Glivec

INSTRUCTIONS for medical use of the medicinal product GLIVEK® (GLIVEK®)

Composition:

Active substance: imatinib;

1 tablet contains imatinib mesylate equivalent to 100 mg or 400 mg of imatinib;
Excipients: tablet core: microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate, colloidal anhydrous silicon dioxide;
coating: iron oxide red (E 172), iron oxide yellow (E 172), macrogol, talc, hypromellose.

Medicinal form. Film-coated tablets.

Main physico-chemical properties:

film-coated tablets 100 mg: round, biconvex, bevelled edges, from very dark yellow to brownish-orange in colour, with a score line on one side and the imprint "NVR" on one side and "SA" (with the score line between the letters) on the other;

film-coated tablets 400 mg: oval, biconvex, bevelled edges, from very dark yellow to brownish-orange in colour, with the imprint "400" on one side and a score line on the other side with the imprint "SL" (on each side of the score line).

Pharmacotherapeutic group.

Antineoplastic agents. BCR-ABL tyrosine kinase inhibitors. Imatinib.

ATC code L01E A01.

Pharmacological Properties

Pharmacodynamics

Imatinib is a low molecular weight inhibitor of protein-tyrosine kinase that potently inhibits the activity of tyrosine kinase (TK) Bcr-Abl, 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-α and PDGFR-β). Imatinib may also inhibit cellular processes mediated by activation of these receptor kinases.

Imatinib is a protein-tyrosine kinase inhibitor that strongly suppresses 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 (Ph+) chronic myeloid leukemia (CML) 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 receptors for platelet-derived growth factor (PDGF), embryonic cell factor (ECF), and c-Kit, and suppresses PDGF- and ECF-mediated cellular changes. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells expressing activated Kit mutations.

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

The efficacy of Glivec® is based on standard hematologic and cytogenetic response rates and progression-free survival in CML, standard hematologic 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 drug's effects were studied following doses ranging from 25 to 1000 mg. Plasma pharmacokinetic profiles were analyzed on Day 1 and again on Day 7 or Day 28, when steady-state plasma concentrations had been achieved.

Absorption. The mean absolute bioavailability of the drug is 98%. Marked inter-individual variability in plasma AUC of imatinib was observed after oral administration. When administered with a high-fat meal, imatinib absorption was minimally reduced (11% decrease in Cmax and 1.5-hour prolongation of tmax) with a slight reduction in AUC (7.4%) compared to fasting conditions. The effect 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, with minor binding to lipoproteins.

Metabolism. The major circulating metabolite in humans is the N-demethylated derivative of piperazine, which demonstrates in vitro potency similar to that of the parent compound. Plasma AUC for 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(0–48h)). 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 relevance.

In vitro data demonstrate that imatinib is a competitive inhibitor of marker substrates for CYP2C9, CYP2D6, and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5, and 7.9 µmol/L, respectively. Maximum plasma concentrations of imatinib in patients range from 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 it 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 clinically significant interaction is expected when 5-fluorouracil or paclitaxel is co-administered with imatinib.

Excretion. After oral administration of radiolabeled 14C-imatinib, approximately 81% of the dose is excreted within 7 days, with 68% in feces and 13% in urine. About 25% of the dose is excreted unchanged (20% in feces and 5% in urine). The remainder is 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 was linear and dose-proportional following oral imatinib doses ranging from 25 mg to 1000 mg. No changes in imatinib kinetics were observed after repeated dosing, and accumulation at steady state with once-daily administration was 1.5–2.5-fold.

Pharmacokinetics in Patients with Gastrointestinal Stromal Tumors (GIST)

In patients with gastrointestinal stromal tumors, steady-state exposure was 1.5-fold higher than in patients with CML receiving the same dose (400 mg daily). Based on prior population pharmacokinetic analysis, three variables (albumin, leukocyte count, and bilirubin) were found to have a statistically significant relationship with imatinib pharmacokinetics in GIST patients. Decreased albumin levels were associated with reduced clearance (CL/f); higher leukocyte counts were associated with reduced CL/f. However, this relationship was not strong enough to require dose adjustment. In this patient group, hepatic metastases may likely contribute 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 are expected to have a mean clearance of 8.5 L/h, while those 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 in children achieved exposure comparable to 400 mg and 600 mg doses in adults, respectively. Comparison of AUC(0–24) on Day 8 versus Day 1 with a dose of 340 mg/m²/day showed 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 had no clinically significant impact on imatinib exposure. The analysis confirms that imatinib exposure in children receiving 260 mg/m² once daily (not exceeding 400 mg once daily) or 340 mg/m² (not exceeding 600 mg once daily) is similar to that in adults receiving 400 mg or 600 mg once daily.

Organ Dysfunction

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 1.5–2-fold, 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 analyses revealed substantial 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+) (presence of the Philadelphia chromosome (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 phase of the disease;
• in combination chemotherapy of 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 acute lymphoblastic leukemia (Ph+ ALL) in relapse or refractory disease;
• 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 Glivec® in combination with 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 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, locally advanced dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic dermatofibrosarcoma that cannot be surgically removed.

Contraindications. Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Medicinal products that may increase plasma concentrations of imatinib

Active substances that inhibit the activity of CYP3A4 isoenzymes 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 imatinib metabolism and increase its plasma concentration. A significant increase (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). Glivec® should be used with caution when co-administered with CYP3A4 inhibitors.

Medicinal products that may decrease plasma concentrations of imatinib

Active 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 Glivec® 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 administration without rifampicin. Similar results were observed in patients with malignant glioma receiving Glivec® while taking enzyme-inducing antiepileptic drugs such as carbamazepine, oxcarbazepine, and phenytoin. Plasma AUC of imatinib 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 plasma concentrations may be altered by Glivec®

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, caution is advised when co-administering Glivec® with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine).

Glivec® may increase plasma concentrations of other drugs metabolized by CYP3A4 (e.g., 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 anticoagulation should receive low-molecular-weight or standard heparin rather than coumarin derivatives such as warfarin.

In vitro, Glivec® inhibits the activity of the CYP2D6 isoenzyme of cytochrome P450 at concentrations similar to those affecting CYP3A4 activity. Imatinib at a dose of 400 mg twice daily has shown 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 that have a narrow therapeutic window, such as metoprolol. Clinical monitoring should be considered for patients receiving metoprolol.

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

Therefore, caution is required when high doses of Glivec® and paracetamol are used concomitantly.

In patients after thyroidectomy who are taking levothyroxine, plasma exposure to levothyroxine may be reduced when Glivec® 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 Glivec® 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 enhanced, particularly hepatotoxicity, myelosuppression, or other toxicities; concomitant use of L-asparaginase has also been reported to increase liver toxicity. Therefore, use of Glivec® in combination regimens requires precautionary measures.

Special precautions for use.

When prescribing Gleevec® concomitantly with other medicinal products, there is a potential risk of drug interactions. The concomitant use of Gleevec® with other drugs carries the potential for drug interactions. Caution should be exercised when administering Gleevec® 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 Gleevec® may be significantly reduced, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided.

Hypothyroidism

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

Hepatotoxicity

Metabolism of Gleevec® occurs primarily in the liver, with only 13% metabolized by the kidneys. In patients with hepatic dysfunction (mild, moderate, or severe), peripheral blood counts and liver enzymes should be carefully monitored. It should be noted that patients with GIST may have liver metastases, which can lead to hepatic failure.

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

Severe impairment of liver function has been observed during combination therapy of Gleevec® with high-dose chemotherapy agents. Liver function should be closely monitored, as imatinib combined with chemotherapy may cause its 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 treated with Gleevec®. 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 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 with any 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 events were reversible with systemic steroids, hemodynamic support measures, and temporary discontinuation of imatinib. Cardiac adverse reactions during imatinib administration have been infrequent. Benefit/risk of imatinib therapy should be carefully assessed prior to initiation in the HES/CEL population. Myelodysplastic/myeloproliferative disorders with PDGFRA 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 referred for cardiology consultation prior to initiation of imatinib therapy, undergo echocardiography, and have serum troponin levels determined. If pathological reactions are observed, 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 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 hemorrhage should be applied.

Additionally, post-marketing surveillance reports have described gastric antral vascular ectasia as a rare cause of gastrointestinal hemorrhage in patients with CML, ALL, and other conditions. If necessary, discontinuation of Gleevec® 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 prior to initiation of Gleevec® therapy.

Hepatitis B reactivation

Hepatitis B reactivation in patients who are chronic carriers of this virus has occurred after these patients received 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 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. Patients who are hepatitis B virus carriers and require treatment with Gleevec® should be carefully monitored for signs of active hepatitis B infection during treatment and for several months after completion of therapy.

Photosensitivity

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

Thrombotic microangiopathy

The use of BCR-ABL tyrosine kinase inhibitors has been associated with thrombotic microangiopathy (TMA), including isolated reports with Gleevec® (see section "Adverse reactions"). If patients receiving Gleevec® 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 anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity, treatment with Gleevec® should not be continued.

Laboratory tests

Complete blood counts should be performed regularly during Gleevec® therapy. Treatment of patients with chronic myeloid leukemia with Gleevec® 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 frequently observed in patients with CML in the accelerated phase or blast crisis phase compared to patients with CML in the chronic phase. Treatment with Gleevec® 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 Gleevec®.

Exposure to imatinib in plasma is higher in patients with impaired renal function than in individuals with normal renal function, possibly due to increased plasma levels of alpha-1 acid glycoprotein, a protein that binds imatinib. Patients with impaired renal function should receive the minimum initial dose. Patients with severe renal insufficiency should be treated with caution. The dose should be reduced in case of intolerance (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 initiation of imatinib therapy and monitored during treatment, with particular attention to patients who have risk factors for renal dysfunction. If renal dysfunction is observed, treatment should be administered according to standard guidelines.

Children

Cases of growth retardation have been reported in children and prepubertal children receiving imatinib. In an observational study involving children with CML, statistically significant reductions (but of uncertain clinical significance) in mean standard deviation scores for height were observed at 12 and 24 months of treatment in two small subgroups, regardless of patient sex or pubertal status. Therefore, careful monitoring of growth in children receiving imatinib is recommended.

In adults and children, the efficacy of Gleevec® is evaluated based on data regarding 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 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 Gleevec® in patients with MDS/MPD associated with PDGFR gene rearrangement is very limited. Except for newly diagnosed chronic phase CML, controlled studies demonstrating clinical benefit or increased survival in these conditions have not been conducted.

Use during pregnancy or breastfeeding.

Women of reproductive potential.

Women of reproductive potential should be advised to use effective contraception during treatment and for at least 15 days after discontinuation of Gleevec®.

Pregnancy. There are no adequate data on the use of Gleevec® in pregnant women. In the post-marketing period, spontaneous abortions and congenital defects in newborns whose mothers received Gleevec® have been reported. However, animal studies have revealed reproductive toxicity, and the potential risk to the fetus is unknown. Gleevec® should not be used during pregnancy except in life-threatening situations. If the drug is administered during pregnancy, the patient should be informed of the potential risk to the fetus.

Lactation. Information regarding 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 milk. Considering the combined 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 impact of low-dose imatinib exposure on the infant is unknown, women receiving Gleevec® should not breastfeed during treatment and for at least 15 days after discontinuation of Gleevec®.

Fertility. Fertility in male and female rats was not impaired in preclinical studies. Studies in patients receiving Gleevec® to evaluate the effect of the drug on fertility and gametogenesis have not been conducted. If a patient has concerns about the effect of Gleevec® 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 during imatinib administration. Therefore, patients should be advised to exercise caution when driving or operating machinery.

Administration and Dosage

Treatment should be administered by a physician experienced in the management of patients with hematologic malignancies and malignant sarcomas, depending on the specific nosology.

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

For doses other than 400 mg and 800 mg (see dosage recommendations below), 100 mg tablets, which are divisible, 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 drug is administered at doses of 400 or 600 mg once daily. The 800 mg dose should be administered as 400 mg twice daily, in the morning and evening.

For patients unable to swallow film-coated tablets, the tablet 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 suspension should be consumed immediately after complete dissolution of the tablet.

Dosage in Chronic Myeloid Leukemia (CML) in Adult Patients

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

The recommended dose of Gleevec® for adult patients in the accelerated phase is 600 mg/day. 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 promyelocytes ≥ 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 Gleevec® for adult patients with blast crisis is 600 mg/day. 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 studies, treatment with Gleevec® was continued until disease progression. The effect of discontinuing treatment after achieving a complete cytogenetic response has not been studied.

Dose escalation from 400 mg to 600 mg or 800 mg may be considered for patients in the chronic phase, or from 600 mg to a maximum of 800 mg (administered as 400 mg twice daily) for patients in the accelerated phase or blast crisis, provided there are no severe adverse drug 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 treatment; lack of cytogenetic response after 12 months of treatment; 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

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

Dose escalation from 340 mg/m² to 570 mg/m² (without exceeding a total dose of 800 mg) may be considered for children, provided there are no severe adverse drug 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 treatment; lack of cytogenetic response after 12 months of treatment; 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 Gleevec® for the treatment of adult patients with Ph+ ALL is 600 mg/day. Treatment for this condition should be conducted under the supervision of a hematologic oncology expert throughout all phases of therapy.

Treatment regimen: Based on available data, the efficacy and safety of Gleevec® at a dose of 600 mg/day in combination with chemotherapy have been demonstrated during induction, consolidation, and maintenance phases of chemotherapy for adult patients with newly diagnosed Ph+ ALL. The duration of Gleevec® 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 Gleevec® at a dose of 600 mg/day is safe and effective and may be continued until disease progression.

Dosage in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in Pediatric Patients

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

Dosage in Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

The recommended dose of Gleevec® 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; treatment with Gleevec® 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 Gleevec® 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 who do not experience adverse reactions and who have an inadequate response to treatment.

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) 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 Gleevec® for the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) is 400 mg once daily. Data on 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, treatment with Gleevec® 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 discontinuing treatment after achieving a response has not been studied.

The recommended dose of Gleevec® for adjuvant treatment of adult patients after resection of gastrointestinal stromal tumors is 400 mg/day. 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 Treatment of Patients with Unresectable, Locally Advanced Dermatofibrosarcoma Protuberans (DFSP) and Adult Patients with Recurrent and/or Metastatic Dermatofibrosarcoma Not Amenable to Surgical Resection

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

Dose Modifications in the Event of Adverse Effects

Non-hematologic Adverse Effects

In the event of severe non-hematologic adverse effects during treatment with Gleevec®, therapy should be interrupted until improvement in the patient's condition. Treatment may then be resumed at a dose adjusted according to the severity of the adverse effects observed at the previous dose.

If bilirubin levels are more than 3 times the upper limit of normal (or if liver transaminase levels are elevated more than 5 times the upper limit of normal), administration of Gleevec® should be withheld until bilirubin decreases to less than 1.5 times the upper limit of normal and transaminases decrease to less than 2.5 times the upper limit of normal. Treatment with Gleevec® may then be resumed at reduced daily doses. For adults, the dose should be reduced from 400 to 300 mg/day or from 600 to 400 mg/day, or from 800 mg 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 interruption of treatment is recommended as outlined in Table 1.

Table 1

Special Populations

Hepatic impairment

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

Classification of hepatic impairment

Table 2

ULN – upper limit of normal, as defined by the treating institution.

AST – aspartate aminotransferase.

Renal impairment

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

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 Gleevec® 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/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. Currently available published data do not allow for dosage recommendations.

Overdose.

Information regarding administration of doses exceeding the recommended therapeutic doses is limited. Isolated cases of overdose with Gleevec® have been reported (spontaneously or mentioned in publications). In case of overdose, the patient should be monitored and appropriate supportive treatment should be administered. In general, outcomes in such cases have been described as improvement or resolution of symptoms. The following events have been reported at various dose ranges.

Overdose in adults.

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

1800 to 3200 mg (duration 6 days 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, and 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 received a single dose of 400 mg, vomiting, diarrhea, and anorexia were observed; in another 3-year-old boy after a single dose of 980 mg – decreased white blood cell count and diarrhea.

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

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 trials involving patients with CML, discontinuation of the drug due to adverse drug reactions was observed in 2.4% of newly diagnosed patients, 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 the case of GIST, the investigational drug was discontinued due to drug-related adverse reactions in 4% of patients.

Adverse reactions were similar across all indications, except for two. In patients with CML, more cases of myelosuppression were observed compared to patients with gastrointestinal stromal tumors, likely due to the underlying disease. During 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 site of gastrointestinal tumor localization may be the source of gastrointestinal bleeding. Gastrointestinal and tumor hemorrhages can be severe and sometimes fatal. For both conditions, the most frequently reported (≥10%) drug-related adverse reactions included mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle spasms, and rash. Superficial edema was common in all studies and was predominantly described as periorbital edema or edema of the lower extremities. However, these edemas were rarely severe and could be managed with diuretics, other supportive measures, or by reducing the dose of Gleevec®.

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, the adverse reactions reported in children to date are comparable to the safety profile in adult patients with Ph+ ALL. The safety profile for children with Ph+ ALL is very limited, but 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 Gleevec® therapy or with diuretics and other appropriate supportive measures. However, occasionally these reactions may be serious or life-threatening, and some reactions occurring in patients with blast crisis were fatal (pleural effusion, congestive heart failure, and renal failure were noted in the patient's clinical history). No specific safety-related events were observed in pediatric clinical trials.

Adverse reactions occurring more frequently than isolated cases are classified by system organ classes and frequency using the following conventional terms: 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).

The adverse reactions and their frequencies are listed in Table 3.

Table 3

* These types of reactions were observed primarily during the post-marketing use of Gleevec®. 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. Because these reactions were reported in populations of uncertain size, it is often not possible to reliably estimate their frequency or establish a causal relationship to imatinib use.

1 Pneumonia was reported most frequently in patients with transformed CML and 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-phase CML.

4 Flushing was reported most frequently in patients with gastrointestinal stromal tumors (GIST), and hemorrhagic events (hematomas, hemorrhages) – 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 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 There have been reports of some fatal cases of liver failure and hepatic necrosis.

9 Musculoskeletal pain during or after discontinuation of imatinib treatment was observed during post-marketing surveillance.

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 comorbid conditions.

12 Including nodular erythema.

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, it should be noted that the occurrence of neutropenia is also clearly 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 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 patients with 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 neutropenic and thrombocytopenic episodes was 2–3 weeks and 3–4 weeks, respectively. These events are usually managed by dose reduction or temporary interruption of Gleevec®; however, in rare cases, they may lead to permanent discontinuation of therapy. In pediatric patients with CML, grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia, and anemia, are the most common manifestations of toxicity. These events mostly occur during the first few months of therapy.

In a study of 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 may have been associated with gastrointestinal or intratumoral hemorrhage. Grade 3 and 4 neutropenia occurred 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 occurred predominantly during the first six weeks of therapy; thereafter, values remained relatively stable.

Biochemical blood tests

Marked elevations in transaminases (<5%) or bilirubin (<1%) were observed in CML patients and were mostly managed by dose reduction or temporary treatment interruption (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 elevation in ALT (alanine aminotransferase) and 4.8% experienced grade 3 or 4 elevation in AST (aspartate aminotransferase). Bilirubin elevation occurred in less than 3% of patients.

Cases of cytolytic and cholestatic hepatitis and hepatic failure have been reported, some of which were fatal, including in 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 administration of BCR-ABL tyrosine kinase inhibitors (TKIs). In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in death.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life

3 years.

Storage conditions.

100 mg tablets.

Store at temperatures not exceeding 30°C, in the original packaging. Keep out of reach and sight of children.

400 mg tablets.

Store at temperatures not exceeding 25°C, in the original packaging. Keep out of reach and sight of children.

Packaging.

100 mg tablets: 10 tablets in a blister; 6 blisters in a carton.

400 mg tablets: 10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

1. Novartis Pharma Stein AG / Novartis Pharma Stein AG (full-cycle manufacturing)
2. Novartis Pharma Produktions GmbH / Novartis Pharma Produktions GmbH (full-cycle manufacturing)
3. Lek Pharmaceuticals d.d., Production site Lendava / Lek Pharmaceuticals d.d., PE Proizvodnja Lendava (primary and secondary packaging, batch release)

Manufacturer's address and location of operations.

1. Schaffhauserstrasse, 4332 Stein, Switzerland
2. Oeflinger Strasse 44, 79664 Wehr, Germany
3. Trimlini 2d, Lendava/Lendva, 9220, Slovenia