The active ingredient of this product is imatinib mesylate.
This product is a dark yellow to brown-yellow biconvex film-coated tablet.
Used to treat the chronic phase, accelerated phase or blast phase of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML);
For the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST);
Combined chemotherapy to treat newly diagnosed pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL);
For the treatment of adult patients with relapsed and refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Imatinib mesylate should be taken with meals and a large glass of water to minimize the risk of gastrointestinal disorders. Usually adults once a day, 400mg or 600mg each time, and a daily dose of 800mg or 400mg twice a day (in the morning and evening). Children and adolescents take it once or twice a day (morning and evening).
Patients (including children) who cannot swallow the tablets can disperse the tablets in gas-free water or apple juice (approximately 50ml for 100mg tablets and 200ml for 400mg tablets). The suspension should be stirred, and the tablet should be taken as soon as it disintegrates completely.
As long as the patient continues to benefit, the treatment with this product should continue. Please follow your doctor's prescription for medication.
The overall safety characteristics of imatinib in human clinical use are summarized and described through the use of imatinib for more than 12 years. In clinical development, most patients will experience adverse events at some point in treatment. The most frequently reported adverse events (>10%) were neutropenia, thrombocytopenia, anemia, headache, indigestion, edema, weight gain, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, skin rash, fatigue and stomach ache. The severity of these events is mild to moderate, and only 2% to 5% of patients have permanent discontinuation of treatment due to drug-related adverse events.
People who are allergic to the active substance of this medicine or any excipient ingredients are prohibited [Precautions]
Patients at risk of cardiovascular disease or patients with heart disease should be closely monitored. Elderly patients treated with this product or patients with a history of heart disease should first measure the left ventricular ejection fraction (LVEF). During the treatment, the patient has obvious Symptoms of heart failure should be fully checked and treated according to clinical symptoms.
Imatinib mesylate should be checked once a week for the first month of treatment, and once every two weeks for the second month, and then as needed (for example, once every 2-3 months). If severe neutrophil or thrombocytopenia occurs, the dose should be adjusted.
Liver function (transaminase, bilirubin, and alkaline phosphatase) should be checked before starting treatment, and then checked once a month or according to the clinical situation, and the dose should be adjusted if necessary. The blood picture and liver enzymes should be monitored for patients with mild, moderate and severe liver damage.
The exposure of imatinib mesylate in patients with liver failure may increase, and patients with liver damage should use this product with caution.
Approximately 2.5% of newly diagnosed CML patients experience severe fluid retention (pleural effusion, edema, pulmonary edema, ascites, and superficial edema) when taking imatinib mesylate, so regular weight monitoring is recommended.
[Medication for pregnant women and lactating women]
Animal studies have shown that the drug has reproductive toxicity (see the reproductive toxicity section of toxicological studies).
There are no clinical trials of imatinib in pregnant women. There have been post-marketing reports of spontaneous abortion and infant congenital abnormalities in women taking Gleevec. Women of childbearing age should be advised to use effective contraception while taking imatinib mesylate.
Imatinib and its metabolites can be secreted into human milk. Since the impact of low doses of imatinib on infant exposure is not yet known, women who are taking this product should not breastfeed.
There is no medication experience for children under 3 years old
[ Geriatric medication]
The age-related reduction in creatinine clearance has no significant effect on the pharmacokinetics of imatinib mesylate.
Elderly patients treated with this product or patients with a history of heart disease should first measure the left ventricular ejection fraction. During the treatment, the patient has obvious symptoms of heart failure and should be fully checked and treated according to the clinical symptoms.
Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment.
1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain.
6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.
8 to 10 g (single dose): Vomiting and GI pain have been reported.
Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.
Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology
Animal Toxicology and/or Pharmacology
Toxicities from Long-Term Use
It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39 week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
Mechanism of Action
Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients.
In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.
The pharmacokinetics of Gleevec have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of Gleevec are similar in CML and GIST patients.
Absorption and Distribution
Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when Gleevec is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein.
CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that Gleevec is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 µM, respectively.
Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.
Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.
Store below 30°C.