution is recommended when using imatinib in patients with cardiac dysfunction.

Patients with heart disease

Patients with cardiac disease, risk factors for heart failure, or a history of renal insufficiency should be closely monitored. Patients exhibiting any signs or symptoms suggestive of cardiac or renal failure should be thoroughly evaluated and appropriate therapy initiated.

In patients with hypereosinophilic syndrome (HES) with occult myocardial infiltration by HES cells, isolated cases of cardiogenic shock/left ventricular dysfunction associated with HES cell degranulation have been observed prior to initiation of imatinib therapy. These events were reversible with systemic steroids, hemodynamic support measures, and temporary discontinuation of imatinib. Rare adverse cardiac reactions have been observed during imatinib therapy; therefore, benefit-risk assessment of imatinib therapy should be carefully performed in the HES/CEL population prior to treatment initiation. Myelodysplastic/myeloproliferative disorders with PDGFR gene rearrangement may be associated with high levels of eosinophilia. Patients with HES/CEL and patients with MDS/MPD associated with high levels of eosinophilia should be evaluated by a cardiologist, undergo echocardiography, and have serum troponin levels determined before starting imatinib therapy. If pathological reactions occur, cardiology monitoring and prophylactic use of systemic steroids (1–2 mg/kg) for 1–2 weeks as concomitant therapy with imatinib during the initial treatment phase are recommended.

Gastrointestinal hemorrhage

During studies in patients with unresectable and/or metastatic GIST, gastrointestinal and intratumoral hemorrhages were reported. Based on available data, no predisposing factors (e.g., tumor size and location, coagulation disorders) have been identified that increase the risk of any type of hemorrhage in GIST patients. Since increased vascularity and bleeding tendency are part of the clinical presentation and course of GIST, standard practices and procedures for monitoring and managing all patients with hemorrhage should be applied.

Additionally, during post-marketing surveillance, gastric antral vascular ectasias, a rare cause of gastrointestinal bleeding, have been reported in patients with CML, ALL, and other conditions. If necessary, discontinuation of imatinib may be considered.

Tumor lysis syndrome

Due to the potential for tumor lysis syndrome, clinically evident dehydration and elevated uric acid levels should be corrected prior to initiation of imatinib therapy.

Hepatitis B reactivation

Reactivation of hepatitis B virus has been observed in patients who are chronic carriers of hepatitis B virus following treatment with Bcr-Abl tyrosine kinase inhibitors. In some cases, acute liver failure or fulminant hepatitis requiring liver transplantation, or resulting in fatal outcome, has occurred.

Before initiating imatinib therapy, patients should be tested for hepatitis B virus (HBV) infection. Patients with positive serological testing for hepatitis B (including active infection) before starting therapy, and patients with positive HBV infection tests during treatment, should be referred to specialists in liver disease and hepatitis B management. Patients who are carriers of hepatitis B virus and require imatinib treatment should be closely monitored for signs and symptoms of active infection both during and for several months after completion of therapy.

Photosensitivity

Exposure to direct sunlight should be minimized or avoided due to the risk of photosensitivity associated with imatinib use. Patients should be informed about preventive measures such as wearing protective clothing and applying sunscreen with a high sun protection factor (SPF).

Thrombotic microangiopathy

BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including case reports with imatinib. If a patient receiving imatinib develops laboratory or clinical signs suggestive of TMA, treatment should be discontinued and a thorough evaluation for TMA should be performed, including ADAMTS13 activity and anti-ADAMTS13 antibody testing. Imatinib therapy should not be resumed if anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity.

Laboratory tests

Complete blood counts should be performed regularly during imatinib therapy. Treatment of patients with chronic myeloid leukemia (CML) with imatinib is associated with the development of neutropenia or thrombocytopenia. However, the occurrence of these cytopenias depends on the disease phase during which treatment is administered and is more frequent in patients with CML in the accelerated phase or blast crisis compared to those in the chronic phase. Treatment with imatinib may be interrupted or the dose reduced in case of neutropenia or thrombocytopenia (see section "Dosage and administration").

Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib.

Patients with impaired renal function have higher plasma exposure to imatinib than those with normal renal function, possibly due to increased plasma levels of alpha-1 acid glycoprotein, a protein that binds imatinib. Patients with renal impairment should receive the lowest initial dose. Caution should be exercised when treating patients with severe renal insufficiency. In case of intolerance, the dose should be reduced (see section "Dosage and administration").

Long-term imatinib therapy may be associated with clinically significant decline in renal function. Therefore, renal function should be assessed before starting imatinib therapy and carefully monitored during treatment, with special attention to patients at risk of renal impairment. If renal dysfunction occurs, appropriate care and treatment should be provided according to standard guidelines.

Children

Cases of growth retardation have been reported in children and prepubertal children receiving imatinib. In an observational study in the pediatric CML population, statistically significant reductions in height standard deviation scores (but not clinically significant) were reported at 12 and 24 months of treatment in two small subgroups, regardless of sexual maturity status and gender. Similar results were reported in an observational study in the pediatric ALL population. Therefore, careful monitoring of growth in children receiving imatinib is recommended.

Use during pregnancy or breastfeeding.

Women of reproductive potential.

Women of reproductive potential are advised to use effective contraception during treatment and for at least 15 days after discontinuation of imatinib therapy.

Pregnancy.

The amount of data on imatinib use during pregnancy is limited. Post-marketing reports include spontaneous abortions and congenital defects in newborns of women who used imatinib. Animal studies have shown reproductive toxicity, but the potential risk to the fetus is unknown. The drug may be used during pregnancy only if clearly necessary. If use during pregnancy is required, the patient should be informed of the potential risk to the fetus.

Breastfeeding.

Limited information is available on the passage of imatinib into human breast milk. Studies in two breastfeeding women confirmed that both imatinib and its active metabolite can pass into breast milk. In one study, the ratio of imatinib and its metabolite concentrations in breast milk to plasma was 0.5 and 0.9, respectively, indicating greater transfer of the metabolite into breast milk. Considering the total concentration of imatinib and its metabolite and the maximum amount of breast milk ingested by the infant, the expected total drug exposure is low (~10% of the therapeutic dose). However, since the effects of low doses of imatinib on infants are unknown, breastfeeding is not recommended for women taking imatinib during treatment and for at least 15 days after discontinuation of imatinib therapy.

Fertility.

In preclinical studies, fertility in male and female rats was not increased, although effects on reproductive parameters were observed. Clinical studies evaluating the effect of imatinib on fertility and gametogenesis have not been conducted. If a patient has concerns regarding the effect of imatinib on fertility, they should consult their physician.

Ability to affect reaction speed when driving or operating machinery.

Patients should be aware of the possibility of developing adverse effects such as dizziness, blurred vision, or somnolence when taking imatinib. Therefore, patients should be advised to exercise caution when driving or operating machinery.

Method of Administration and Dosage

Treatment should be prescribed by a physician experienced in managing patients with malignant hematological disorders and malignant tumors.

The drug should be taken orally during a meal, with a large amount of water to minimize the risk of gastrointestinal complications. The drug at doses of 400–600 mg should be administered once daily, whereas the daily dose of 800 mg should be given as 400 mg twice daily, in the morning and evening.

For patients (including children) unable to swallow capsules, the capsule contents may be dissolved in one glass of water or apple juice. Due to data on reproductive toxicity and potential risk to human fertility, women of reproductive age who open capsules should exercise caution to avoid contact of the drug with skin or eyes, as well as inhalation.

Hands must be washed immediately after opening the capsule.

Dosage for CML in Adult Patients

The recommended dose for adult patients with chronic myeloid leukemia (CML) in the chronic phase is 400 mg/day.

The chronic phase of CML is defined by the following criteria: blasts < 15% in blood and bone marrow, basophils in peripheral blood < 20%, platelets > 100×10⁹/L.

The recommended dose for adult patients in the accelerated phase is 600 mg/day.

The accelerated phase is defined by the presence of at least one of the following criteria: blasts ≥ 15% but < 30% in blood and bone marrow, blasts and promyelocytes ≥ 30% in blood or bone marrow (with < 30% blasts), basophils in peripheral blood ≥ 20%, platelets < 100×10⁹/L unrelated to therapy.

The recommended dose for patients in the blast crisis phase is 600 mg/day.

The blast crisis phase is defined by the presence of blasts ≥ 30% in blood and bone marrow or extramedullary disease (excluding hepatosplenomegaly).

Treatment should continue as long as clinical benefit is observed. The effect of discontinuing treatment after achieving a complete cytogenetic response has not been studied.

Dose escalation from 400 mg to 600 mg in patients with chronic-phase disease, and from 600 mg to the maximum dose of 800 mg (administered as 400 mg twice daily) in patients with disease in the accelerated or blast crisis phase, may be considered in the absence of severe adverse reactions and significant neutropenia or thrombocytopenia unrelated to the underlying disease, and in the following situations: disease progression (at any stage); lack of adequate hematological response after 3 months of treatment; loss of previously achieved hematological and/or cytogenetic response, or lack of cytogenetic response after 12 months of therapy. Patients should be closely monitored after dose escalation, as the frequency of adverse reactions increases with higher doses.

Dosage for CML in Pediatric Patients

Doses for children should be determined based on body surface area (mg/m²). For children with chronic-phase CML and accelerated phase, the recommended dose is 340 mg/m²/day (dose should not exceed 800 mg). The drug may be administered once daily or the daily dose may be divided into two doses – morning and evening. The recommended dose is based on studies conducted in a small number of pediatric patients. There is no experience with the use of the drug in children under 2 years of age.

In the absence of severe adverse reactions and significant leukemia-related complications, neutropenia, or thrombocytopenia in children, the dose may be gradually increased from 340 mg/m²/day to 570 mg/m²/day (dose should not exceed 800 mg) in the following cases: disease progression (at any stage); lack of adequate hematological response after 3 months of treatment; lack of cytogenetic response after 12 months of therapy; loss of previously achieved hematological and/or cytogenetic response. Patients should be closely monitored after dose escalation, as the frequency of adverse reactions increases with higher doses.

Dosage for (Ph+ ALL) in Adult Patients

The recommended dose for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is 600 mg/day. Patients should be closely monitored at any disease stage.

Treatment regimen: The drug is effective and safe at a dose of 600 mg/day in combination with chemotherapy during induction, consolidation, and maintenance chemotherapy for adult patients with Ph+ ALL. The duration of treatment may vary depending on the treatment program used, but longer exposure is expected to yield a more pronounced effect.

For adult patients with relapsed disease or Ph+ ALL that is refractory to treatment, the drug should be used as monotherapy at a dose of 600 mg/day, which is safe and effective, and may continue until disease progression occurs.

Dosage for Ph+ ALL in Pediatric Patients

Doses for children should be based on body surface area (mg/m²). For children with Ph+ ALL, the recommended dose is 340 mg/m²/day (total dose should not exceed 600 mg).

Dosage for MDS/MPN

The recommended dose for patients with MDS/MPN is 400 mg/day.

Duration of treatment: To date, only one clinical trial has been completed; imatinib treatment continues until disease progression. At the time of analysis, the median duration of treatment was 47 months (24 days – 60 months).

Dosage for GIST and HES

The recommended dose for patients with GIST/HES is 100 mg/day.

Dose escalation from 100 mg to 400 mg may be considered for patients who do not experience adverse reactions and in whom the response to treatment is insufficient.

Treatment may continue as long as clinical improvement is observed.

Dosage for Malignant Gastrointestinal Stromal Tumors

The recommended dose for patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors is 400 mg/day.

There are limited data on the effect of increasing the dose from 400 mg to 600 mg or 800 mg/day in patients with progressive disease who are receiving the lowest dose.

Duration of Treatment. Treatment of patients with malignant gastrointestinal stromal tumors should continue until disease progression. The median duration of treatment is 7 months (ranging from 7 days to 13 months). The effect of discontinuing treatment after achieving a response has not been studied. The recommended dose for adjuvant therapy in adult patients following resection of GIST is 400 mg/day. The optimal duration of treatment has not been established. In clinical trials supporting the use of the drug for this indication, the duration of treatment was 36 months.

Dosage for DFSP

The recommended dose for patients with dermatofibrosarcoma protuberans (DFSP) is 800 mg/day.

Dose Adjustment for Adverse Reactions

Non-hematological adverse reactions.

If severe non-hematological adverse reactions occur during therapy, treatment should be discontinued until the causes of the reactions are clarified. Treatment may be resumed after identifying and eliminating the factors that triggered the adverse reactions.

If bilirubin levels exceed 3 times the upper limit of normal, or if liver transaminase levels increase more than 5 times the upper limit of normal, therapy should be discontinued until bilirubin levels decrease to less than 1.5 times the upper limit of normal and transaminase levels decrease to less than 2.5 times the upper limit of normal. After normalization, treatment may be continued at a reduced daily dose. For adult patients, the dose should be reduced from 400 mg to 300 mg, from 600 mg to 400 mg, or from 800 mg to 600 mg; for children – from 340 to 260 mg/m²/day.

Hematological adverse reactions.

In the event of severe neutropenia or thrombocytopenia, dose reduction or discontinuation of treatment is recommended as indicated in the table below.

Dose adjustment for neutropenia or thrombocytopenia:

Hepatic impairment. Imatinib is primarily metabolized in the liver. Patients with mild, moderate, and severe hepatic impairment should be treated with the minimum recommended daily dose of 400 mg. If the treatment regimen allows, the dose may be reduced.

Classification of hepatic impairment

ULN – upper limit of normal.

AST – aspartate aminotransferase.

Renal impairment.

In patients with impaired renal function or those on dialysis, the drug should be administered at the minimum recommended initial dose of 400 mg once daily. However, the drug should be administered with caution in such patients. The dose may be reduced in case of intolerance or increased in case of insufficient efficacy.

Elderly patients.

Pharmacokinetics in elderly patients has not been studied. In clinical trials including 20% of patients aged 65 years and older, no age-related differences in the pharmacokinetics of the drug were observed. Therefore, no specific dosage recommendations for elderly patients are available.

Children.

The safety and efficacy of imatinib in children have not been established. Currently, only limited data are available, which are insufficient to recommend the use of the drug in children.

There is no experience with the use of imatinib in children under 2 years of age with CML, or in children under 1 year of age with Ph+ ALL. Experience in treating children with MDS/MPN, dermatofibrosarcoma protuberans, GIST, and HES/CEL is very limited.

The safety and efficacy of imatinib in children (under 18 years of age) with MDS/MPN, DFSP, GIST, and HES/CEL have not been established in clinical trials. Currently available published data do not allow providing dosage recommendations.

Overdose.

Data regarding overdose are limited. Cases of imatinib overdose have been described in the literature and spontaneous reports have also been received. In the event of overdose, patients should be monitored and appropriate symptomatic therapy should be administered. In general, recovery or improvement was reported in these cases. The following reports relate to specific dose ranges described below.

Overdose in adult patients.

In patients who received doses from 1200 mg to 1600 mg (duration of administration ranged from 1 to 10 days), nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle cramps, thrombocytopenia, pancytopenia, abdominal pain, headache, and decreased appetite were reported.

In patients who received doses from 1800 mg to 3200 mg (up to 3200 mg daily for 6 days): weakness, myalgia, increased creatine phosphokinase levels, increased bilirubin levels, and gastrointestinal pain.

One case of a single 6400 mg dose intake was reported, resulting in nausea, vomiting, abdominal pain, pyrexia, facial edema, decreased neutrophil count, and increased transaminase levels.

In patients who received single doses from 8 g to 10 g, vomiting and gastrointestinal pain were observed.

Overdose in children.

In a 3-year-old boy who ingested a 400 mg dose, nausea, vomiting, diarrhea, and anorexia occurred. In another 3-year-old boy who ingested a 980 mg dose, decreased leukocyte count and diarrhea were observed.

Adverse Reactions

Patients with terminal-stage malignancy may be in a condition where it is difficult to assess the causal relationship of adverse effects due to the presence of numerous symptoms from the underlying disease, its progression, and concomitant administration of multiple medications.

In clinical studies involving patients with CML, drug discontinuation due to adverse drug reactions was observed in 2.4% of newly diagnosed patients, in 4% of patients in late chronic phase after failure of interferon therapy, in 4% of patients in the accelerated phase after failure of interferon therapy, and in 5% of patients with blast crisis after failure of interferon therapy. In the case of GIST, the investigational drug was discontinued due to drug-related adverse reactions in 4% of patients.

Adverse reactions were generally similar across all indications, except for two differences. In patients with CML, there were more cases of myelosuppression compared to patients with gastrointestinal stromal tumors (GIST), likely due to the underlying disease. In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors, grade 3/4 gastrointestinal hemorrhage according to Common Toxicity Criteria (CTC) occurred in 7 (5%) patients, including intratumoral hemorrhage (3 patients) or both (1 patient). The location of the GIST tumor may be a source of gastrointestinal bleeding. Gastrointestinal and tumor hemorrhages can be serious and sometimes fatal. For both conditions, the most commonly reported (≥10%) drug-related adverse reactions included mild nausea, vomiting, diarrhea, abdominal pain, fatigue, muscle spasms, and rash. Periorbital edema or edema of the lower extremities were frequently reported as superficial swelling across all studies. However, these edemas were rarely severe and could usually be managed with diuretics, other supportive measures, or dose reduction of imatinib.

When imatinib was used in combination with high-dose chemotherapy in patients with Ph+ ALL, hepatic toxicity manifestations such as elevated transaminase levels and hyperbilirubinemia were observed. Given the limited safety data, adverse reactions previously reported in children are consistent with the safety profile observed in adult patients with Ph+ ALL. The safety profile for children with Ph+ ALL remains very limited; however, no new safety concerns have been identified.

Various adverse reactions such as pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema may collectively be described as fluid retention. These reactions can usually be managed by temporary interruption of imatinib or with diuretics and other appropriate supportive measures. However, occasionally these reactions may be serious or life-threatening, and some cases occurring in patients with blast crisis have been fatal (with pleural effusion, congestive heart failure, and renal failure noted in the clinical history). No specific safety-related events were observed in pediatric clinical trials.

Adverse reactions occurring more frequently than isolated cases have been classified by organ system class and frequency using the following conventional frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

The adverse reactions and their frequencies are presented in Table 1.

Table 1. Summary of adverse reactions in tabular form

* These types of reactions were mainly reported during the post-marketing period of imatinib use. They include spontaneous case reports as well as serious adverse effects observed during long-term studies, expanded access programs, clinical pharmacology studies, and investigational use outside approved indications. Since these reactions were observed in populations of uncertain size, it is not always possible to reliably determine their frequency or establish a causal relationship with imatinib use.

1 Pneumonia was reported most frequently in patients with transformed CML and in patients with gastrointestinal stromal tumors (GIST).

2 Headache was reported most frequently in patients with gastrointestinal stromal tumors (GIST).

3 Based on patient-year calculations, cardiac function disorders, including congestive heart failure, were observed more frequently in patients with transformed CML than in patients with chronic CML.

4 Flushing was most frequently observed in patients with gastrointestinal stromal tumors (GIST), while hemorrhages (hematomas, hemorrhages) occurred more frequently in patients with gastrointestinal stromal tumors (GIST) and transformed CML (CML-AP and CML-BC).

5 Pleural effusion was reported more frequently in patients with gastrointestinal stromal tumors (GIST) and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.

6+7 Abdominal pain and gastrointestinal hemorrhages were common in patients with gastrointestinal stromal tumors (GIST).

8 Cases of fatal hepatic failure and liver necrosis have been reported.

9 Musculoskeletal pain during or after imatinib treatment was observed during the post-marketing period.

10 Musculoskeletal pain and similar reactions were observed more frequently in patients with CML than in patients with gastrointestinal stromal tumors (GIST).

11 Fatal cases have been reported in patients with advanced disease stages, severe infections, severe neutropenia, and other serious concomitant disorders.

12 Including nodular erythema.

Laboratory test abnormalities

Complete blood count

In CML, cytopenia, particularly neutropenia and thrombocytopenia, was consistent across all studies, with a higher frequency observed at higher doses ≥ 750 mg (Phase I study). However, it should be noted that the occurrence of neutropenia also has a clear correlation with the stage of the disease; the frequency of grade 3 or 4 neutropenia (ANC < 1.0 x 10⁹/L) and thrombocytopenia (platelet count < 50 x 10⁹/L) was 4–6 times higher in blast crisis and in the acceleration phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) compared to patients with newly diagnosed chronic-phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic-phase CML, grade 4 neutropenia (ANC < 0.5 x 10⁹/L) and thrombocytopenia (platelet count < 10 x 10⁹/L) were observed in 3.6% and <1% of patients, respectively. The median duration of episodes of neutropenia and thrombocytopenia ranged from 2 to 3 weeks and from 3 to 4 weeks, respectively. These events are usually manageable by dose reduction or temporary interruption of imatinib, but in rare cases they may lead to permanent discontinuation of therapy. In pediatric patients with CML, the most common manifestation of toxicity is grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia, and anemia. These events are mostly observed during the first few months of therapy.

In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST), grade 3 and 4 anemia was observed in 5.4% and 0.7% of patients, respectively, and in at least some of these patients could be related to gastrointestinal or intratumoral hemorrhages. Grade 3 and 4 neutropenia was observed in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. Decreases in white blood cell and neutrophil counts were observed primarily during the first six weeks of therapy; thereafter, values remained relatively stable.

Blood biochemistry

Marked elevations in transaminases (<5%) or bilirubin (<1%) were observed in patients with CML and were mostly managed by dose reduction or treatment interruption (median duration of these episodes was approximately 1 week). Treatment was permanently discontinued due to abnormal liver function test results in less than 1% of patients with CML. In patients with gastrointestinal stromal tumors (GIST), grade 3 or 4 elevations in ALT (alanine aminotransferase) were observed in 6.8% of cases and grade 3 or 4 elevations in AST (aspartate aminotransferase) in 4.8% of cases. Elevated bilirubin levels were reported in less than 3% of patients.

Cases of cytolytic and cholestatic hepatitis and hepatic failure have been reported; some of these were fatal, including in one patient who was taking high doses of paracetamol.

Description of selected adverse reactions

Hepatitis B reactivation

Hepatitis B reactivations have been reported with Bcr-Abl TKIs. In some cases, acute liver failure or fulminant hepatitis developed, leading to liver transplantation or death.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 6 or 12 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

JSC "Grindeks".

Manufacturer's address and location of its business operations.

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./Fax: +371 67083205 / +371 67083505.

E-mail: [email protected].