Imatero®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMATERO® (IMATERO®)

Composition:

Active substance: imatinib;

One tablet contains imatinib mesylate equivalent to 100 mg or 400 mg of imatinib;
Excipients: magnesium stearate; coating: Opadry White 03F58763 (hypromellose, polyethylene glycol, talc, titanium dioxide).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

100 mg tablets: white or almost white, round, film-coated tablets with bevel and score line, marked with "H" on one side and "19" on the other; digits 1 and 9 separated by a line;

400 mg tablets: white or almost white, capsule-shaped, film-coated tablets with bevel and score line, marked with "H" on one side and "20" on the other; digits 2 and 0 separated by a line.

Pharmaco-therapeutic group. Antineoplastic agents. Other antineoplastic agents. Protein kinase inhibitors. Imatinib.

ATC code L01X E01.

Pharmacological Properties.

Pharmacodynamics.

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

Imatinib is a protein tyrosine kinase inhibitor that potently inhibits Bcr-Abl tyrosine kinase at the cellular level. This compound selectively suppresses proliferation and induces apoptosis in Bcr-Abl-positive cell lines, as well as in freshly isolated leukemic cells from patients with the Philadelphia chromosome in leukocytes in 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) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular changes. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells expressing activating kit mutations.

Constitutive activation of the PDGF receptor or Bcr-Abl protein tyrosine kinase results from fusion with various proteins or stimulation of PDGF synthesis and has been implicated in the pathogenesis of MDS/MPD (myelodysplastic/myeloproliferative disorders), HES/CEL (hypereosinophilic syndrome/chronic eosinophilic leukemia), and DFSP (dermatofibrosarcoma protuberans). Imatinib inhibits the signaling leading to cell proliferation associated with activated PDGFR and Bcr-Abl tyrosine kinase activity.

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

Pharmacokinetics.

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

Absorption. The mean absolute bioavailability of the drug is 98%. Considerable inter-patient variability in plasma AUC of imatinib was observed after oral administration. When the drug was taken with a high-fat meal, imatinib absorption was minimally reduced (11% decrease in Cmax and a 1.5-hour prolongation of tmax) with a slight reduction in AUC (7.4%) compared to fasting conditions. The impact of prior gastrointestinal surgery on drug absorption has not been studied.

Distribution. In vitro data indicate that at clinically relevant concentrations, imatinib binding to plasma proteins is 95% (primarily to albumin and acid α-glycoprotein, to a minor extent to lipoproteins).

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

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

In vitro studies indicate that CYP3A4 is the primary human P450 enzyme responsible for the biotransformation of imatinib. Among a panel of potentially interacting drugs (acetaminophen, acyclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V), only erythromycin (IC50 50 µmol) and fluconazole (IC50 118 µmol) were shown to inhibit imatinib metabolism, which may have clinical significance.

In vitro studies have demonstrated that imatinib is 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 the metabolism of concomitantly administered drugs metabolized by CYP2D6 and/or CYP3A4/5 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 µmol/L). This Ki value is significantly higher than the expected plasma concentration of imatinib in patients; therefore, no interaction is expected when 5-fluorouracil or paclitaxel is co-administered with imatinib.

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

Plasma Pharmacokinetics.

After oral administration to healthy volunteers, the elimination half-life (t1/2) was approximately 18 hours, supporting once-daily dosing. The increase in mean AUC with increasing dose was linear and dose-proportional over the oral dose range of 25 mg to 1000 mg. No changes in imatinib kinetics were observed after repeated dosing, and accumulation at steady state was 1.5–2.5-fold with once-daily administration.

Pharmacokinetics in Patients with Gastrointestinal Stromal Tumors (GIST).

In patients with gastrointestinal stromal tumors, steady-state exposure was 1.5 times higher than in patients with CML receiving the same dose (400 mg daily). Based on previous population pharmacokinetic analysis in patients with gastrointestinal stromal tumors, three variables (albumin, leukocyte count, and bilirubin) were found to have a statistically significant relationship with imatinib pharmacokinetics. Decreased albumin levels led to reduced clearance (CL/f); higher leukocyte counts also led to reduced CL/f. However, this relationship was not strong enough to require dose adjustment. In this patient group, liver metastases may likely lead to hepatic insufficiency and reduced metabolism.

Pharmacokinetics in Populations.

Population pharmacokinetic analysis of data from CML patients showed a minor effect of age on volume of distribution (12% increase in patients >65 years). This change is not considered clinically significant. The effect of body weight on imatinib clearance is such that patients with a body weight of 50 kg have an expected mean clearance of 8.5 L/h, whereas patients with a body weight of 100 kg have a clearance of 11.8 L/h. These changes are not considered sufficient to require dose adjustment based on body weight. No effect of patient sex on imatinib kinetics has been observed.

Pharmacokinetics in Children.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients in phase I and phase II studies. Doses of 260 and 340 mg/m²/day achieved exposure similar to 400 mg and 600 mg doses in adults, respectively. Comparison of AUC(0–24) on day 8 and day 1 after administration of 340 mg/m²/day showed 1.7-fold accumulation after repeated once-daily dosing.

Based on a pooled population pharmacokinetic analysis in children with hematological disorders (CML, Ph+ ALL, or other hematological 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 a clinically important effect 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 adult patients receiving 400 mg or 600 mg once daily.

Organ Function Impairment.

Imatinib and its metabolites are not significantly excreted by the kidneys. Patients with mild to moderate renal impairment have higher plasma exposure than patients with normal renal function. The increase is approximately 1.5–2 times, corresponding to a 1.5-fold increase in plasma alpha-1-acid glycoprotein levels, to which imatinib is extensively bound. Free drug clearance 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 analysis results showed significant 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.

• Treatment of patients (adults and children) with newly diagnosed Philadelphia chromosome-positive (Ph+) (with presence of 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 accelerated phase, or in blast crisis of the disease;
• as part of chemotherapy for patients (adults and children) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with presence of Philadelphia chromosome in leukocytes;
• as monotherapy for adult patients with acute lymphoblastic leukemia (Ph+ ALL) in relapse or refractory to treatment;
• treatment of adults with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with rearrangement of the platelet-derived growth factor receptor (PDGFR) gene;
• treatment of adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα gene rearrangement.

The effect of imatinib on bone marrow transplantation has not been sufficiently studied.

Also indicated for:

• treatment of adult patients with Kit (CD117)-positive unresectable 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) following 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 (DFSP) not amenable to surgical removal.

Contraindications.

Hypersensitivity to the active substance or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Medicinal products that may increase imatinib plasma concentration

Active substances that inhibit CYP3A4 isoenzyme activity of the cytochrome P450 system (e.g., indinavir, lopinavir/ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; antifungal agents including ketoconazole, itraconazole, posaconazole, voriconazole; macrolides such as erythromycin, clarithromycin, telithromycin) may reduce metabolism and increase imatinib plasma concentration. A significant increase in parameters (mean Cmax and AUC of imatinib by 26% and 40%, respectively) was observed in healthy volunteers when imatinib was administered concomitantly with a single dose of ketoconazole (a CYP3A4 inhibitor). Imatinib should be used with caution when co-administered with CYP3A4 inhibitors.

Medicinal products that may decrease imatinib plasma concentration

Active substances that are inducers of CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, or St. John’s wort [Hypericum perforatum]) may substantially reduce imatinib plasma concentrations, potentially increasing the risk of treatment failure.

Following prior administration of multiple doses of rifampicin (600 mg) and subsequent single-dose administration 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 during treatment with enzyme-inducing antiepileptic drugs such as carbamazepine, oxcarbazepine, and phenytoin. Plasma AUC of imatinib was reduced by 73% compared to that in patients not receiving enzyme-inducing antiepileptic drugs. Concomitant use of rifampicin or other potent CYP3A4 inducers with imatinib should be avoided.

Medicinal products whose plasma concentration may change when using Imatero®

Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2-fold and 3.5-fold, respectively, indicating inhibition of CYP3A4 by imatinib. Therefore, Imatero® should be used with caution together with CYP3A4 substrates having a narrow therapeutic window (e.g., cyclosporine or pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine).

Imatero® may increase plasma concentrations of other drugs metabolized by CYP3A4 (such as triazole benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, including statins, etc.).

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

In vitro, imatinib inhibits the activity of the cytochrome P450 CYP2D6 isoenzyme at concentrations similar to those affecting CYP3A4 activity. Imatinib at a dose of 400 mg twice daily shows 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; however, caution is recommended with CYP2D6 substrates having a narrow therapeutic window, 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 Imatero® concomitantly with paracetamol.

In patients after thyroidectomy who are taking levothyroxine, plasma exposure to levothyroxine may be reduced when Imatero® 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 interactions between imatinib and chemotherapeutic agents are not fully defined. Adverse effects of imatinib may be enhanced, particularly hepatotoxicity, myelosuppression, or others; concurrent use of L-asparaginase has also been reported to increase hepatic toxicity. Therefore, use of Imatero® as part of combination therapy requires precautionary measures.

Special precautions for use.

When prescribing the medicinal product Imatereo® together with other drugs, there is a potential risk of interaction. Caution should be exercised when using Imatereo® with protease inhibitors, azole antifungals, certain macrolides (see section "Interaction with other medicinal products and other forms of interaction"), substrates of CYP3A4 with a narrow therapeutic window (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 the medicinal product Imatereo® should be avoided.

Hypothyroidism

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

Hepatotoxicity

Metabolism of imatinib occurs primarily in the liver, with only 13% metabolized by the kidneys. Patients with hepatic dysfunction (mild, moderate, or severe) should be carefully 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 failure.

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

Severe liver function abnormalities have been observed during combination therapy with imatinib and high-dose chemotherapy agents. Liver function should be closely monitored, as imatinib together with chemotherapy may cause hepatic dysfunction.

Fluid retention

Marked fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial swelling) has been observed in approximately 2.5% of patients with newly diagnosed CML treated with imatinib. Therefore, regular monitoring of patients' body weight is recommended. In case of sudden rapid weight gain, a thorough examination of the patient 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 advised in patients with cardiac dysfunction.

Patients with heart disease

Patients with heart disease, risk factors for heart failure, or a history of renal insufficiency should be closely monitored. Patients presenting 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 have been observed, associated with HES cell degranulation prior to initiation of imatinib therapy. These effects were reversible with systemic steroids, hemodynamic support measures, and temporary discontinuation of imatinib. Cardiac adverse reactions during imatinib therapy have been infrequent. Before initiating therapy, benefit/risk of imatinib treatment should be carefully assessed in patients with HES/CEL. 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 undergo cardiology consultation, echocardiography, and serum troponin measurement 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 phase of treatment are recommended.

Gastrointestinal hemorrhage

During studies, gastrointestinal and intratumoral hemorrhages were reported in patients with unresectable and/or metastatic GIST. 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 bleeding in patients with GIST. 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 bleeding should be applied.

Additionally, during post-marketing surveillance, gastric antral vascular ectasias have been reported as a rare cause of gastrointestinal bleeding in patients with CML, ALL, and other conditions. If necessary, discontinuation of the medicinal product Imatereo® should be considered.

Tumor lysis syndrome

Due to the potential occurrence of tumor lysis syndrome, correction of clinically evident dehydration and elevated uric acid levels is recommended before initiating therapy with Imatereo®.

Hepatitis B reactivation

Reactivation of hepatitis B has occurred in patients who are chronic carriers of the virus after receiving BCR-ABL tyrosine kinase inhibitors.

In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in fatal outcomes. Before initiating treatment, patients should be screened for hepatitis B virus (HBV) infection.

Patients with positive serological tests for hepatitis B (including those with active disease) and patients with confirmed HBV infection should be referred for consultation with infectious disease specialists and hepatologists experienced in managing hepatitis B before starting treatment. HBV carriers requiring treatment with Imatereo® should be closely monitored for signs of active hepatitis B infection during treatment and for several months after therapy completion.

Photosensitivity

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

Thrombotic microangiopathy

Use of BCR-ABL tyrosine kinase inhibitors has been associated with thrombotic microangiopathy (TMA), including isolated reports with imatinib (see section "Adverse reactions"). If patients receiving Imatereo® develop laboratory or clinical signs suggestive of TMA, treatment should be discontinued and a thorough evaluation for TMA performed, including ADAMTS13 activity and anti-ADAMTS13 antibody testing. If elevated anti-ADAMTS13 antibodies are found in combination with low ADAMTS13 activity, treatment with Imatereo® should not be continued.

Laboratory tests

Complete blood counts should be performed regularly during Imatereo® therapy. Treatment of patients with chronic myeloid leukemia with imatinib is associated with the development of neutropenia or thrombocytopenia. However, the occurrence of these cytopenias depends on the disease stage at which treatment is initiated and is more frequent in patients with CML in the accelerated or blast phase compared to those in the chronic phase. Treatment with Imatereo® 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 regularly monitored in patients receiving Imatereo®.

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

Long-term use of imatinib may be associated with clinically significant worsening of renal function. Renal function should be assessed before starting imatinib therapy and monitored during treatment, with particular attention to patients who have risk factors for renal dysfunction. If renal impairment occurs, treatment should be administered according to standard guidelines.

Children

Cases of growth retardation have been reported in children, including prepubertal children, receiving imatinib. The long-term impact of prolonged imatinib treatment on children's development is unknown. Therefore, careful monitoring of development in children receiving imatinib is recommended.

In adults and children, the efficacy of imatinib is evaluated based on data regarding overall hematologic and cytogenetic response rates and progression-free survival in CML, hematologic and cytogenetic response rates in Ph+ ALL, MDS/MPD, hematologic response rates in HES/CEL, and objective response rates in adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors and dermatofibrosarcoma protuberans, as well as progression-free survival in adjuvant treatment of patients with malignant gastrointestinal stromal tumors. 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 in these conditions have not been conducted.

Use during pregnancy or breastfeeding.

Pregnancy. There are no adequate data on the use of Imatereo® in pregnant women. Spontaneous abortions and congenital malformations in newborns have been reported in the post-marketing period in mothers who received imatinib. Animal studies have shown reproductive toxicity, and the potential risk to the fetus is unknown. Imatereo® should not be used during pregnancy except in life-threatening situations. If the drug is administered during pregnancy, the patient must be informed of the potential risk to the fetus.

Women of childbearing potential should be advised to use effective contraception during treatment.

Lactation. Information on the excretion of imatinib into breast milk is limited. Studies in two breastfeeding women showed that imatinib and its active metabolite can be excreted into breast milk. The ratio of drug concentration in plasma to breast milk, studied in one patient, was 0.5 for imatinib and 0.9 for the metabolite, indicating greater distribution of the metabolite into breast milk. Considering the concentration of imatinib and its metabolite and the maximum daily milk intake by an infant, total exposure would be low (approximately 10% of the therapeutic dose). However, since the effects of low-dose imatinib on infants are unknown, women taking Imatereo® should not breastfeed.

Fertility. Fertility in male and female rats was not impaired in preclinical studies. No studies in patients have been conducted to evaluate the effect of imatinib on fertility and gametogenesis. If a patient has concerns about the effect of Imatereo® on fertility, they should consult their physician.

Ability to affect reaction speed when driving or operating machinery.

Patients should be aware of the possible occurrence of adverse effects such as dizziness, blurred vision, or somnolence when taking imatinib. Therefore, caution should be advised when driving or operating machinery.

Method of Administration and Dosage

Treatment should be initiated and supervised by a physician experienced in the management of patients with hematologic malignancies and sarcomas, depending on the specific diagnosis.

For doses of 400 mg and higher (see dosing recommendations below), 400 mg tablets (non-divisible) should be used.

For doses other than 400 mg and 800 mg (see dosing recommendations below), 100 mg tablets, which may be divided, should be used.

The prescribed doses should be taken orally with food and a large glass of water to minimize the risk of gastrointestinal irritation. The 400 mg or 600 mg dose should be administered once daily, whereas the 800 mg dose should be divided into two 400 mg doses taken in the morning and evening.

For patients unable to swallow the coated tablet, it may be dissolved in a glass of mineral water or apple juice. The required number of tablets should be placed in an appropriate volume of liquid (approximately 50 mL for a 100 mg tablet and 200 mL for a 400 mg tablet) and stirred with a spoon. The resulting suspension should be consumed immediately.

Dosage in Chronic Myeloid Leukemia (CML) in Adult Patients

The recommended dose of the medicinal product Imitero® for adult patients with CML in chronic phase is 400 mg once daily. Chronic phase CML is defined by meeting all of the following criteria: blasts < 15% in blood and bone marrow, basophils in peripheral blood < 20%, platelets > 100 × 10⁹/L.

The recommended dose of Imitero® for adult patients in the accelerated phase is 600 mg once daily. The accelerated phase is defined by the presence of any of the following criteria: blasts ≥ 15% but < 30% in blood or bone marrow, blasts and prolymphocytes ≥ 30% in blood or bone marrow (provided blasts < 30%), basophils in peripheral blood ≥ 20%, platelets < 100 × 10⁹/L regardless of treatment.

The recommended dose of Imitero® for adult patients with blast crisis is 600 mg once daily. Blast crisis is defined by blasts ≥ 30% in blood or bone marrow, or the presence of extramedullary disease manifestations, excluding hepatosplenomegaly.

Duration of Treatment: In clinical trials, imatinib treatment was continued until disease progression. The effect of treatment discontinuation after achieving complete cytogenetic response has not been studied.

Dose escalation from 400 mg to 600 mg or 800 mg may be considered for patients with chronic phase disease, or from 600 mg to a maximum of 800 mg (administered as two 400 mg doses daily) for patients in accelerated phase or blast crisis, provided there are no severe adverse reactions and no severe non-leukemia-related neutropenia or thrombocytopenia, in the following situations: disease progression (at any time); lack of adequate hematologic response after at least 3 months of therapy; lack of cytogenetic response after 12 months of therapy; or loss of previously achieved hematologic and/or cytogenetic response. After dose escalation, patients require close monitoring due to the increased likelihood of adverse reactions with higher doses.

Dosage in Chronic Myeloid Leukemia (CML) in Pediatric Patients

Pediatric dosing is based on body surface area (mg/m²). For children with CML in chronic or progressive phase, the recommended dose is 340 mg/m²/day (not to exceed a maximum daily dose of 800 mg). The drug may be administered once daily or the total daily dose may be divided into two doses, morning and evening. The recommended doses are currently based on limited experience with a small number of pediatric patients. There is no experience with the use of Imitero® in children under 2 years of age.

Dose escalation from 340 mg/m² to 570 mg/m² (not to exceed a total dose of 800 mg) may be considered for pediatric patients in the absence of severe adverse reactions and severe non-leukemia-related neutropenia or thrombocytopenia, in the following situations: disease progression (at any time); lack of adequate hematologic response after at least 3 months of therapy; lack of cytogenetic response after 12 months of therapy; or loss of previously achieved hematologic and/or cytogenetic response. After dose escalation, patients require close monitoring due to the increased likelihood of adverse reactions with higher doses.

Dosage in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Adult Patients

The recommended dose of Imitero® for the treatment of adult patients with Ph+ ALL is 600 mg once daily. Treatment for this condition should be managed under the supervision of a hematologist throughout all phases of therapy.

Treatment regimen: Based on available data, Imitinib has demonstrated efficacy and safety at a dose of 600 mg/day in combination with chemotherapy during induction, consolidation, and maintenance phases in adult patients with newly diagnosed Ph+ ALL. The duration of Imitero® therapy may vary depending on the chosen treatment protocol, but longer treatment duration generally leads to better outcomes.

For adult patients with relapsed or refractory Ph+ ALL, monotherapy with Imitero® at a dose of 600 mg once daily is safe and effective and may be continued until disease progression.

Dosage in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients

Pediatric dosing should be based on body surface area (mg/m²). The recommended daily dose for children with Ph+ ALL is 340 mg/m²/day (not to exceed a maximum daily dose of 600 mg).

Dosage in Myelodysplastic/Myeloproliferative Disorders (MDS/MPD)

The recommended dose of Imitero® for the treatment of patients with MDS/MPD is 400 mg once daily.

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

Dosage in Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia (HES/CEL)

The recommended dose of Imitero® for the treatment of patients with HES/CEL is 100 mg once daily. Dose escalation from 100 mg to 400 mg may be considered for patients without adverse reactions and in whom the response to treatment is suboptimal.

Treatment should be continued as long as the patient continues to benefit.

Dosage for Patients with Kit (CD117)-Positive Unresectable and/or Metastatic Malignant Gastrointestinal Stromal Tumors (GIST) and for Adjuvant Therapy in Adult Patients at High Risk of Recurrence of Kit (CD117)-Positive Malignant Gastrointestinal Stromal Tumors (GIST) after Resection

The recommended dose of Imitero® for the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) is 400 mg once daily. Data on the benefit of dose escalation from 400 mg to 600 mg or 800 mg in patients with disease progression on lower doses are limited.

Duration of Treatment: In clinical trials involving patients with gastrointestinal stromal tumors, imatinib treatment was continued until disease progression. At the time of analysis, the median duration of treatment was 7 months (range: 7 days to 13 months). The effect of treatment discontinuation after achieving response has not been studied.

The recommended dose of Imitero® for adjuvant therapy in adult patients after resection of gastrointestinal stromal tumors is 400 mg once daily. The optimal duration of treatment has not yet been established. In clinical trials supporting the use of the drug for this indication, the treatment duration was 36 months.

Dosage for the Treatment of Patients with Unresectable, Locally Advanced Dermatofibrosarcoma Protuberans (DFSP) and Adult Patients with Recurrent and/or Metastatic Dermatofibrosarcoma (DFSP) Not Amenable to Surgical Resection

The recommended dose of Imitero® for the treatment of adult patients with DFSP is 800 mg once daily.

Dose Adjustment in the Event of Adverse Effects

Non-Hematologic Adverse Effects

In the event of severe non-hematologic adverse effects during treatment with Imitero®, therapy should be interrupted until improvement. Treatment may then be resumed at a reduced dose, depending on the severity of the previously observed adverse effects.

If bilirubin levels exceed three times the upper limit of normal (ULN), or if liver transaminase levels increase more than five times ULN, administration of imatinib should be withheld until bilirubin decreases to less than 1.5 times ULN and transaminases decrease to less than 2.5 times ULN. Treatment with imatinib may then be resumed at a reduced daily dose. For adults, the dose should be reduced from 400 to 300 mg/day, from 600 to 400 mg/day, or from 800 to 600 mg/day. For pediatric patients, the dose should be reduced from 340 to 260 mg/m²/day.

Hematologic Adverse Effects

In the event of severe neutropenia or thrombocytopenia, dose reduction or treatment interruption is recommended as outlined in Table 1.

Table 1

Special populations

Hepatic impairment

Imatinib is primarily metabolized in the liver. Imatinib should be administered at the minimum recommended daily dose of 400 mg in patients with mild, moderate, and severe hepatic impairment. The dose may be reduced in case of intolerance.

Table 2

Classification of hepatic impairment

ULN — upper limit of normal, as established by the medical institution.

AST — aspartate aminotransferase.

Renal impairment

For patients with renal impairment or those undergoing dialysis, the drug should be administered at the minimum recommended initial dose of 400 mg once daily. However, imatinib should be used with caution in such patients. The dose may be reduced in case of intolerance or increased if efficacy is insufficient.

Elderly patients

The pharmacokinetics of imatinib in elderly patients has not been specifically studied. In clinical trials involving 20% of patients aged 65 years and older, no age-related differences in the pharmacokinetics of the drug were observed. No special dosage recommendations are required for elderly patients.

Children

There is no experience with the use of Imatero® 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 Ph+ ALL is limited, and experience in treating children with MDS/MPD, dermatofibrosarcoma protuberans (DFSP), GIST, and HES/CEL is very limited.

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

Overdose.

Information on cases of drug intake exceeding the recommended therapeutic doses is limited. Isolated cases of imatinib overdose have been reported (spontaneously or mentioned in publications). In case of overdose, the patient should be examined and appropriate supportive therapy should be administered. Overall, outcomes in such cases have generally been described as improvement or resolution of symptoms. The following events have been reported at various dose ranges.

Overdose in adults.

From 1200 to 1600 mg (duration from 1 to 10 days): nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

From 1800 to 3200 mg (6 days duration with 3200 mg daily): weakness, myalgia, elevated creatine phosphokinase, elevated bilirubin, gastrointestinal pain.

6400 mg (single dose): in one patient (published data), nausea, vomiting, abdominal pain, fever, facial swelling, decreased neutrophil count, elevated transaminase levels were observed.

8 to 10 g (single dose): vomiting and gastrointestinal pain.

Overdose in children.

In a 3-year-old boy who took a single dose of 400 mg, vomiting, diarrhea, and anorexia were observed; in another 3-year-old boy after a single 980 mg dose — decreased white blood cell count and diarrhea.

In case of overdose, the patient requires monitoring and appropriate symptomatic treatment.

Adverse reactions.

Patients with advanced stages of malignant disease may be in a condition where it is difficult to assess the causal relationship of adverse effects due to the presence of numerous symptoms related to the underlying disease, its progression, and concomitant administration of multiple medications.

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

Adverse reactions were similar across all indications, with two exceptions. In patients with CML, a higher incidence of myelosuppression was observed compared to patients with gastrointestinal stromal tumors, likely due to the underlying disease. In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors, grade 3/4 gastrointestinal (GI) 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 gastrointestinal (GI) tumor may be a source of GI bleeding. GI and intratumoral hemorrhages can be serious and sometimes fatal. For both diseases, the most commonly reported (≥10%) drug-related adverse reactions were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, muscle cramps, and rash. Superficial edema was common in all studies and was predominantly described as periorbital edema or edema of the lower limbs. However, these edemas were rarely severe and could be managed with diuretics, other supportive measures, or by reducing the dose of Imatero®.

When imatinib was used in combination with high-dose chemotherapy in patients with Ph+ ALL, signs of hepatotoxicity were observed, including elevated transaminase levels and hyperbilirubinemia. Given the limited safety data, adverse reactions reported so far in children are consistent with the safety profile observed in adult patients with Ph+ ALL. The safety profile for children with Ph+ ALL is 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 temporarily interrupting imatinib treatment 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 (pleural effusion, congestive heart failure, and renal failure were noted in the clinical history of these patients). No specific drug-related safety events were observed during pediatric clinical trials.

Adverse reactions occurring more frequently than isolated cases are classified by system organ class and frequency: 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); frequency not known (cannot be estimated from available data).

Unwanted reactions and their frequencies are listed in Table 3.

Table 3

* These types of reactions were observed primarily 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 trials of off-label use. Since these reactions were observed in populations of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship with imatinib use.

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

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

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

4 Flushing was most frequently observed in patients with gastrointestinal stromal tumors (GIST), while hemorrhages (hematomas, hemorrhages) occurred most frequently in patients with gastrointestinal stromal tumors (GIST) and transformed CML (CML-AP [accelerated phase] and CML-BC [blast crisis]).

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

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

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

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

10 Fatal cases have been reported in patients with advanced stages of disease, severe infections, severe neutropenia, and other serious comorbid conditions.

Laboratory test abnormalities

Complete blood count

In CML, cytopenia, particularly neutropenia and thrombocytopenia, was consistent across all studies and occurred more frequently at higher doses ≥ 750 mg (Phase I studies). However, the occurrence of neutropenia was also closely related to the stage of disease; the frequency of grade 3 or 4 neutropenia (ANC < 1.0 × 10⁹/L) and thrombocytopenia (platelet count < 50 × 10⁹/L) was 4–6 times higher in blast crisis and accelerated 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 × 10⁹/L) and thrombocytopenia (platelet count < 10 × 10⁹/L) occurred in 3.6% and <1% of patients, respectively. The median duration of neutropenia and thrombocytopenia episodes was 2–3 weeks and 3–4 weeks, respectively. These events are usually manageable by dose reduction or temporary interruption of imatinib, but in rare cases may require permanent discontinuation of therapy. In pediatric patients with CML, the most common manifestation of toxicity is grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These events mostly occur 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 associated with gastrointestinal or intratumoral hemorrhages. Grade 3 and 4 neutropenia occurred in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia occurred in 0.7% of patients. No patient developed grade 4 thrombocytopenia. Decreases in leukocyte 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 temporary interruption of therapy (median duration of these episodes was approximately one week). Treatment was permanently discontinued due to abnormal liver function test results in less than 1% of CML patients. In patients with gastrointestinal stromal tumors (study B2222), 6.8% of patients experienced grade 3 or 4 increases in ALT (alanine aminotransferase) levels and 4.8% experienced grade 3 or 4 increases in AST (aspartate aminotransferase) levels. Increases in bilirubin levels were observed in less than 3% of patients.

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

Description of selected adverse reactions

Hepatitis B reactivation

Hepatitis B reactivation has been reported in patients after taking a BCR-ABL tyrosine kinase inhibitor (TKI). In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in fatal outcomes.

Shelf life.

2 years.

Storage conditions. Store at temperatures not exceeding 30°C, in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister, 1 or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Hetero Labs Limited.

Manufacturer's address and location of business operations.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.