Imatinib-vista efg
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMATINIB-VISTA AC
Composition:
Active substance: imatinib;
1 tablet contains 119.5 mg or 478 mg of imatinib mesylate, equivalent to 100 mg or 400 mg of imatinib, respectively;
Excipients: microcrystalline cellulose (E 460), low-substituted hydroxypropylcellulose (E 463), povidone (E 1201), crospovidone (type A) (E 1202), colloidal anhydrous silicon dioxide (E 551), magnesium stearate (E 470b);
Coating: hypromellose (E 464), macrogol 400, talc (E 553b), red iron oxide (E 172), yellow iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
100 mg: film-coated tablets, from dark yellow to brownish-orange in color, round-shaped, with a break line on one side and '100' on the other side.
400 mg: film-coated tablets, from dark yellow to brownish-orange in color, oval-shaped, with a break line on one side and '400' on the other side.
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 kinases that strongly suppresses the activity of tyrosine kinase (TK) BCR-ABL, as well as certain receptor TKs: stem cell factor receptor Kit, encoded by the proto-oncogene c-Kit, 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 potently inhibits BCR-ABL tyrosine kinase in vitro, at the cellular level, and in vivo. This compound selectively inhibits proliferation and induces apoptosis in BCR-ABL-positive cell lines, as well as in freshly isolated leukemic cells from patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ 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 tyrosine kinase receptors 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, which are involved in the pathogenesis of MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasms), 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 imatinib is based on standard hematological and cytogenetic response rates and progression-free survival in CML (chronic myeloid leukemia), standard hematological and cytogenetic response rates in Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia), MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasms), and objective responses in GIST and unresectable DFSP (dermatofibrosarcoma protuberans).
Pharmacokinetics
The activity of imatinib was studied following doses ranging from 25 to 1000 mg. Plasma pharmacokinetic profiles 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 imatinib is 98%. Considerable interpatient variability in plasma AUC of imatinib was observed after oral administration. When administered with a high-fat meal, absorption of imatinib 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 administration under fasting conditions. The effect of prior gastrointestinal surgery on imatinib absorption has not been studied.
Distribution. In vitro data indicate that at clinically relevant concentrations, imatinib is 95% bound to plasma proteins (mainly to albumin and α1-acid glycoprotein, to a lesser extent 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. The plasma AUC of this metabolite is only 16% of the AUC of imatinib. 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 (AUC0–48h). 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 drugs with potential for interaction (acetaminophen, acyclovir, allopurinol, amphotericin B, 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. After 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 of imatinib 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 of imatinib. 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 administration, and accumulation at steady state was 1.5–2.5-fold with once-daily dosing.
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 prior population pharmacokinetic analysis in patients with GIST, three variables (albumin, white blood cell count, and bilirubin) were found to have a statistically significant relationship with imatinib pharmacokinetics. Decreased albumin levels led to reduced clearance (CL/f); higher white blood cell counts also reduced CL/f. However, this relationship was not pronounced enough to require dose adjustment. In this patient group, hepatic 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 in children achieved exposure comparable to 400 mg and 600 mg doses in adults, respectively. Comparison of AUC0–24 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 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 have no clinically significant effect on imatinib exposure. The analysis confirms that imatinib exposure in children receiving 260 mg/m² once daily (but not exceeding 400 mg once daily) or 340 mg/m² (but 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 patients with normal renal function. The increase is approximately 1.5–2-fold, corresponding to a 1.5-fold increase in plasma levels of α1-acid glycoprotein, to which imatinib is highly bound. Free imatinib clearance is likely similar in patients with renal impairment and those with normal renal function, as renal excretion is a minor elimination pathway for imatinib. Although pharmacokinetic analyses showed considerable interindividual 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. The medicinal product is indicated:
- for the treatment of patients (adults and children) with newly diagnosed Philadelphia chromosome-positive [Ph+] (with the 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;
- for the 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;
- for use in combination with chemotherapy in patients (adults and children) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the presence of the Philadelphia chromosome in leukocytes;
- as monotherapy in adult patients with acute lymphoblastic leukemia (Ph+ ALL) in relapsed or refractory disease;
- for the treatment of adult patients with myelodysplastic syndrome/myeloproliferative disorders (MDS/MPD) associated with rearrangement of the platelet-derived growth factor receptor (PDGFR) gene;
- for the treatment of adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα gene rearrangement.
The effect of the medicinal product in 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) after resection. Patients at low or minimal risk may not require adjuvant therapy;
- treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic dermatofibrosarcoma that cannot be surgically removed.
Contraindications. Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
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 metabolism and increase plasma concentrations of imatinib. A significant increase in parameters (mean Cmax and AUC of imatinib by 26% and 40%, respectively) was observed in healthy volunteers after co-administration of imatinib with a single dose of ketoconazole (a CYP3A4 inhibitor). The medicinal product should be used with caution when co-administered with CYP3A4 inhibitors.
Medicinal products that may reduce plasma concentrations of imatinib. 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 significantly reduce imatinib plasma concentrations, increasing the risk of treatment failure. When multiple doses of rifampicin (600 mg) were administered followed by a single dose of imatinib 400 mg, a reduction in maximum concentration (Cmax) and area under the concentration-time curve from 0 to ∞ (AUC0–∞) by 54% and 74%, respectively, was observed compared to values without rifampicin. Similar results were observed in patients with malignant glioma receiving imatinib during concomitant use of enzyme-inducing antiepileptic drugs such as carbamazepine, oxcarbazepine, and phenytoin. The AUC of imatinib in plasma 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 concentrations may be altered by imatinib. Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2-fold and 3.5-fold, respectively, indicating inhibition of CYP3A4 by imatinib. Therefore, caution should be exercised when co-administering the medicinal product with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase plasma concentrations of other medicinal products metabolized by CYP3A4 (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors such as statins). Due to the known increased risk of bleeding associated with imatinib (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 CYP2D6 isoenzyme of cytochrome P450 at concentrations similar to those affecting CYP3A4 activity. Imatinib at a dose of 400 mg twice daily inhibits CYP2D6-mediated metabolism of metoprolol, increasing the Cmax and AUC of metoprolol by approximately 23% (90% CI [confidence interval] 1.16–1.30). Dose adjustment does not appear necessary when imatinib is co-administered with CYP2D6 substrates, but caution is recommended for CYP2D6 substrates with a narrow therapeutic window, such as metoprolol. If a patient is taking metoprolol, clinical monitoring should be considered.
In vitro, imatinib inhibits the 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 co-administering high doses of imatinib and paracetamol.
In patients after thyroidectomy who are taking levothyroxine, plasma exposure to levothyroxine may be reduced when imatinib is co-administered. In such cases, caution is recommended. However, the mechanism of this interaction is currently unknown. There is clinical experience with concomitant use of imatinib and chemotherapy in patients with Ph+ ALL, but the interaction characteristics between imatinib and chemotherapy regimens are not fully defined. Adverse effects of imatinib may be intensified, particularly hepatotoxicity, myelosuppression, or others; concurrent use of L-asparaginase has also been reported to enhance hepatotoxic effects. Thus, the use of imatinib in combination requires precautionary measures.
Special precautions for use
When imatinib is prescribed together with other medicinal products, there is a potential risk of interaction. Caution should be exercised when using imatinib 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, increasing the risk of treatment inefficacy. 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 were receiving levothyroxine replacement therapy during imatinib treatment. In such patients, thyroid-stimulating hormone (TSH) levels should be closely monitored.
Hepatotoxicity. Imatinib is primarily metabolized 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 could lead to hepatic failure.
Hepatic injury, including hepatic failure and hepatic necrosis, has been observed. Severe hepatic function abnormalities have been reported during combination therapy with imatinib and high-dose chemotherapy agents. Liver function should be closely monitored, as imatinib combined with chemotherapy may cause hepatic dysfunction.
Fluid retention. Marked fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial swelling) occurred in approximately 2.5% of patients with newly diagnosed CML who received the drug. 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 should be initiated if necessary. During clinical trials, increased frequency of such events was observed in elderly patients and patients with a history of cardiovascular diseases. 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 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 associated with HES cell degranulation have been observed prior to initiation of imatinib therapy. These events were reversible with systemic steroids, hemodynamic support measures, and temporary discontinuation of imatinib. Cardiac adverse reactions during imatinib treatment 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 be evaluated by a cardiologist, undergo echocardiography, and have serum troponin levels determined before starting imatinib therapy. If pathological reactions occur, cardiology monitoring and prophylactic use of systemic steroids (1–2 mg/kg) for 1–2 weeks as concomitant therapy with imatinib during the initial treatment phase are recommended.
Gastrointestinal hemorrhage. During studies in patients with unresectable and/or metastatic GIST, gastrointestinal and intratumoral hemorrhages were reported. Based on available data, no predisposing factors (e.g., tumor size and location, coagulation disorders) have been identified that increase the risk of any type of hemorrhage in GIST patients. Since increased vascularity and bleeding tendency are part of the clinical presentation and course of GIST, standard practices and procedures for monitoring and managing all patients with hemorrhage should be applied. Additionally, during post-marketing surveillance in patients with CML, ALL, and other conditions, gastric antral vascular ectasias have been reported as a rare cause of gastrointestinal hemorrhage. If necessary, discontinuation of imatinib should be considered.
Tumor lysis syndrome. Due to the potential for tumor lysis syndrome, correction of clinically evident dehydration and elevated uric acid levels is recommended before initiating imatinib therapy.
Hepatitis B reactivation. Reactivation of hepatitis B has occurred in patients who are chronic carriers of the virus after they 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 hepatitis B virus (HBV) infection.
Patients with positive serological tests for hepatitis B (particularly 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 imatinib therapy. HBV carriers requiring imatinib treatment 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 use. Patients should be advised to use protective measures such as protective clothing and sunscreen with a high sun protection factor (SPF).
Thrombotic microangiopathy (TMA). The use of BCR-ABL tyrosine kinase inhibitors has been associated with thrombotic microangiopathy (TMA), including isolated cases during imatinib use (see section "Adverse reactions"). If patients receiving the drug develop laboratory or clinical signs of TMA, treatment should be discontinued and a thorough evaluation for TMA should be performed, including assessment of ADAMTS13 activity and testing for anti-ADAMTS13 antibodies. If anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity, imatinib therapy should not be resumed.
Laboratory tests. Complete blood counts should be performed regularly during imatinib therapy. Treatment of patients with chronic myeloid leukemia (CML) with imatinib is associated with the development of neutropenia or thrombocytopenia. However, the occurrence of these cytopenias depends on the disease phase during which treatment is administered and is more frequently observed in patients with CML in the accelerated phase or blast crisis compared to those in the chronic phase. The use of the drug 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 the drug.
In patients with impaired renal function, imatinib plasma concentrations are higher than in individuals with normal renal function, possibly due to increased plasma levels of alpha-1 acid glycoprotein—the protein that binds imatinib. The minimum initial dose should be used in patients with renal impairment. Caution should be exercised when treating patients with severe renal insufficiency. The dose should be reduced if not tolerated (see section "Dosage and administration").
Prolonged 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 dysfunction occurs, treatment should be administered according to standard medical practice.
Children. Cases of growth retardation have been reported in children, particularly in prepubertal children receiving imatinib. In an observational study involving children with CML, statistically significant (but of uncertain clinical significance) reductions in mean standard deviation scores for height were observed at 12 and 24 months of treatment in two small subgroups, regardless of sexual maturation or patient sex. Therefore, careful monitoring of growth in children receiving imatinib is recommended.
In adults and children, the efficacy of imatinib is evaluated based on the rates of overall hematologic and cytogenetic response and progression-free survival in CML, rates of hematologic and cytogenetic response in Ph+ ALL, MDS/MPD, rate of hematologic response in HES/CEL, and rate 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 imatinib use in patients with MDS/MPD associated with PDGFR (platelet-derived growth factor receptor) gene rearrangement is very limited. Except for newly diagnosed CML in the chronic phase, 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 are advised to use effective contraception during treatment and for at least 15 days after discontinuation of the drug.
Pregnancy. There are no adequate data on imatinib use in pregnant women. Spontaneous abortions and congenital defects in newborns whose mothers used imatinib have been reported in the post-marketing period. Animal studies have shown reproductive toxicity, but the potential risk to the fetus is unknown. The drug should not be used during pregnancy except in cases of life-threatening conditions. If the drug is administered during pregnancy, the patient should be informed of the potential risk to the fetus.
Breastfeeding. Information regarding the excretion of imatinib into breast milk is limited. Studies involving two breastfeeding women showed that imatinib and its active metabolite can be excreted into breast milk. The ratio of imatinib concentration in plasma to breast milk, determined in one patient, was 0.5 for imatinib and 0.9 for the metabolite, indicating a higher distribution of the metabolite into milk. Considering the total 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 doses of imatinib on infants is unknown, women receiving the drug should not breastfeed during treatment and for at least 15 days after discontinuation of imatinib.
Fertility. In preclinical studies, fertility in male and female rats was not impaired. Studies on the effect of imatinib on fertility and gametogenesis in humans have not been conducted. If a patient has concerns about the effect of imatinib on fertility, they should consult their physician.
Ability to affect reaction speed when driving or operating machinery
Patients should be aware of the possibility of developing adverse effects such as dizziness, blurred vision, or somnolence when using imatinib. Caution is recommended when driving or operating machinery.
Method of Administration and Dosage
Therapy should be administered by a physician experienced in the treatment of patients with malignant hematological neoplasms and malignant sarcomas, depending on the nosology.
For administration of imatinib doses of 400 mg and 800 mg (see dosage recommendations below), 400 mg tablets (non-divisible) should be used.
For administration of imatinib doses other than 400 mg and 800 mg (see dosage recommendations below), 100 mg tablets, which may be divided, should be used.
The prescribed doses should be taken orally with food and a large amount of water to minimize the risk of gastrointestinal irritation. The medicinal product at doses of 400 or 600 mg is administered once daily, whereas the 800 mg dose should be administered as 400 mg twice daily, in the morning and evening.
For patients unable to swallow the film-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 suspension should be consumed immediately after complete dissolution of the tablet.
Dosage in Chronic Myeloid Leukemia (CML) in Adult Patients
The recommended dose of imatinib 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 imatinib for adult patients with CML 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 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 imatinib for adult patients with blast crisis is 600 mg/day. Blast crisis is defined by blasts ≥ 30% in blood or bone marrow or presence of extramedullary manifestations of disease, excluding hepatosplenomegaly.
Duration of treatment: In clinical trials, imatinib treatment was continued until disease progression. The effect of discontinuing treatment after achieving complete cytogenetic response has not been studied.
Dose escalation from 400 mg to 600 mg or 800 mg for patients with chronic phase disease, or from 600 mg to a maximum of 800 mg (400 mg twice daily) for patients with accelerated phase or blast crisis, may be considered in the absence of severe adverse drug reactions and severe non-leukemia-related neutropenia or thrombocytopenia, under the following circumstances: 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 is based on body surface area (mg/m2). For children with CML in chronic phase and accelerated phase, the recommended dose is 340 mg/m2/day (but not exceeding 800 mg/day). The medicinal product may be administered once daily or the daily dose may be divided into two doses—morning and evening. The recommended doses are based on limited experience with imatinib in a small number of pediatric patients. There is no experience with imatinib use 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 in the absence of severe adverse drug reactions and severe non-leukemia-related neutropenia or thrombocytopenia, under the following circumstances: 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 imatinib 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 hematological expert throughout all phases of therapy.
Treatment regimen: The efficacy and safety of imatinib at a dose of 600 mg/day in combination with chemotherapy have been demonstrated in the induction, consolidation, and maintenance phases of chemotherapy for adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy may vary depending on the chosen treatment protocol, but generally, longer imatinib administration leads to better outcomes.
For adult patients with relapsed or refractory Ph+ ALL, monotherapy with imatinib 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 is based on body surface area (mg/m2). The recommended daily dose for children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is 340 mg/m2 (but not exceeding 600 mg/day).
Dosage in Myelodysplastic Syndrome/Myeloproliferative Disorders (MDS/MPD)
The recommended dose of imatinib 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 (24 days to 60 months).
Dosage in Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia (HES/CEL)
The recommended dose of imatinib 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 with inadequate response to treatment. Treatment should be continued as long as the patient continues to benefit.
Dosage for the Treatment of 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 imatinib 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, imatinib treatment was continued until disease progression. At the time of analysis, the median duration of treatment was 7 months (7 days to 13 months). The effect of discontinuing treatment after achieving response has not been studied.
The recommended dose of imatinib 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. The duration of treatment in clinical trials conducted to support the use of imatinib for this indication was 36 months.
Dosage for the Treatment of Unresectable Dermatofibrosarcoma Protuberans (DFSP) and Adult Patients with Recurrent and/or Metastatic Dermatofibrosarcoma Not Amenable to Surgical Resection
The recommended dose of imatinib for the treatment of adult patients with DFSP is 800 mg once daily.
Dose Adjustment in Case of Adverse Effects
Non-hematologic Adverse Effects
In the event of severe non-hematologic adverse effects during imatinib therapy, treatment should be discontinued until the patient's condition improves. Treatment may later be resumed, taking into account the severity of adverse effects experienced at the previous dose. If bilirubin levels are more than 3 times the upper limit of normal (or if liver transaminase levels exceed 5 times the upper limit of normal), imatinib should be discontinued until bilirubin levels decrease to less than 1.5 times the upper limit of normal and transaminase levels decrease to less than 2.5 times the upper limit of normal. Imatinib therapy may then be resumed at reduced daily doses. 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 children, the dose should be reduced from 340 to 260 mg/m2/day.
Hematologic Adverse Effects
In case of severe neutropenia and thrombocytopenia, dose reduction or discontinuation of imatinib is recommended as specified in Table 1.
Table 1
| Indications |
Parameters |
Recommendations |
| CML/ALL (initial dose 100 mg) |
ANC < 1.0 × 109/L and/or platelets < 50 × 109/L |
|
| Chronic phase CML, MDS/MPN, GIST (initial dose 400 mg); CML/ALL (at a dose of 400 mg) |
ANC < 1.0 × 109/L and/or platelets < 50 × 109/L |
|
| Children with chronic phase CML (at a dose of 340 mg/m²) |
ANC < 1.0 × 109/L and/or platelets < 50 × 109/L |
|
| Blast crisis phase of CML, Ph+ ALL (initial dose 600 mg) |
ANCa < 0.5 × 109/L and/or platelets < 10 × 109/L |
|
| Accelerated phase CML or blast crisis in pediatric patients (initial dose 340 mg/m²) |
ANCa < 0.5 × 109/L and/or platelet count < 10 × 109/L |
|
| Unresectable dermatofibrosarcoma protuberans (DFSP), as well as recurrent and/or metastatic dermatofibrosarcoma in adult patients not amenable to surgical removal (at a dose of 800 mg) |
ANC < 1.0 × 109/L and/or platelet count < 50 × 109/L |
|
| ANC — absolute neutrophil count. a Observed at least one month after initiation of treatment. |
||
Special populations
Hepatic impairment
Imatinib is primarily metabolized in the liver. For patients with mild, moderate, and severe hepatic impairment, the medicinal product should be administered at the minimum recommended daily dose of 400 mg. If the dose is not tolerated, it may be reduced.
Table 2
Classification of hepatic impairment
| Hepatic function impairment |
Hepatic function tests |
| Mild |
Total bilirubin — 1.5 ULN; AST > ULN (may be normal or < ULN if total bilirubin > ULN) |
| Moderate |
Total bilirubin > 1.5–3.0 ULN; AST — any value |
| Severe |
Total bilirubin > 3–10 ULN; AST — any value |
ULN — upper limit of normal, as defined by the medical institution.
AST — aspartate aminotransferase.
Renal impairment
The medicinal product should be administered at the minimum recommended starting dose of 400 mg once daily in patients with renal impairment or patients on dialysis. However, the medicinal product should be used with caution in such patients. The dose may be reduced in case of intolerance to imatinib or increased in case of insufficient efficacy.
Elderly patients
The pharmacokinetics of imatinib in elderly patients has not been specifically studied. During clinical trials involving 20% of patients aged 65 years and older, no age-related differences in the pharmacokinetics of imatinib were observed. There are no specific dosage recommendations for elderly patients.
Children
There is no experience with the use of imatinib in children under 2 years of age with CML, or in children under 1 year of age with Ph+ ALL. Experience in treating children with MDS/MPS, dermatofibrosarcoma protuberans, GIST, and GES/HEL is very limited.
The safety and efficacy of imatinib in children (under 18 years of age) with MDS/MPS, DFSP, GIST, and GES/HEL have not been established in clinical trials. Currently available published data do not allow for dosage recommendations.
Overdose
Symptoms
Information regarding cases of imatinib 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 monitored and appropriate supportive therapy should be administered. In general, symptoms improved or resolved in the reported cases. The following manifestations have been reported at various dose ranges.
Overdose in adults
1200 to 1600 mg (duration from 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 of 6 days in the case of 3200 mg daily): weakness, myalgia, increased levels of creatine phosphokinase, 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 intake of imatinib 980 mg — decreased leukocyte count, diarrhea.
Treatment
In case of overdose, the patient requires monitoring and appropriate symptomatic treatment.
Adverse Reactions
Patients with end-stage malignancy may be in a condition where it is difficult to assess the causal relationship between adverse effects and drug action due to the presence of numerous symptoms from the underlying disease, its progression, and concomitant administration of multiple medications.
In clinical studies involving patients with CML, discontinuation of imatinib due to adverse drug reactions was required in 2.4% of patients with newly diagnosed CML, 4% of patients with late chronic-phase CML after ineffective interferon therapy, 4% of patients with accelerated-phase CML after ineffective interferon therapy, and 5% of patients with blast crisis after ineffective interferon therapy. In GIST cases, imatinib treatment was discontinued due to adverse reactions in 4% of patients.
Adverse reactions were similar across all indications, except for two. Patients with CML experienced more cases of myelosuppression compared to patients with gastrointestinal stromal tumors (GIST), likely due to the underlying disease. In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors, grade 3/4 gastrointestinal (GI) bleeding 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 tumor hemorrhages can be severe and sometimes fatal. For both diseases, the most common (≥10%) drug-related adverse reactions were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle spasms, and rash. Superficial edema was common across all studies and was primarily described as periorbital edema or peripheral 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 imatinib.
When imatinib was used in combination with high-dose chemotherapy in patients with Ph+ ALL, hepatotoxic effects were observed, including elevated transaminase levels and hyperbilirubinemia. Available safety data suggest that adverse reactions in children are comparable to those in adult patients with Ph+ ALL. The safety profile for children with Ph+ ALL remains limited, but no new safety concerns have been identified.
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 are usually manageable by temporarily interrupting imatinib therapy or with diuretics and other appropriate supportive measures. However, in some cases, these reactions may be serious or life-threatening: certain events occurring in patients with blast crisis resulted in fatalities (with clinical histories including pleural effusion, congestive heart failure, and renal failure). In pediatric clinical trials, there were no specific serious events related to imatinib use.
The adverse reactions listed in Table 3 below occurred more frequently than isolated cases. Adverse reactions are classified by organ systems 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).
Table 3
| Infections and infestations |
|
| Uncommon |
Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis |
| Rare |
Fungal infection |
| Frequency unknown |
Reactivation of hepatitis B* |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
|
| Rare |
Tumour lysis syndrome |
| Frequency unknown |
Tumour haemorrhage / tumour necrosis* |
| Immune system disorders |
|
| Frequency unknown |
Anaphylactic shock* |
| Blood and lymphatic system disorders |
|
| Very common |
Neutropenia, thrombocytopenia, anemia |
| Common |
Pancytopenia, febrile neutropenia |
| Uncommon |
Thrombocytopenia, lymphopenia, bone marrow suppression, eosinophilia, lymphadenopathy |
| Rare |
Hemolytic anemia, thrombotic microangiopathy |
| Metabolism and nutrition disorders |
|
| Common |
Anorexia |
| Uncommon |
Hypokalemia, increased appetite, hypophosphatemia, decreased appetite, dehydration, gout, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia |
| Rare |
Hyperkalemia, hypomagnesemia |
| Psychiatric disorders |
|
| Common |
Insomnia |
| Uncommon |
Depression, decreased libido, anxiety |
| Rare |
Confusion |
| Nervous system disorders |
|
| Very common |
Headache2 |
| Common |
Dizziness, paraesthesia, taste disturbance, hypoaesthesia |
| Uncommon |
Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, intracranial haemorrhage |
| Rare |
Increased intracranial pressure, seizures, optic neuritis |
| Frequency unknown |
Brain edema* |
| Eye disorders |
|
| Common |
Periorbital edema, increased lacrimation, conjunctival haemorrhage, conjunctivitis, dry eyes, blurred vision |
| Uncommon |
Eye irritation, eye pain, orbital edema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular edema |
| Rare |
Cataract, glaucoma, optic disc edema |
| Frequency unknown |
Vitreous haemorrhage* |
| Ear and labyrinth disorders |
|
| Uncommon |
Vertigo, tinnitus, hearing loss |
| Cardiac disorders |
|
| Uncommon |
Palpitations, tachycardia, congestive heart failure3, pulmonary edema |
| Rare |
Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion |
| Frequency unknown |
Pericarditis*, cardiac tamponade* |
| Vascular disorders4 |
|
| Common |
Hyperemia, bleeding |
| Uncommon |
Arterial hypertension, hematoma, subdural hematoma, cold sensation in extremities, arterial hypotension, Raynaud's syndrome |
| Frequency unknown |
Thrombosis/embolism* |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
Dyspnea, epistaxis, cough |
| Uncommon |
Pleural effusion5, throat and larynx pain, pharyngitis |
| Rare |
Pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage |
| Frequency unknown |
Acute respiratory failure11*, interstitial lung disease* |
| Gastrointestinal disorders |
|
| Very common |
Nausea, diarrhea, vomiting, dyspepsia, abdominal pain6 |
| Common |
Flatulence, abdominal distension, gastroesophageal reflux, constipation, dry mouth, gastritis |
| Uncommon |
Stomatitis, oral ulceration, gastrointestinal haemorrhage7, eructation, melena, esophagitis, ascites, gastric ulcer, vomiting of blood, cheilitis, dysphagia, pancreatitis |
| Rare |
Colitis, intestinal obstruction, inflammatory bowel disease |
| Frequency unknown |
Intestinal obstruction / bowel obstruction*, gastrointestinal perforation*, diverticulitis*, vascular ectasia of gastric antrum* |
| Hepatobiliary disorders |
|
| Common |
Elevated liver enzymes |
| Uncommon |
Hyperbilirubinemia, hepatitis, jaundice |
| Rare |
Hepatic failure8, liver necrosis |
| Skin and subcutaneous tissue disorders |
|
| Very common |
Periorbital edema, dermatitis/eczema/rash |
| Common |
Pruritus, facial swelling, dry skin, erythema, alopecia, night sweats, photosensitivity reaction |
| Uncommon |
Pustular rash, bruising, excessive sweating, urticaria, ecchymosis, increased tendency to bruising, hypotrichosis, hypopigmentation of skin, exfoliative dermatitis, brittle nails, folliculitis, petechiae, psoriasis, purpura, hyperpigmentation of skin, bullous rashes, panniculitis12 |
| Rare |
Acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discoloration, angioneurotic edema, vesicular rash, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, severe skin reactions and rashes, pemphigus* |
| Frequency unknown |
Palmar-plantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria* |
| Musculoskeletal and connective tissue disorders |
|
| Very common |
Muscle spasms and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain10 |
| Common |
Joint swelling |
| Uncommon |
Joint and muscle stiffness, osteonecrosis* |
| Rare |
Muscle weakness, arthritis, rhabdomyolysis/myopathy |
| Frequency unknown |
Impaired growth in children* |
| Renal and urinary disorders |
|
| Uncommon |
Renal pain, hematuria, acute renal failure, increased frequency of urination |
| Frequency unknown |
Chronic renal failure |
| Reproductive system and breast disorders |
|
| Uncommon |
Gynecomastia, erectile dysfunction, menorrhagia, irregular menstrual cycle, sexual dysfunction, nipple pain, breast enlargement, scrotal edema |
| Rare |
Hemorrhagic corpus luteum cyst / hemorrhagic ovarian cyst |
| General disorders and administration site conditions |
|
| Very common |
Fluid retention and edema, fatigue |
| Common |
Weakness, pyrexia, anasarca, chills, shivering |
| Uncommon |
Chest pain, malaise |
| Investigations |
|
| Very common |
Weight increased |
| Common |
Weight decreased |
| Uncommon |
Elevated blood creatinine, elevated blood creatine phosphokinase, elevated blood lactate dehydrogenase, elevated blood alkaline phosphatase |
| Rare |
Elevated blood amylase |
* These types of reactions were mainly observed during the post-marketing period of imatinib use. They include cases reported spontaneously, as well as serious adverse effects observed in long-term studies, expanded access programs, clinical pharmacology studies, and investigational use outside approved indications. Since these reactions were observed in populations of uncertain size, it is not always possible to reliably determine their frequency or establish a causal relationship with imatinib use.
1 Pneumonia was most frequently observed in patients with transformed CML and patients with gastrointestinal stromal tumors.
2 Headache occurred most frequently in patients with gastrointestinal stromal tumors.
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 most frequently observed in patients with gastrointestinal stromal tumors, while hemorrhages (hematomas, hemorrhages) occurred most frequently in patients with gastrointestinal stromal tumors and transformed CML (in the accelerated phase and blast crisis phase).
5 Pleural effusion was observed more frequently in patients with gastrointestinal stromal tumors and patients with transformed CML (in the accelerated phase and blast crisis phase) than in patients with chronic phase CML.
6+7 Abdominal pain and gastrointestinal hemorrhages were most frequent in patients with gastrointestinal stromal tumors.
8 There have been reports of some fatal cases of liver failure and liver necrosis.
9 Musculoskeletal pain occurred during post-marketing studies either during treatment with imatinib or after discontinuation of treatment.
10 Musculoskeletal pain and similar reactions were observed more frequently in patients with CML than in patients with gastrointestinal stromal tumors.
11 Fatal cases have been reported in patients with advanced stages of disease, 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 with higher doses ≥ 750 mg (Phase I studies). However, the occurrence of neutropenia also has a clear association with disease stage; the frequency of grade 3 or 4 neutropenia (ANC [absolute neutrophil count] < 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 CML in chronic phase (16.7% for neutropenia and 8.9% for 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 neutropenia and thrombocytopenia episodes ranged from 2 to 3 weeks and 3 to 4 weeks, respectively. These events are usually manageable by dose reduction or temporary interruption of imatinib, but rarely lead to permanent discontinuation of therapy. In pediatric patients with CML, the most common manifestation of toxicity is grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia, and anemia. These events mostly occur within the first few months of therapy.
In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors, grade 3 and 4 anemia was observed in 5.4% and 0.7% of patients, respectively, and in at least some of these patients could be related to gastrointestinal or intratumoral hemorrhages. Grade 3 and 4 neutropenia 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 leukocyte and neutrophil counts were observed primarily within the first six weeks of therapy; thereafter, counts remained relatively stable.
Biochemical blood analysis
Marked elevations in transaminases (<5%) or bilirubin (<1%) were observed in CML patients and were mostly managed by dose reduction or temporary interruption of therapy (median duration of these events was approximately one week). Treatment was permanently discontinued due to abnormal liver function laboratory values 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). Elevated bilirubin levels were reported in less than 3% of patients.
Cases of hepatocellular and cholestatic hepatitis and liver failure have been reported; some of these were fatal, including in one patient who was taking high doses of paracetamol.
Description of selected adverse reactions
Hepatitis B reactivation. Reactivation of hepatitis B has been reported in patients after taking a BCR-ABL tyrosine kinase inhibitor. 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 adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua
Shelf life. 3 years.
Storage conditions. No special storage conditions required. Keep out of reach of children.
Packaging. 100 mg tablets: 10 tablets in a blister; 12 blisters in a cardboard pack.
400 mg tablets: 10 tablets in a blister; 3 blisters in a cardboard pack.
Prescription category. Prescription only.
Manufacturer. REMEDICA LTD
Manufacturer's address and location of its business operations
Acharnon Street, Limassol Industrial Estate, Limassol, 3056, Cyprus