Veenat

Imatinib instructions

Common name: Gleevec

Trade name: Imatinib mesylate tablets

Full names: Gleevec, imatinib, Imatinib, Gleevec, veenat

Indications:

For the treatment of 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).

For the treatment of adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
u2003u2003 is indicated for the treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIPlLl-PDGFRα fusion kinase.
u2003u2003 is indicated for the treatment of adult patients with myelodysplastic syndrome/myeloproliferative disease (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
u2003u2003 is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM) without D816V c-Kit gene mutation or unknown c-Kit gene mutation.
u2003u2003 is indicated for the treatment of unresectable, recurrent or metastatic dermatofibrosarcoma protuberans (DFSP).
u2003u2003 is indicated for the adjuvant treatment of adult patients with significant risk of developing Kit(CDll7)-positive GIST after surgical resection. Patients at very low and low risk of recurrence should not receive this adjuvant therapy.

Usage and dosage:

Treatment should be carried out by physicians who have experience in treating patients with malignant tumors.
u2003u2003Imatinib mesylate should be taken with a meal and with a large glass of water.
u2003u2003Usually once a day for adults. 400㎎ or 600㎎ each time, and the daily dosage is 800㎎ or 400㎎ twice a day (in the morning and evening). Children and adolescents take once or twice daily (morning and evening).
u2003u2003Patients (including children) who cannot swallow tablets can disperse the tablets in gas-free water or apple juice (approximately 50ml for a 100㎎ tablet, and approximately 200ml for a 400㎎ tablet).
u2003u2003The suspension should be stirred and taken as soon as the tablet is completely disintegrated.
u2003u2003 Therapeutic dose of Ph+CML patients
u2003u2003 Adults
u2003u2003 The recommended dose of imatinib mesylate for patients in the chronic phase is 400㎎/day, and for patients in the blast crisis and accelerated phase, it is 600mg/day.
u2003u2003For first-line treatment of CML patients with WBC] 50000/μl, treatment experience is limited to patients who have received hydroxyurea therapy. This treatment may need to be started with imatinib mesylate.
u2003u2003 Medication should be continued as long as it is effective.
u2003u2003 has no serious adverse drug reactions and if the blood picture permits, the dose may be considered to be increased from 400㎎/day to 600㎎/day, or from 600㎎/day to 800㎎/day under the following circumstances: disease progression occurs at any time, satisfactory hematological response cannot be obtained after at least 3 months of treatment, no cytogenetic response is obtained after 12 months of treatment, and the hematological and/or cytogenetic response has disappeared again.
u2003u200 Children and adolescents over 33 years old
u2003u2003 At present, clinical data on children at home and abroad are limited. The efficacy and safety of pediatric patients need to be closely monitored, and the dosage should be adjusted in a timely manner if necessary.
u2003u2003 The safety and effectiveness information of this product for children and adolescents over 3 years old mainly comes from foreign clinical research data.
u2003u2003 Based on the dose for adults, the recommended daily dose is: 260㎎/m2 in the chronic phase (maximum dose: 400㎎), 340㎎/m2 in the accelerated phase and blast phase (maximum dose: 600mg). The recommended daily dose for pediatric patients is formulated. The calculated dose should generally be adjusted up or down to the full 100 mg. The dose for children under 12 years of age should generally be adjusted up or down to the full fifty milligrams.
u2003u2003There is no experience in treating children under 3 years old.
u2003u2003Therapeutic dose of Ph+ALL patients
u2003u2003For refractory and relapsed adult Ph+ALL patients, the recommended dose of imatinib mesylate is 600㎎/day.
u2003u2003 Therapeutic dose of GIST patients
u2003u2003 For patients with unresectable and/or metastatic malignant GIST, the recommended dose of imatinib mesylate is 400mg/day.
u2003u2003 If you fail to obtain a satisfactory response after treatment, if there are no serious adverse drug reactions, the dose may be considered to be increased from 400㎎/day to 600㎎/day or 800㎎/day.
u2003u2003For patients with GIST, treatment with imatinib mesylate should be continued unless the disease progresses.
u2003u2003 The recommended dose for adjuvant therapy in adult patients after complete resection of GIST is 400 mg/day. In clinical studies, imatinib was administered for 1 year. The optimal duration of adjuvant imatinib therapy is unknown.
u2003u2003 Dosage for HES/CEL patients
u2003u2003 The recommended dose of this product for the treatment of HES/CEL is mainly based on the dose reported in foreign studies.
u2003u2003For HES∕CEL demonstrating the presence of FIPlLl-PDGFR-α fusion kinase, the recommended starting dose is 100㎎/day. If after treatment, appropriate testing confirms that adequate relief is not obtained and no adverse reactions occur, the dose from 100 mg/day may be considered to be increased to 400 mg/day.
u2003u2003 Dosage for patients with ASM
u2003u2003 The recommended dose of this product for the treatment of ASM is mainly based on the dose reported in foreign studies.
u2003u2003 The recommended dose of imatinib mesylate for adult patients with ASM without D816V c-Kit mutation is 400 mg/day. If the c-Kit mutation status of ASM patients is unknown or cannot be measured, and when other therapies cannot obtain satisfactory relief, imatinib mesylate 400 mg/day should be considered for treatment.
u2003u2003For ASM patients with eosinophilia (a clonal hematological disease related to FIPlLl-PDGFR-α fusion kinase), the recommended starting dose of imatinib mesylate is 100mg/day. If after treatment, appropriate testing confirms that adequate relief is not obtained and no adverse reactions occur, the dose from 100 mg may be considered to be increased to 400 mg.
u2003u2003 Dosage for patients with MDS/MPD
u2003u2003 The recommended dose of this product for the treatment of MDS/MPD is mainly based on the dose reported in foreign studies.
u2003u2003 The recommended dosage of imatinib mesylate for adult patients with atypical MDS/MPD with hypereosinophilic syndrome and PDGFR-α or -β gene rearrangement is 400 mg/day.
u2003u2003 Therapeutic dosage for DFSP patients
u2003u2003 The recommended dosage of this product for the treatment of DFSP is mainly based on the dosage reported in foreign studies.
u2003u2003The recommended dose of imatinib mesylate for adult patients with DFSP is 400mg/day. The dose can be increased to 800mg daily if necessary.
u2003u2003 Dose adjustment after adverse reactions occur
u2003u2003 If serious non-hematological adverse reactions (such as severe water retention) occur during treatment with imatinib mesylate, the drug should be discontinued until the adverse reactions disappear, and then the dose should be adjusted according to the severity of the adverse reactions.
u2003u2003 Dose adjustment in case of severe liver toxicity
u2003u2003 If bilirubin is elevated [3 times the upper limit of the normal range] or transaminase is elevated] 5 times the upper limit of the normal range, it is advisable to stop taking imatinib mesylate until the above indicators drop to less than 1.5 or 2.5 times the upper limit of the normal range respectively.
u2003u2003After treatment with imatinib mesylate, the dose can be reduced and continued. The daily dose for adults should be reduced from 400㎎ to 300㎎, or from 600mg to 400㎎, or from 800㎎ to 600㎎; for children and adolescents, the daily dose should be reduced from 260㎎/m2 to 200㎎/m2 or from 340㎎/m2 to 260㎎/m2.
u2003u2003 Dose adjustment in neutropenia or thrombocytopenia
u2003u2003Ph+CML accelerated phase or blast phase, Ph+ALL (starting dose 600㎎/day, or 340㎎/m2/day for children and adolescents): If severe neutrophils and thrombocytopenia occur (neutrophils <0.5 ×109/L and/or platelets <10×109/L), it should be determined whether the cytopenias are related to leukemia (bone marrow extraction or biopsy). If the cytopenias are not caused by leukemia, it is recommended that the dose be reduced to 400㎎/day or 260㎎/m2/day for children and adolescents. If the cytopenia persists for 2 weeks, further reduce the dose to 300 mg/day or 200 mg/m/m[sup]2[/sup]/day for children and adolescents. If the cytopenia persists for 4 weeks, the drug should be discontinued until neutrophils ≥1×109/L and platelets ≥20×109/L. The dosage for reuse is 300㎎/day; or 200㎎/m2/day for children and adolescents.
u2003u2003 Patients with chronic phase of CML and GIST (initial dose 400㎎/day or 260㎎/m2/day for children and adolescents): Neutrophils <1.0×109/L and/or platelets <50×10[s The drug should be stopped when neutrophils ≥1.5×109/L and platelets ≥75×109/L. Treatment can be resumed to a dose of 400㎎/day or 260㎎/m2/day for children and adolescents. If critical values ​​reappear (neutrophils <1.0 × 109/L and/or platelets <50 × 109/L), the re-treatment dose after treatment interruption is reduced to 300 mg/day or 200 mg/m2/day for children and adolescents.
u2003u2003HES/CEL (starting dose is 100㎎/day):
u2003u2003 should be discontinued when neutrophil ANC is <1.0×109/L and/or platelet is 50×109/L. Medication should be resumed only when neutrophil ANC is ≥1.5×109/L and platelet is ≥75×109/L. Administration may be resumed at the previous dose (i.e., the dose before the serious adverse event occurred).
u2003u2003ASM (starting dose 100 mg/day):
u2003u2003 should be discontinued when neutrophil ANC <1.0×109/L and/or platelet <50×109/L, and should be resumed only when neutrophil ANC≥1.5×109/L and platelet ≥75×109/L. Administration may be resumed at the previous dose (i.e., the dose before the serious adverse event occurred).
u2003u2003HES/CEL, ASM, MDS/MPD (starting dose is 400㎎/day):
u2003u2003 should be discontinued when neutrophils <1.0×109/L and/or platelets <50×109/L, and when neutrophils ≥1.5×109/L and platelets ≥75× Medication should be resumed only when the concentration reaches 109/L, and the treatment dose should be 400mg/day. If critical values ​​reappear (where neutrophils <1.0×109/L and/or platelets <50×109/L), the re-treatment dose should be reduced to 300 mg.
u2003u2003DFSP (dose 800㎎/day)
u2003u2003 should be discontinued when neutrophils <1.0×109/L and/or platelets <50×109/L. Medication should be resumed only when neutrophils ≥1.5×109/L and platelets ≥75×109/L. The dose of re-treatment is 600㎎/day. If critical values ​​reappear (neutrophils [1.0 × 109/L and/or platelets [50 × 109/L)), the re-treatment dose should be reduced to 400mg
u2003u2003Dose in patients with liver impairment
u2003u2003For patients with mild or moderate liver function impairment, the recommended minimum dose is 400㎎/day. There is currently no data on the use of 400 mg/day in patients with severe hepatic impairment (bilirubin 3 times the normal range). These patients should use this product after carefully weighing the risk assessment.
u2003u2003 Dosage in Patients with Renal Failure
u2003u2003 The renal clearance of imatinib is negligible. For this reason, no reduction in systemic clearance is expected in patients with renal impairment. However, special attention still needs to be paid to patients with severe renal impairment.
u2003u2003 Dosage for Elderly Patients
u2003u2003 has no special dosage adjustments for elderly patients.

Adverse reactions:

Patients with advanced malignant tumors may experience mixed clinical symptoms, but because they are related to the underlying disease, the progression of the disease itself, and the simultaneous use of multiple drugs, it is often difficult to determine their causal relationship.
u2003u2003 Generally speaking, long-term daily oral administration of this product is well tolerated by CML patients, including pediatric patients. Most adult patients will experience adverse events at some point during treatment, but the vast majority are mild to moderate, and in clinical trials only 2.4% of newly diagnosed patients, 4% of patients in late chronic phase who failed interferon therapy, 4% of patients in accelerated phase who failed interferon therapy, and 5% of patients in blast crisis who failed interferon therapy had treatment discontinued due to drug-related adverse events. In the GIST study, 4% of patients discontinued treatment with this product due to drug-related adverse events.
u2003u2003 Adverse reactions occurred in patients with all indications were similar, with only two exceptions: patients with GIST had less myelosuppression, and intratumoral hemorrhage was only observed in patients with GIST. The most commonly reported adverse events related to drug treatment are mild nausea, vomiting, diarrhea, myalgia, muscle cramps, and rash, which are all easily managed. Edema was reported in all studies and may initially manifest as periorbital or lower extremity edema. However, severe edema is rare and can be relieved by diuretics, other supportive therapies, or in some patients by reducing the dose of this product.
u2003u2003A variety of adverse events such as pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without edema can be collectively referred to as "retention."
u2003u2003These adverse events can be alleviated by temporarily discontinuing this product and/or using diuretics and/or appropriate supportive therapy. However, a few events are severe or life-threatening, and individual blast crisis patients die due to complex pleural effusion, congestive heart failure, and renal failure.
u2003u2003 adverse reactions are arranged in descending order of incidence, using the following regulations: 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), including case reports.
u2003u2003The following adverse reactions are the incidence rates in clinical studies of CML and GIST.
u2003u2003 Systemic abnormalities
u2003u2003 Very common: water retention, peripheral edema (56%), fatigue (15%)
u2003u2003 Common: fatigue, fever, chills, generalized edema, chills, stiffness
u2003u2003 Uncommon: Chest pain, discomfort, bleeding
u2003u2003 Infectious diseases/infections
u2003u2003 Uncommon: Sepsis, pneumonia1, herpes simplex, shingles, upper respiratory tract infection, gastroenteritis, nasopharyngitis, sinusitis, cellulitis, influenza, urinary tract infection
u2 003u2003Rare: fungal infection
u2003u2003Abnormalities of the blood and lymphatic system
u2003u2003Common: neutropenia (14%), thrombocytopenia (14%), and anemia (11%)
u2003u2003Common: whole blood cells Decreased, febrile neutropenia
u2003u2003 Uncommon: thrombocytosis, lymphopenia, myelosuppression, eosinophilia, lymphadenopathy
u2003u2003 Rare: Hemolytic anemia
u2003u2003 Metabolic and nutritional imbalances
u2003u2003Common: loss of appetite
u2003u2003Uncommon: dehydration, hyperuricemia, hypokalemia, increased appetite, decreased appetite, gout, hypophosphatemia, hypercalcemia, hyperglycemia, hyponatremia
u2003 u2003 Rare: hyperkalemia, hypermagnesemia
u2003u2003 Mental disorder
u2003u2003 Common: insomnia
u2003u2003 Uncommon: depression, anxiety, decreased libido
u2003u 2003 Rare: Confusion
u2003u2003 Nervous system abnormalities
u2003u2003 Very common: Headache 2 (11%)
u2003u2003 Common: Dizziness, dysgeusia, paresthesias, hypoesthesia< br>u2003u2003 Uncommon: cerebral hemorrhage, syncope, peripheral neuropathy, drowsiness, migraine, memory impairment, sciatica, hyperactivity leg syndrome, tremor
u2003u2003 Uncommon: cerebral edema, increased intracranial pressure, convulsions, optic neuritis< br>u2003u2003 Eye abnormalities
u2003u2003 Common: eyelid edema, conjunctivitis, increased tearing, blurred vision, subconjunctival hemorrhage, dry eyes
u2003u2003 Uncommon: eye irritation, eye pain, periorbital bloating Swelling, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema
u2003u2003 Rare: papilledema, vitreous hemorrhage, glaucoma, catarrhal symptoms
u2003u2003 Ear and labyrinth abnormalities
u2003u200 3 Uncommon: dizziness, tinnitus, hearing loss
u2003u2003 Heart abnormalities
u2003u2003 Uncommon: palpitations, congestive heart failure 3, pulmonary edema, tachycardia
u2003u2003 Rare: cardiac arrhythmia , atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, pericarditis, acute cardiac tamponade
u2003u2003 Vascular abnormalities
u2003u2003 Common: flushing 4, bleeding 4
u2003u2003 Uncommon: blood Swelling, hypertension, hypotension, cold limbs, Raynaud's phenomenon
u2003u2003 Rare: thrombosis/embolism
u2003u2003 Abnormalities of the respiratory tract, chest and mediastinum
u2003u2003 Common: epistaxis, dyspnea, cough Cough
u2003u2003 Uncommon: Pleural effusion5, sore throat, pharyngitis
u2003u2003 Rare: Pleuralgia, pulmonary fibrosis, interstitial pneumonia, pulmonary hypertension, pulmonary hemorrhage
u2003u2003 Very rare: Passed Sensitivity shock
u2003u2003Digestive system abnormalities
u2003u2003Very common: nausea (51%), vomiting (25%), diarrhea (25%), indigestion (13%), abdominal pain 6 (14%)
u200 3u2003 Common: abdominal distension, gas, constipation, gastroesophageal reflux, oral ulcer, dry mouth, gastritis
u2003u2003 Uncommon: stomatitis, gastrointestinal bleeding7, melena, ascites, gastric ulcer, hiccup, heating, esophagitis, hematemesis, cheilitis, dysphagia , Pancreatitis
u2003u2003 Rare: colitis, diverticulitis, intestinal obstruction, tumor hemorrhage/tumor necrosis (especially in patients with GIST), gastrointestinal perforation, enteritis
u2003u2003 Abnormalities of the hepatobiliary system
u2003u 2003 Common: elevated liver enzymes
u2003u2003 Uncommon: jaundice, hepatitis, hyperbilirubinemia
u2003u2003 Rare: liver failure 9, hepatic necrosis 9
u2003u2003 Skin and subcutaneous tissue abnormalities
>u2003u2003Very common: general edema (32%), dermatitis/eczema/rash (26%)
u2003u2003Common: facial edema, periorbital edema, itching, erythroderma, dry skin, alopecia, sparse hair, night sweats, photoallergic reaction Should
u2003u2003Uncommon: Pustular rash, ecchymoses, bruises, hyperhidrosis, urticaria, nail fractures, purpura, cheilitis, skin hyperpigmentation, skin hypopigmentation, psoriasis, exfoliative dermatitis, bullous rash, easy bruising, folliculitis, petechiae
u2003u2003 Rare: Acute febrile neutrophilic dermatosis (Sweet syndrome), angioedema, vesicles, nail discoloration, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP)
u2003u2003 Abnormalities of skeletal muscle, connective tissue, and bone
u2003 u2003 Very common: Myospasm, painful myospasm (36%), musculoskeletal pain including myalgia (14%), arthralgia, bone pain8
u2003u2003 Common: Joint swelling
u2003u2003 Uncommon: Sciatica, joint muscle stiffness
u2003u2003 Rare: Avascular necrosis/hip necrosis, myasthenia, arthritis
u20 03u2003 Renal and urinary system abnormalities
u2003u2003 Uncommon: renal failure, renal pain, frequent urination, hematuria
u2003u2003 Reproductive system and breast abnormalities
u2003u2003 Uncommon: gynecomastia, erectile dysfunction, breast enlargement, scrotal edema, menorrhagia, menstrual disorders, nipple pain, sexual dysfunction
u20 03u2003 Abnormal examination
u2003u2003 Very common: weight gain
u2003u2003 Common: weight loss
u2003u2003 Unusual See: increased blood alkaline phosphatase, increased blood creatine phosphokinase, increased blood creatine and blood lactate dehydrogenase
u2003u2003 Rare: increased blood amylase
u2003u20031 Adverse effects of pneumonitis are most common in patients with progressive CML and GIST.
u2003u20032 in patients with GIST. Headache is the most common adverse reaction.
u2003u20033 Cardiac events, including congestive heart failure, are more common in patients with progressive CML than in patients with chronic phase CML, reported on a patient-year basis.
u2003u20034 Flushing is the most common adverse reaction in patients with GIS1, and bleeding (hematoma, hemorrhage) is the most common adverse reaction in patients with GIS1 and progression of CML (CML-AP and CML-BC).
u2003u20035 Pleural effusion is more common in patients with GIST and in patients with progressive CML (CML-AP and CML-BC) than in the chronic phase of CML.
u2003u20036/7 Adverse reactions of abdominal pain and gastrointestinal bleeding are the most common in patients with GIST.
u2003u20038 Musculoskeletal pain and related adverse events are more common in CML patients than in GIST patients.
u2003u20039 Cases of death due to liver failure and hepatic necrosis have been reported.

Adjuvant Treatment of GIST
u2003u2003 The most commonly reported adverse reactions are similar to those reported in other clinical study populations and include diarrhea, fatigue, nausea, edema, hemoglobin reduction, rash, vomiting, and abdominal pain. No newly identified adverse reactions were reported during adjuvant treatment of GIST. Fifty-seven (17%) of imatinib-treated patients and 11 (3%) of placebo-treated patients discontinued treatment due to adverse reactions. The most commonly reported adverse reactions upon discontinuation were edema, gastrointestinal disturbances (nausea, vomiting, bloating, and diarrhea), fatigue, low hemoglobin, and rash.
u2003u2003The following are adverse reaction reports that occurred in post-marketing clinical applications. Since these adverse reaction reports come from studies with uncertain sample sizes, the frequency of these adverse reactions or the causal relationship with imatinib exposure is uncertain.
u2003u2003 Nervous system abnormalities
u2003u2003 Uncommon: cerebral edema
u2003u2003 Eye abnormalities
u2003u2003 Rare: vitreous hemorrhage
u2003u2003 Cardiac abnormalities
u2003 u2003 Rare: Pericarditis, cardiac tamponade
u2003u2003 Vascular abnormalities
u2003u2003 Uncommon: Thrombosis/embolism
u2003u2003 Very rare: Anaphylactic shock
u2003u2003 Respiratory, thoracic and mediastinal abnormalities
u2003u2003 Uncommon: acute respiratory failure1, interstitial pneumonia
u2003u2003 Digestive system abnormalities
u2003u2003 Uncommon: intestinal obstruction, tumor bleeding/tumor necrosis, gastrointestinal perforation2
u2003u2003 Rare: diverticulitis
u2003u2003 Skin and subcutaneous tissue abnormalities
u2003u2003 Uncommon: Hand-foot syndrome
u2003u2003 Rare: Lichenoid keratosis, lichen planus
u2003u2003 Very rare: Toxic epidermal necrolysis type drug eruption
u2003u2003 Abnormalities of skeletal muscle, connective tissue and bone
u2003u2003 Rare: avascular necrosis/necrosis of the hip, rhabdomyolysis/myopathy
u2003u2003 Uncommon: developmental delay in children
u2003u2003 Reproductive system Abnormal
u2003u2003 Very rare: Luteal hemorrhage/ovarian cyst hemorrhage
u2003u2003 Benign, malignant, and unspecified tumors (including cysts and polyps)
u2003u2003 Rare: Tumor lysis syndrome
u2003u20031 Cases of death caused by advanced disease, severe infection, and other severe comorbidities have been reported
u2003u20032 Cases of death caused by gastrointestinal perforation have been reported

Abnormal laboratory tests
u2003u2003 Blood system
u2003u2003 Among CML patients, all studies reported cytopenias, especially neutrophil and thrombocytopenia, with a higher incidence at high doses of >750 mg/day (Phase I study). However, the incidence of cytopenias also obviously depends on the stage of the disease. Patients with newly diagnosed CML have a lower incidence of cytopenias than other CML patients. Grade 3 or 4 neutropenia (ANC <1.0 × 109/L) and thrombocytopenia (platelet count <50 × 109/L), the incidence rates in the blast phase and accelerated phase (the incidence rates of neutropenia and thrombocytopenia are 59% to 61%, 44% to 63%, respectively) compared with newly diagnosed patients in the chronic phase (the incidence rate of neutropenia is 16.7%, the incidence rate of thrombocytopenia is 8.9%) is 4 and 6 times higher. The incidence rates of grade 4 neutropenia (ANC <1.0×109/L) and thrombocytopenia (platelet count <50×109/L) in patients with newly diagnosed chronic-phase CML were 3.6% and [1%, respectively. The median duration of neutrophil and thrombocytopenia was 2 to 3 weeks and 3 to 4 weeks, respectively. Such events can generally be alleviated by reducing the dose or suspending the medication; only in individual cases, long-term discontinuation of medication is required. The most common toxicity in pediatric CML patients is grade 3 or 4 cytopenias. These include neutropenia, thrombocytopenia, and anemia. These toxicities usually occur within the first few months of initial treatment.
u2003u2003In patients with GIST, the incidence rates of grade 3 and grade 4 anemia were 5.4% and 0.7%, respectively, and at least some of these patients were related to gastrointestinal or intratumoral bleeding. The incidence of grade 3 and 4 neutropenia was 7.5% and 2.7%, respectively, while the incidence of grade 3 thrombocytopenia was 0.7%. No patients developed grade 4 thrombocytopenia. The decrease in complete blood cell and neutrophil counts mainly occurred in the first 6 weeks of treatment, and the cell counts remained relatively stable thereafter.
u2003u2003
u2003u2003 Biochemical examination
u2003u2003 Significant transaminase elevations (<5%) or bilirubin elevations (<1%) in CML patients are uncommon and can be relieved by dose reduction or discontinuation (median duration is approximately one week). Less than 1% of patients discontinue medication long-term due to abnormal liver function laboratory tests. Among patients with GIST (Study B2222), 6.8% had grade 3 or 4 serum alanine aminotransferase (SGPT) elevations, and 4.8% had grade 3 or 4 serum aspartate aminotransferase (SGOT) elevations. The incidence of elevated bilirubin is less than 3%.
u2003u2003Cases of cytolytic, cholestatic hepatitis or liver failure, some of which are fatal, have also been seen.

Contraindications:

It is prohibited for those who are allergic to the active substance of this medicine or any excipient ingredients.

Drug interactions:

Drugs that can alter the plasma concentration of imatinib
u2003u2003CYP3A4 inhibitors: After concurrent administration of a single dose of ketoconazole (CYP3A4 inhibitor) to healthy subjects, the drug exposure of imatinib was significantly increased (the mean maximum plasma concentration (Cmax) and the area under the imatinib curve (AUC) could be increased by 26% and 40%, respectively). There is no experience with coadministration with other CYP3A4 inhibitors (eg, itraconazole, erythromycin, and clarithromycin).
u2003u2003CYP3A4 inducer: After healthy volunteers took rifampicin, the clearance of imatinib increased 3.8-fold (90% confidence interval = 3.5-4.3-fold), but Cmax, AUC (0-24) and AUC (0-8) decreased by 54%, 68% and 74% respectively. In clinical studies, it was found that the plasma concentration of imatinib was reduced after simultaneous administration of phenytoin, resulting in a reduction in efficacy. Similar results were observed in patients with malignant glioma who were taking enzyme-inducing anti-epileptic deugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and deoxyphenytoin and were treated with this product. Compared with EIAEDs not taken at the same time, the AUC of imatinib is reduced to 73%. Other CYP3A4 inducers, such as dexamethasone, catamizine, phenobarbital, etc., may have similar problems, so simultaneous use of imatinib and CYP3A4 inducers should be avoided. In two published studies, coadministration of imatinib with preparations containing St John's wort extract resulted in a 30-32% decrease in the AUC of imatinib.
u2003u2003 Imatinib mesylate can alter plasma concentrations of the following drugs
u2003u2003 Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) by 2-fold and 3.5-fold, respectively. It should be remembered that imatinib can increase the plasma concentrations of other drugs metabolized by CYP3A4 (such as benzodiazepines, dihydropyridines, calcium channel blockers, and other HMG-CoA reductase inhibitors). Therefore, caution should be exercised when coadministering this drug with CYP3A4 substrates with narrow therapeutic windows (such as cyclosporine, pimozide).
u2003u2003 Imatinib can also inhibit the activity of CYP2D6 in vitro at concentrations similar to those that inhibit CYP3A4 activity. Therefore, when taken simultaneously with imatinib mesylate, it may increase the systemic exposure to CYP2D6 substrates. Although no specific studies have been conducted, it is recommended to use with caution.
u2003u2003Imatinib can also inhibit the activities of CYP2C9 and CYP2C19 in vitro. Prolongation of prothrombin time can be seen after taking warfarin at the same time. Therefore, prothrombin time should be monitored short-term during the beginning and end of imatinib mesylate treatment or when changing the dose, if dicoumarol is also used.
u2003u2003 The inhibitory effect of imatinib 400mg twice a day on the metabolism of metoprolol induced by CYP2D6 is very weak, and the Cmax and AUC of metoprolol increase by approximately 23%. When imatinib is coadministered with CYP2D6 inducers such as metoprolol, there does not appear to be a risk factor for drug-drug interactions, and dose adjustment is not necessary.
u2003u2003 In vitro experiments show that imatinib can inhibit the 0-glucuronidation of acetaminophen.
u2003u2003Patients should be warned to avoid over-the-counter and prescription drugs containing acetaminophen.

Notes:

It has been reported that patients treated with this product have significant reductions in left ventricular ejection fraction (LVEF) and symptoms of congestive heart failure. Animal experiments have shown that c-Abl enzyme inhibitors can cause a strong response in cardiomyocytes. Myocardial disease has been reported in carcinogenicity studies in rats. Therefore, patients at risk of cardiovascular disease or with heart disease should be closely monitored. Elderly patients treated with this product or patients with a history of heart disease should first have their left ventricular ejection fraction (LVEF) measured. During treatment, patients with obvious symptoms of heart failure should be comprehensively examined and treated accordingly according to clinical symptoms.
u2003u2003 Complete blood count should be checked once a week in the first month of treatment with imatinib mesylate, once every two weeks in the second month, and then as needed (for example, once every 2-3 months). If severe neutropenia or thrombocytopenia occurs, the dose should be adjusted.
u2003u2003 Liver function (transaminases, bilirubin and alkaline phosphatase) should be checked before starting treatment, and then checked once a month or based on clinical conditions, and the dose should be adjusted if necessary. Patients with mild, moderate, and severe hepatic impairment should have their blood and liver enzymes monitored. Imatinib mesylate exposure may be increased in patients with hepatic failure. People with liver damage should use this product with caution. Imatinib mesylate should only be used in patients with severe liver failure after a careful risk-benefit assessment. It should be kept in mind that patients with GIST may have liver metastases, thereby increasing liver function damage. One patient who was routinely taking acetaminophen for fever died of acute liver failure. Although the exact cause of death is unknown, caution is advised when taking imatinib mesylate and acetaminophen concomitantly.
u2003u2003Transient hepatotoxicity has been observed when imatinib was combined with high-dose chemotherapy drugs, and patients had elevated transaminases and hyperbilirubinemia. When chemotherapy is combined with imatinib, it may cause liver dysfunction. Pay attention to monitoring liver function.
u2003u2003Concomitant administration of imatinib mesylate and a CYP3A4 inducer may significantly reduce the total exposure of imatinib and therefore increase the risk of potential treatment failure. Therefore, coadministration of imatinib mesylate with CYP3A4 inducers should be avoided.
u2003u2003 Approximately 2.5% of newly diagnosed CML patients develop severe water retention (pleural effusion, edema, pulmonary edema, ascites, and superficial edema) when taking imatinib mesylate, so regular weight monitoring is recommended. Weight gain should be carefully evaluated and appropriate supportive care instituted if necessary. Particularly in pediatric patients, water retention may occur without identifiable edema.
u2003u2003 Water retention can aggravate or lead to heart failure. There is currently no clinical experience in the clinical use of imatinib mesylate in patients with severe heart failure (classes III to IV according to the New York Heart Association classification). This drug should be used with caution in these patients, as well as in patients with glaucoma.
u2003u2003 It has been confirmed that in some patients with hypereosinophilic syndrome (HES) and cardiac damage, the occurrence of cardiogenic shock/left ventricular dysfunction is related to the use of imatinib. Improvement has been reported with systemic steroids, circulatory support therapy, and temporary discontinuation of imatinib. Myelodysplasia/myeloproliferative disorders and systemic mastocytosis may be associated with high eosinophil concentrations. Therefore, echocardiography and serum troponin measurement should be considered in patients with HES/CEL, MDS/MPD, or patients with SM caused by high eosinophils. If any of the measurement results are abnormal, prophylactic systemic steroid therapy (1-2 mg/kg) should be used for 1-2 weeks and concurrent treatment with imatinib.
u2003u2003 In GIST clinical trials, gastrointestinal bleeding was reported in 8 patients (5.4%) and intratumoral bleeding in 4 patients (2.7%). Depending on the location of the tumor, intratumoral bleeding may occur within the abdominal cavity or within the liver. Intratumoral bleeding in such patients may also manifest as gastrointestinal bleeding, and therefore patients should be monitored for gastrointestinal symptoms during the initial phase of treatment.
u2003u2003Laboratory examinations
u2003u2003 Complete blood count examinations should be performed regularly during treatment with this product. CML patients treated with this product are often accompanied by neutropenia or thrombocytopenia. However, the occurrence of cytopenias also depends on the stage of the disease, being more common in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. At this time, treatment with this product should be interrupted or the dose should be reduced.
u2003u2003Patients receiving this product should regularly monitor liver function (transaminases, bilirubin, alkaline phosphatase). If abnormalities occur, the dose should be interrupted and/or reduced.
u2003u2003This product and its metabolites are hardly excreted through the kidneys. Creatinine clearance (CrCL) decreases with age, but age has no significant effect on the pharmacokinetics of this product. Imatinib plasma exposure appears to be higher in patients with renal impairment than in patients with normal renal function, possibly due to increased plasma levels of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. Plasma exposure of imatinib was not associated with renal insufficiency as measured by creatinine clearance, i.e., mild (CrC-L: 40-59 ml/min) and severe (CrCL: <20 ml/min) renal insufficiency. However, as recommended in Dosage and Administration, the starting dose of imatinib can be reduced if the patient cannot tolerate it.
u2003u2003 Preclinical studies have shown that imatinib does not easily pass through the blood-brain barrier. It has not been studied in humans.
u2003u2003's 2-year carcinogenicity study results in rats have shown cancerous changes in the vulva foreskin, clitoris, kidneys and bladder, but no increase in bladder and kidney cancer has been reported in humans.
u2003u2003 Hypothyroidism has been reported in thyroidectomized patients treated with levothyroxine during treatment with this product, and TSH levels should be monitored in such patients.
u2003u2003Children and Adolescents
u2003u2003 Developmental delays have been reported in children and preadolescent adolescents receiving imatinib. The long-term effects of extended treatment with imatinib on children's development are unknown. Therefore, close monitoring of the development of children treated with imatinib is recommended.
u2003u2003 Effects on the abilities of drivers and machine operators
u2003u2003 There is no information on possible effects on the abilities of drivers or machine operators. The adverse reactions of this product remind patients that they may experience dizziness or blurred vision during treatment. Therefore, patients should pay attention when driving or operating machinery.

Drug Overdose:

Experience with administration of above-therapeutic doses is limited. There are only individual cases of overdose with imatinib mesylate reported spontaneously and in the literature. Generally, the condition of these cases improves or recovers. If overdose occurs, the patient should be closely observed and appropriate supportive treatment given.
The events reported at different doses of u2003u2003 are as follows:
u2003u2003 Overdose in adults:
u2003u2003 1200 to 1600 mg (duration ranging from 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle cramps, thrombocytopenia, various cytopenias, abdominal pain, headache, loss of appetite. 1800 to 13200mg (daily dose up to 3200mg, use for 6 days): weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): A case of nausea, vomiting, abdominal pain, fever, facial swelling, decreased neutrophil count, and elevated transaminases was reported in the literature.
u2003u20038-10g (single dose): Vomiting and gastrointestinal pain have been reported.
u2003u2003
u2003u2003 Overdose in children
u2003u2003 A three-year-old boy exposed to a single dose of 400mg developed vomiting, diarrhea and anorexia, and another three-year-old boy exposed to a single dose of 980mg developed a drop in white blood cell count and diarrhea.

Storage:

Store below 30℃.