Imatinib shilpa
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMATINIB SHILPA
Composition:
Active substance: imatinib (in the form of imatinib mesylate);
1 tablet contains 119.50 mg of imatinib mesylate equivalent to 100 mg of imatinib;
1 tablet contains 478.00 mg of imatinib mesylate equivalent to 400 mg of imatinib;
Excipients: povidone K-30, magnesium stearate, Opadry Brown 02F86982 film-coating composition.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
100 mg film-coated tablets: round, biconvex, with bevelled edges, from dark yellow to brownish-orange in color, with a break line on one side and inscriptions “S” and “1” separated by the line;
400 mg film-coated tablets: capsule-shaped, biconvex, with bevelled edges, from dark yellow to brownish-orange in color, with inscriptions “S” and “2” on one side.
Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors. Imatinib.
ATC code L01XE01.
Pharmacological Properties.
Pharmacodynamics.
Imatinib is a low-molecular-weight inhibitor of protein-tyrosine kinase that strongly suppresses the activity of Bcr-Abl tyrosine kinase (TK), as well as certain receptor TKs: 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 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 suppresses PDGF- and SCF-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 kinases, resulting from gene fusion or overproduction of PDGF, is involved in the pathogenesis of MDS/MPD (myelodysplastic/myeloproliferative disorders), HES/CEL (hypereosinophilic syndrome/chronic eosinophilic leukemia), and DFSP (dermatofibrosarcoma protuberans). Imatinib inhibits signaling pathways leading to cell proliferation driven by activated PDGFR and Bcr-Abl tyrosine kinase activity.
The efficacy of imatinib is based on standard hematologic and cytogenetic response rates and progression-free survival in CML (chronic myeloid leukemia), standard hematologic and cytogenetic response rates in Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia), MDS/MPD (myelodysplastic/myeloproliferative disorders), and objective responses in GIST and DFSP [unresectable dermatofibrosarcoma protuberans].
Pharmacokinetics. The drug's effects were studied following administration in doses ranging from 25 to 1000 mg. 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 the drug is 98%. Considerable inter-individual variability in plasma AUC of imatinib was observed after oral administration. When the drug was taken with a high-fat meal, imatinib absorption was minimally reduced (11% decrease in Cmax and 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 is 95% bound to plasma proteins (primarily to albumin and alpha-1-acid glycoprotein, to a lesser extent to lipoproteins).
Metabolism. The main 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. 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 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 ranges 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 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 was excreted as metabolites.
Plasma Pharmacokinetics
After oral administration to healthy volunteers, the elimination half-life (t1/2) was approximately 18 hours, supporting once-daily dosing. The increase in mean AUC was linear and dose-proportional over the dose range of 25 mg to 1000 mg administered orally. No changes in imatinib kinetics were observed after repeated dosing, and accumulation at steady state was 1.5–2.5-fold with once-daily administration.
Pharmacokinetics in Patients with Gastrointestinal Stromal Tumors (GIST)
In patients with gastrointestinal stromal tumors, steady-state exposure was 1.5-fold higher than in patients with CML receiving the same dose (400 mg daily). Based on prior population pharmacokinetic analysis in patients with gastrointestinal stromal tumors, three variables (albumin, white blood cell count, and bilirubin) were found to have a statistically significant relationship with imatinib pharmacokinetics. Decreased albumin levels were associated with reduced clearance (CL/f); higher white blood cell counts also led to 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 impairment and reduced metabolism.
Pharmacokinetics in Populations
Population pharmacokinetic analysis in 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 a clearance of 8.5 L/h is expected in patients weighing 50 kg, increasing to 11.8 L/h in patients weighing 100 kg. 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 at 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 conditions treated with imatinib), imatinib clearance increases with increasing body surface area. After adjusting for body surface area, other demographic factors such as age, body weight, and body mass index do not have a clinically significant impact on imatinib exposure. The analysis confirms that imatinib exposure in children receiving 260 mg/m² once daily (without exceeding 400 mg once daily) or 340 mg/m² (without exceeding 600 mg once daily) is similar to that in adult patients receiving 400 mg or 600 mg once daily.
Organ 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 showed considerable inter-subject variability, mean imatinib exposure was not increased in patients with varying degrees of hepatic impairment compared to patients with normal liver function.
Clinical characteristics.
Indications.
The medicinal product Imatinib Shilpa is indicated:
- for the treatment of patients (adults and children) with newly diagnosed Philadelphia chromosome-positive (Ph+) [with the presence of the bcr-abl gene 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 the accelerated phase, or in the 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 the presence of the Philadelphia chromosome in leukocytes;
- as monotherapy in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in relapsed or refractory disease;
- for the treatment of adult patients with myelodysplastic/myeloproliferative diseases (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 imatinib in the context of bone marrow transplantation has not been sufficiently studied.
The medicinal product is 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 (DFSP) 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 imatinib plasma concentrations
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 in parameters (mean Cmax and AUC of imatinib by 26% and 40%, respectively) was observed in healthy volunteers when imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Concomitant administration of imatinib with CYP3A4 inhibitors should be performed with caution.
Medicinal products that may decrease imatinib plasma concentrations
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, 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 under a regimen without rifampicin. Similar results were observed in patients with malignant glioma receiving imatinib while taking enzyme-inducing antiepileptic drugs such as carbamazepine, oxcarbazepine, and phenytoin. The AUC of imatinib in plasma was reduced by 73% compared to 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 change during treatment with Imatinib Shilpa
Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2 and 3.5 times, respectively, indicating inhibition of CYP3A4 by imatinib. Therefore, caution is advised when co-administering imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine).
Imatinib may increase plasma concentrations of other drugs metabolized by CYP3A4 (e.g., triazole benzodiazepines, 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 anticoagulant therapy should receive low-molecular-weight heparin or unfractionated 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 has been shown to have 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 does not appear to be necessary when imatinib is co-administered with CYP2D6 substrates; however, caution is recommended with CYP2D6 substrates that have 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 high doses of imatinib and paracetamol are used concomitantly.
In patients after thyroidectomy who are taking levothyroxine, plasma exposure to levothyroxine may be reduced when imatinib is used concomitantly. Caution is recommended in such cases. However, the mechanism of this interaction is currently unknown.
There is clinical experience with concomitant use of imatinib and chemotherapy in patients with Ph+ ALL, but the interaction characteristics between imatinib and chemotherapy regimens are not fully defined. Adverse effects of imatinib may be enhanced, particularly hepatotoxicity, myelosuppression, or others; concurrent use of L-asparaginase has also been reported to increase liver toxicity. Therefore, the use of imatinib in combination regimens requires precautionary measures.
Special precautions for use.
When prescribing the medicinal product Imatinib Shilpa concomitantly with other drugs, there is a potential risk of drug interactions. Caution should be exercised when using Imatinib Shilpa with protease inhibitors, azole antifungal agents, certain macrolides (see section "Interaction with other medicinal products and other forms of interaction"), substrates of CYP3A4 with a narrow therapeutic window (such as cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine), or warfarin and other coumarin derivatives.
Concomitant administration of imatinib with medicinal products that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or St. John's wort) may significantly reduce imatinib exposure, increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers with 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 carefully 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 closely 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 liver function abnormalities have been reported during combination therapy of imatinib with high-dose chemotherapy agents. Liver function should be closely monitored, as imatinib in combination with chemotherapy may cause hepatic dysfunction.
Fluid retention
Pronounced fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial swelling) has been observed in approximately 2.5% of patients with newly diagnosed CML treated with imatinib. Therefore, regular monitoring of patients' body weight is recommended. In case of sudden rapid weight gain, a thorough patient evaluation should be performed, and appropriate supportive and therapeutic measures should be initiated if necessary. During clinical trials, an increased frequency of such events was observed in elderly patients and patients with a history of cardiovascular disease. Therefore, caution is advised in patients with cardiac dysfunction.
Patients with heart disease
Patients with heart disease, risk factors for heart failure, or a history of renal insufficiency should be closely monitored. Patients presenting any signs or symptoms suggestive of cardiac or renal failure should be thoroughly evaluated and appropriate therapy initiated.
In patients with hypereosinophilic syndrome (HES), 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 corticosteroids, hemodynamic support measures, and temporary discontinuation of imatinib. Cardiac adverse reactions during imatinib therapy have been infrequent. Prior to initiating therapy, a careful benefit-risk assessment of imatinib treatment should be performed in patients with HES/CEL. Myelodysplastic/myeloproliferative disorders with PDGFR gene rearrangement may be associated with high levels of eosinophilia. Patients with HES/CEL and patients with MDS/MPD associated with high levels of eosinophilia should undergo cardiology consultation and echocardiography, and serum troponin levels should be determined before starting imatinib therapy. If pathological reactions occur, cardiology monitoring and prophylactic use of systemic corticosteroids (1–2 mg/kg) for 1–2 weeks as concomitant therapy during the initial phase of treatment are recommended.
Gastrointestinal hemorrhage
During studies in patients with unresectable and/or metastatic GIST, gastrointestinal and intratumoral hemorrhages were reported. Available data do not identify predisposing factors (e.g., tumor size and location, coagulation disorders) that would 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 monitoring practices and procedures should be applied for managing all patients with hemorrhage.
Additionally, reports of gastric antral vascular ectasias as a rare cause of gastrointestinal bleeding have been received during post-marketing surveillance in patients with CML, ALL, and other conditions. 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 prior to initiating imatinib therapy.
Hepatitis B reactivation
Hepatitis B reactivation has occurred in patients who are chronic carriers of the virus after receiving BCR-ABL tyrosine kinase inhibitors.
In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in fatal outcomes. Before initiating treatment, patients should be screened for hepatitis B virus (HBV) infection.
Patients with positive serological tests for hepatitis B (including those with active disease) and patients with confirmed HBV infection should be referred for consultation with infectious disease specialists and hepatologists experienced in managing hepatitis B. Carriers of hepatitis B virus requiring treatment with Imatinib Shilpa should be carefully 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
BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA), including isolated reports with imatinib use (see section "Adverse reactions"). If patients receiving imatinib develop laboratory or clinical signs suggestive of TMA, therapy should be discontinued and a thorough evaluation for TMA should be performed, including ADAMTS13 activity and anti-ADAMTS13 antibody testing. If anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity, treatment with Imatinib Shilpa should not be continued.
Laboratory tests
Complete blood counts should be performed regularly during imatinib therapy. Use of imatinib in patients with chronic myeloid leukemia is associated with the development of neutropenia or thrombocytopenia. However, the occurrence of these cytopenias depends on the disease stage at which treatment is administered and is more frequent in patients with CML in the accelerated phase or blast crisis phase compared to patients with CML in the chronic phase. Therapy with imatinib may be interrupted or the dose reduced in case of neutropenia or thrombocytopenia (see section "Dosage and administration").
Liver function (transaminases, bilirubin, alkaline phosphatase) should be regularly monitored in patients receiving imatinib.
Patients with impaired renal function have higher plasma concentrations of imatinib than those with normal renal function, possibly due to elevated plasma levels of alpha-1 acid glycoprotein, a protein that binds imatinib. The minimum initial dose should be used in patients with renal impairment. Patients with severe renal insufficiency should be treated with caution. The dose should be reduced in case of intolerance (see section "Dosage and administration").
Prolonged use of imatinib may be associated with clinically significant worsening of renal function. Renal function should be assessed prior to 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 guidelines.
Children
Cases of growth retardation have been reported in children and prepubertal children receiving imatinib. In an observational study of children with CML, statistically significant reductions (but of uncertain clinical significance) in mean standard deviation score for height were observed at 12 and 24 months of treatment in two small subgroups, regardless of sexual maturation or sex. Therefore, careful monitoring of growth in children receiving imatinib is recommended.
In adults and children, the efficacy of imatinib is evaluated based on data regarding rates of complete 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 unresectable 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 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.
Pregnancy. There are no adequate data on imatinib use in pregnant women. In the post-marketing period, reports of spontaneous abortions and congenital defects in newborns have been received from women who used imatinib. However, animal studies have shown reproductive toxicity, and the potential risk to the fetus is unknown. Imatinib Shilpa should not be used during pregnancy except in cases of life-threatening indications. If the drug is prescribed during pregnancy, the patient must be informed of the potential risk to the fetus.
Women of reproductive potential should be advised to use effective contraception during treatment.
Breastfeeding. Information on the excretion of imatinib into breast milk is limited. Studies in two breastfeeding women showed that imatinib and its active metabolite may 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 a higher distribution of the metabolite into milk. Considering the total concentration of imatinib and metabolite and the maximum daily milk intake by the infant, overall exposure would be low (approximately 10% of the therapeutic dose). However, since the effects of low doses of imatinib on the infant are unknown, women taking imatinib should not breastfeed.
Fertility. Fertility in male and female rats was not impaired in preclinical studies. Studies on the effect of imatinib on fertility and gametogenesis in humans have not been conducted. If a patient has concerns regarding the effect of imatinib on fertility, they should consult their physician.
Ability to influence reaction speed when driving or operating machinery.
Patients should be aware of the possible development of adverse effects such as dizziness, blurred vision, or somnolence during imatinib use. Therefore, caution should be advised when driving or operating machinery.
Method of 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 indication.
To achieve doses of 400 mg and higher (see dosing recommendations below), 400 mg tablets (which are not divisible) should be used.
To achieve doses other than 400 mg or 800 mg (see dosing recommendations below), 100 mg tablets, which may be divided, should be used.
The prescribed doses should be taken orally with food and a large glass of water to minimize the risk of gastrointestinal irritation. The 400 mg or 600 mg dose is administered once daily, while the 800 mg dose should be given as 400 mg twice daily, in the morning and evening.
For patients unable to swallow the coated tablet, it may be dissolved in a glass of mineral water or apple juice. The required number of tablets should be placed in an appropriate volume of liquid (approximately 50 mL for a 100 mg tablet and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be consumed immediately after complete dissolution of the tablet.
Dosing in Chronic Myeloid Leukemia (CML) in Adult Patients
The recommended dose of Imatinib Shilpa for adult patients with CML in the chronic phase is 400 mg once daily. The chronic phase of CML is defined by meeting all of the following criteria: blasts < 15% in blood and bone marrow, basophils in peripheral blood < 20%, platelets > 100 × 109/L.
The recommended dose of 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 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 imatinib for adult patients with blast crisis is 600 mg/day. Blast crisis is defined by the following criteria: blasts ≥ 30% in blood or bone marrow, or presence of extramedullary disease manifestations, excluding hepatosplenomegaly.
Duration of treatment: In clinical trials, imatinib treatment 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 for patients in chronic phase, or from 600 mg to a maximum of 800 mg (400 mg twice daily) for patients in 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.
Dosing in Chronic Myeloid Leukemia (CML) in Pediatric Patients
Dosing in children should be based on body surface area (mg/m2). For children with CML in chronic or progressive phase, the recommended dose is 340 mg/m2/day (not to exceed a maximum daily dose of 800 mg). The drug may be administered once daily or the daily dose may be divided into two doses – morning and evening. The recommended doses are currently based on experience in a limited number of pediatric patients. There is no experience with imatinib in children under 2 years of age.
Dose escalation from 340 mg/m2 to 570 mg/m2 (not to exceed a total dose of 800 mg) may be considered in children 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.
Dosing in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in Adult Patients
The recommended dose of Imatinib Shilpa for adult patients with Ph+ ALL is 600 mg once daily. Treatment for this condition should be managed by a hematologic 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 during induction, consolidation, and maintenance phases of chemotherapy in adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy may vary depending on the chosen treatment protocol, but longer imatinib treatment generally 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.
Dosing in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in Pediatric Patients
Dosing in children should be 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 (not to exceed a maximum daily dose of 600 mg).
Dosing in Myelodysplastic/Myeloproliferative Disorders (MDS/MPD)
The recommended dose of Imatinib Shilpa for patients with MDS/MPD is 400 mg once daily.
Duration of treatment: Currently, data are available from only one clinical trial in which imatinib treatment was continued until disease progression. At the time of analysis, the median duration of treatment was 47 months (range: 24 days to 60 months).
Dosing in Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia (HES/CEL)
The recommended dose of Imatinib Shilpa for the treatment of patients with HES/CEL is 100 mg once daily. Dose escalation from 100 mg to 400 mg may be considered if the patient does not experience adverse reactions and if the response to treatment is insufficient.
Treatment should be continued as long as the patient continues to benefit.
Dosing for Patients with Kit (CD117)-positive Unresectable and/or Metastatic Malignant Gastrointestinal Stromal Tumors (GIST) and for Adjuvant Therapy in Adult Patients at High Risk of Recurrence of Kit (CD117)-positive Malignant Gastrointestinal Stromal Tumors (GIST) after Resection
The recommended dose of Imatinib Shilpa for the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors is 400 mg once daily. Data on the impact of dose escalation from 400 mg to 600 mg or 800 mg in patients with disease progression on lower doses are limited.
Duration of treatment: In clinical trials involving patients with gastrointestinal stromal tumors, imatinib therapy 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 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. In clinical trials supporting the use of the drug for this indication, the treatment duration was 36 months.
Dosing in the Treatment of Patients with Unresectable Dermatofibrosarcoma Protuberans (DFSP) and Patients with Recurrent and/or Metastatic Dermatofibrosarcoma (DFSP) Not Amenable to Surgical Resection
The recommended dose of Imatinib Shilpa 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 case of severe non-hematologic adverse effects during imatinib treatment, 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 previously observed adverse effects.
If bilirubin levels exceed three times the upper limit of normal (or if liver transaminase levels increase more than five times the upper limit of normal), Imatinib Shilpa should be discontinued 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. Imatinib therapy may then be resumed at a reduced daily dose. In 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; in children, from 340 to 260 mg/m2/day.
Hematologic Adverse Effects
In case of severe neutropenia or thrombocytopenia, dose reduction or treatment interruption is recommended as outlined in the table.
Table 1
| Indications |
Parameters |
Recommendations |
| CML (initial dose 100 mg) |
ANC < 1.0 × 109/L and/or platelet count < 50 × 109/L |
|
| Chronic phase CML, MDS/MPD, GIST (initial dose 400 mg) DFSP/HEL (dose 400 mg) |
ANC < 1.0 × 109/L and/or platelet count < 50 × 109/L |
|
| Pediatric chronic phase CML (dose 340 mg/m²) |
ANC < 1.0 × 109/L and/or platelet count < 50 × 109/L |
|
| Accelerated phase and blast crisis of CML, Ph+ ALL (initial dose 600 mg) |
ANCa < 0.5 × 109/L and/or platelet count < 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, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP) not amenable to surgical removal (dose 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 therapy. |
||
Special populations
Hepatic impairment
Imatinib is primarily metabolized in the liver. In patients with mild, moderate, and severe hepatic impairment, the drug should be administered at the minimum recommended daily dose of 400 mg. The dose may be reduced if not tolerated.
Classification of hepatic impairment Table 2
| Hepatic dysfunction |
Liver 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 accepted in the medical institution.
AST – aspartate aminotransferase.
Renal impairment
In 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, patients aged 65 years and older, who accounted for 20% of the total number of participants, did not show any age-related differences in the pharmacokinetics of the drug. No special dosage recommendations are required 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/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. Available published data to date do not allow for dosage recommendations.
Overdose.
Information regarding cases of intake of doses exceeding the recommended therapeutic doses is limited. Isolated cases of imatinib-based drug overdose have been reported (spontaneously or in scientific literature). In case of overdose, the patient should be examined and appropriate supportive therapy should be initiated. Overall, outcomes in such cases have generally been described as improvement or resolution of symptoms. The following events have been reported at various dose ranges.
Overdose in adults.
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 (6 days duration, with 3200 mg/day): weakness, myalgia, elevated creatine phosphokinase, elevated bilirubin, gastrointestinal pain.
6400 mg (single dose): in one patient (data from scientific literature), 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 400 mg as a single dose, vomiting, diarrhea, and anorexia were observed; in another 3-year-old boy after a single 980 mg dose – decreased white blood cell count and diarrhea.
In case of overdose, the patient requires monitoring and appropriate symptomatic treatment.
Adverse Reactions
Patients with 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.
During clinical studies involving patients with CML, drug discontinuation due to adverse drug reactions was observed in 2.4% of patients with newly diagnosed CML, in 4% of patients with CML in late chronic phase after prior interferon therapy failure, in 4% of patients with CML in the accelerated phase after prior interferon therapy failure, and in 5% of patients with blast crisis after prior interferon therapy failure. In the GIST study, the investigational drug was discontinued due to drug-related adverse reactions in 4% of patients.
Adverse reactions were generally similar across all indications, except for two. Patients with CML experienced more cases of myelosuppression than patients with gastrointestinal stromal tumors, likely due to the underlying disease. In a study involving patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST), grade 3/4 gastrointestinal (GI) bleeding according to the Common Toxicity Criteria (CTC) developed in 7 (5%) patients, including intratumoral hemorrhage (3 patients) or both GI and intratumoral bleeding (1 patient). The location of the gastrointestinal (GI) tumor may be a source of GI bleeding. Gastrointestinal and intratumoral hemorrhages can be serious and sometimes fatal. For both diseases, the most commonly reported (≥ 10%) drug-related adverse reactions were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle spasms, and rash. Periorbital edema or peripheral edema were common during all studies and were mostly described as periorbital swelling or lower limb edema. However, these edemas were rarely severe and could be managed with diuretics, other supportive measures, or by dose reduction of imatinib.
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. Based on limited safety data, adverse reactions reported so far in children are comparable to those observed in adult patients with Ph+ ALL. The safety profile in pediatric patients with Ph+ ALL is very limited; however, no new adverse reactions have been identified.
Various adverse reactions such as pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema may collectively be described as fluid retention. These reactions can usually be managed by temporarily interrupting imatinib therapy or by using 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 have been fatal (with clinical history including pleural effusion, congestive heart failure, and renal failure). In pediatric clinical trials, no specific safety concerns were identified.
Adverse reactions occurring more frequently than isolated case reports are classified by system organ classes 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), and frequency not known (cannot be estimated from available data).
Adverse reactions and their frequencies are presented in Table 3.
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, anaemia |
| Common |
Pancytopenia, febrile neutropenia |
| Uncommon |
Thrombocytopenia, lymphopenia, bone marrow suppression, eosinophilia, lymphadenopathy |
| Rare |
Hemolytic anaemia, thrombotic microangiopathy |
| Metabolism and nutrition disorders |
|
| Common |
Anorexia |
| Uncommon |
Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia |
| Rare |
Hyperkalaemia, hypomagnesaemia |
| Psychiatric disorders |
|
| Common |
Insomnia |
| Uncommon |
Depression, decreased libido, anxiety |
| Rare |
Confusion |
| Nervous system disorders |
|
| Very common |
Headache2 |
| Common |
Dizziness, paraesthesia, taste disturbance, hypaesthesia |
| Uncommon |
Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, intracranial haemorrhage |
| Rare |
Increased intracranial pressure, convulsions, optic neuritis |
| Frequency unknown |
Brain oedema* |
| Eye disorders |
|
| Common |
Periorbital oedema, increased lacrimation, conjunctival haemorrhage, conjunctivitis, dry eyes, blurred vision |
| Uncommon |
Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema |
| Rare |
Cataract, glaucoma, optic disc oedema |
| Frequency unknown |
Vitreous haemorrhage* |
| Ear and labyrinth disorders |
|
| Uncommon |
Vertigo, tinnitus, hearing loss |
| Cardiac disorders |
|
| Uncommon |
Palpitations, tachycardia, congestive heart failure3, pulmonary oedema |
| Rare |
Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion |
| Frequency unknown |
Pericarditis*, cardiac tamponade* |
| Vascular disorders4 |
|
| Common |
Hyperaemia, haemorrhage |
| Uncommon |
Arterial hypertension, haematoma, subdural haematoma, cold extremities, arterial hypotension, Raynaud's syndrome |
| Frequency unknown |
Thrombosis/embolism* |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
Dyspnoea, 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, diarrhoea, vomiting, dyspepsia, abdominal pain6 |
| Common |
Flatulence, abdominal distension, gastroesophageal reflux, constipation, dry mouth, gastritis |
| Uncommon |
Stomatitis, oral ulceration, gastrointestinal haemorrhage7, eructation, melena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis |
| Rare |
Colitis, intestinal obstruction, inflammatory bowel disease |
| Frequency unknown |
Intestinal obstruction/intestinal blockage*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia* |
| Hepatobiliary disorders |
|
| Common |
Elevated liver enzymes |
| Uncommon |
Hyperbilirubinaemia, hepatitis, jaundice |
| Rare |
Hepatic failure8, hepatic necrosis |
| Skin and subcutaneous tissue disorders |
|
| Very common |
Periorbital oedema, dermatitis/eczema/rash |
| Common |
Pruritus, facial oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction |
| Uncommon |
Pustular rash, acne, excessive sweating, urticaria, ecchymosis, increased bruising tendency, hypotrichosis, hypopigmentation of skin, exfoliative dermatitis, brittle nails, folliculitis, petechiae, psoriasis, purpura, hyperpigmentation of skin, bullous rashes, panniculitis (including nodular erythema) |
| Rare |
Acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discoloration, angioneurotic oedema, vesicular rash, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, severe skin reactions and skin rashes |
| Frequency unknown |
Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, erythema multiforme*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria |
| Musculoskeletal and connective tissue disorders |
|
| Very common |
Myalgia and muscle cramps, musculoskeletal pain, including myalgia9, arthralgia, bone pain10 |
| Common |
Joint swelling |
| Uncommon |
Joint and muscle stiffness |
| Rare |
Muscle weakness, arthritis, rhabdomyolysis/myopathy |
| Frequency unknown |
Aseptic necrosis/femoral head necrosis*, growth retardation in children* |
| Renal and urinary disorders |
|
| Uncommon |
Renal pain, haematuria, 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 oedema |
| Rare |
Hemorrhagic corpus luteum cyst / ovarian hemorrhagic cyst |
| General disorders and administration site conditions |
|
| Very common |
Fluid retention and oedema, fatigue |
| Common |
Weakness, pyrexia, anasarca, chills, shivering |
| Uncommon |
Chest pain, malaise |
| Investigations |
|
| Very common |
Increased body weight |
| Common |
Decreased body weight |
| 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, including spontaneous reports, as well as serious adverse effects observed during long-term studies, expanded access programs, clinical pharmacology studies, and investigational use outside approved indications. Since these reactions were reported in populations of uncertain size, it is often not possible to reliably estimate their frequency or establish a causal relationship with imatinib use.
1 Pneumonia was most frequently observed in patients with transformed CML and in patients with gastrointestinal stromal tumors.
2 Headache was most frequently observed 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, and hemorrhages (hematomas, hemorrhages) – in patients with gastrointestinal stromal tumors and transformed CML (CML in accelerated phase and CML in blast crisis phase).
5 Pleural effusion was observed more frequently in patients with gastrointestinal stromal tumors and in patients with transformed CML (CML in accelerated phase and CML in blast crisis phase) than in patients with chronic-phase CML.
6+7 Abdominal pain and gastrointestinal hemorrhages occurred most frequently in patients with gastrointestinal stromal tumors.
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.
11 Fatal cases have been reported in patients with advanced stages of disease, severe infections, severe neutropenia, and other serious concomitant disorders.
Abnormal laboratory findings
Complete blood count
In CML, cytopenia, particularly neutropenia and thrombocytopenia, was consistent across all studies, with higher frequency at higher doses ≥ 750 mg (Phase I study). However, the occurrence of neutropenia also showed a clear association with disease stage; the frequency of grade 3 or 4 neutropenia (ANC < 1.0 × 10⁹/L) and thrombocytopenia (platelet count < 50 × 10⁹/L) was 4–6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) compared to patients with newly diagnosed chronic-phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In patients with newly diagnosed chronic-phase CML, grade 4 neutropenia (ANC < 0.5 × 10⁹/L) and thrombocytopenia (platelet count < 10 × 10⁹/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of neutropenic and thrombocytopenic 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 in rare cases may require permanent discontinuation of therapy. In pediatric patients with CML, the most common manifestation of toxicity is grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These events mostly occur during the first few months of therapy.
In a study of 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 may have been 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 white blood cell and neutrophil counts were observed primarily during the first six weeks of therapy; thereafter, counts remained relatively stable.
Blood biochemistry
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 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% in AST (aspartate aminotransferase). Elevated bilirubin levels were reported in less than 3% of patients.
Cases of hepatocellular and cholestatic hepatitis and liver failure, some of which were fatal, have been reported, including in one patient who used high doses of paracetamol.
Description of selected adverse reactions
Hepatitis B reactivation
Hepatitis B reactivation has been reported in patients following administration of a BCR-ABL tyrosine kinase inhibitor (TKI). In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in fatal outcomes.
Shelf life.
2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 30°C.
Keep out of reach of children.
Packaging.
100 mg tablets: 10 tablets in a PVC/aluminum blister. 3 blisters in a cardboard box.
400 mg tablets: 10 tablets in a PVC/aluminum blister. 3 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Shilpa Medicare Limited, India.
Manufacturer's address and location of operations. Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India.