Imatinib veenat 100mg

[Gleevec: Introduction]

The primary active ingredient in Gleevec is imatinib mesylate. Imatinib is a small-molecule protein tyrosine kinase inhibitor; by inhibiting kinases involved in cellular signaling pathways, it effectively suppresses tumor growth and angiogenesis. Furthermore, it effectively inhibits the activity of the following tyrosine kinase receptors: Kit, the stem cell factor (SCF) receptor encoded by the c-Kit proto-oncogene, discoidin domain receptors (DDR1 and DDR2), the colony-stimulating factor receptor (CSF-1R), and platelet-derived growth factor receptors alpha and beta (PDGFR-α and PDGFR-β). Imatinib also inhibits the cellular behaviors mediated by the activation of these receptor kinases.

[Indications and Usage]

Indicated for the treatment of adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase, accelerated phase, or blast phase.

Indicated for the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

Safety and efficacy data for the following indications are derived primarily from studies conducted outside of China; data specific to the Chinese population are limited:

Indicated for the treatment of adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Indicated for the treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) associated with the FIP1L1-PDGFRα fusion kinase.

Indicated for the treatment of adult patients with myelodysplastic syndrome/myeloproliferative disease (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.Indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit gene mutation, or with an unknown c-Kit gene mutation status.

Indicated for the treatment of unresectable, recurrent, or metastatic dermatofibrosarcoma protuberans (DFSP).

Indicated as adjuvant therapy for adult patients with Kit (CD117)-positive gastrointestinal stromal tumors (GIST) following surgical resection, who are at significant risk of recurrence. Patients with very low or low risk of recurrence should not receive this adjuvant therapy.

[Dosage and Administration]

Recommended Dosage: Typically, for adults, the dose is 400 mg or 600 mg taken once daily; alternatively, it may be taken twice daily, provided that no single dose exceeds 400 mg. For children and adolescents, the dose may be taken once daily or divided into two doses (morning and evening).

Method of Administration: Oral use. The medication should be taken with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. For patients unable to swallow the tablets (including children), the tablets may be dispersed in still water or apple juice (approximately 50 mL for a 100 mg tablet; 200 mL for a 400 mg tablet). The suspension should be stirred and consumed immediately once the tablet has completely disintegrated.

[Side Effects]

The most frequently reported adverse events (>10%) include neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, muscle spasms, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. The severity of these events is generally mild to moderate, and only 2% to 5% of patients permanently discontinued treatment due to drug-related adverse events.

[Contraindications]

Contraindicated in patients with hypersensitivity to the active substance of this drug or to any of its excipients. [Drug Interactions]

Age-related reductions in creatinine clearance have no significant effect on the pharmacokinetics of imatinib mesylate.

Elderly patients or patients with a history of cardiac disease undergoing treatment with this product should undergo an initial assessment of left ventricular ejection fraction (LVEF). During treatment, if patients develop significant symptoms of heart failure, a comprehensive evaluation should be performed, and appropriate treatment administered based on clinical symptoms.

[Drug Interactions]

Drugs That May Alter Imatinib Plasma Concentrations

CYP3A4 Inhibitors: In healthy subjects, the concomitant administration of a single dose of ketoconazole (a CYP3A4 inhibitor) resulted in a significant increase in imatinib exposure (mean maximum plasma concentration [Cmax] and area under the curve [AUC] for imatinib increased by 26% and 40%, respectively). There is currently no clinical experience regarding the concomitant use of other CYP3A4 inhibitors (e.g., itraconazole, erythromycin, and clarithromycin).

CYP3A4 Inducers: In healthy volunteers, the administration of rifampin resulted in a 3.8-fold increase in imatinib clearance (90% confidence interval = 3.5–4.3-fold), while Cmax, AUC(0–24), and AUC(0–8) decreased by 54%, 68%, and 74%, respectively. Clinical studies have demonstrated that the concomitant administration of phenytoin leads to reduced plasma concentrations of imatinib, potentially resulting in diminished therapeutic efficacy. Similar results were observed in patients with malignant glioma receiving treatment with this product while concomitantly taking enzyme-inducing anti-epileptic drugs (EIAEDs), such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. Compared to administration without concomitant EIAEDs, the AUC of imatinib decreased to 73%. Other CYP3A4 inducers—such as dexamethasone, carbamazepine, and phenobarbital—may present similar issues; therefore, the concomitant administration of imatinib with CYP3A4 inducers should be avoided. In two published studies, the concomitant use of imatinib with preparations containing St. John's wort extract resulted in a 30% to 32% decrease in the AUC of imatinib.

Imatinib mesylate may alter the plasma concentrations of the following drugs:

Imatinib increased the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2-fold and 3.5-fold, respectively. It should be noted that imatinib may increase the plasma concentrations of other drugs metabolized via CYP3A4 (e.g., benzodiazepines, dihydropyridine calcium channel antagonists, and other HMG-CoA reductase inhibitors). Therefore, caution is advised when administering imatinib concomitantly with CYP3A4 substrates that possess a narrow therapeutic window (e.g., cyclosporine, pimozide).

At concentrations similar to those that inhibit CYP3A4 activity, imatinib also inhibits CYP2D6 activity *in vitro*; consequently, concomitant administration with imatinib mesylate may increase systemic exposure to CYP2D6 substrates. Although no specific studies have been conducted to date, caution is recommended.

Imatinib also inhibits the activity of CYP2C9 and CYP2C19 *in vitro*; an increase in prothrombin time has been observed following the concomitant administration of warfarin. Therefore, if dicoumarol derivatives are being used concomitantly, prothrombin time should be monitored closely for a short period at the initiation and discontinuation of imatinib mesylate therapy, as well as during dosage adjustments. At a dose of 400 mg administered twice daily, imatinib exerts only a weak inhibitory effect on the CYP2D6-mediated metabolism of metoprolol; the Cmax and AUC of metoprolol increase by approximately 23%. When imatinib is co-administered with CYP2D6 substrates such as metoprolol, there appears to be no significant risk of drug-drug interactions, and dose adjustment is not required.

In vitro studies have demonstrated that imatinib can inhibit the O-glucuronidation of acetaminophen.

A patient who was routinely taking acetaminophen to treat fever died of acute liver failure. While the exact cause of death remains unknown, patients should be advised to avoid the use of both over-the-counter and prescription medications containing acetaminophen.

[Precautions for Use in Special Populations]

Pregnancy: Data regarding the use of imatinib in pregnant women are currently lacking; the potential toxicity to the fetus is currently unknown. Unless absolutely necessary, use during pregnancy is not recommended. If imatinib mesylate is taken during pregnancy, the patient must be informed of the potential hazards to the fetus. Women of childbearing potential taking imatinib mesylate should be advised to use highly effective contraception concurrently. Highly effective contraception is a method of birth control with a low failure rate (i.e., less than 1% per year) when used continuously and correctly.

Lactation: Imatinib and its metabolites are excreted into human breast milk. The milk-to-plasma concentration ratios for imatinib and its metabolites are 0.5 and 0.9, respectively, indicating that the metabolites are excreted into the milk to a greater extent. Based on the combined concentrations of imatinib and its metabolites, and assuming a maximum daily milk intake by an infant, the overall drug exposure in the infant is very low, representing only approximately 10% of the therapeutic dose. However, since the effects of low-dose imatinib exposure on infants are not yet known, women taking this product should not breastfeed. There have been post-marketing reports of spontaneous abortions and congenital anomalies in infants born to women taking imatinib.

Fertility: No human studies have been conducted in male patients receiving imatinib regarding its effects on male fertility and spermatogenesis. Male patients undergoing treatment with imatinib who are concerned about potential effects on their fertility should consult their physician.

Pediatric Use: For use in children aged 3 years and older, please refer to the [Dosage and Administration] section. Data are primarily derived from studies conducted in children abroad; data regarding the safety and efficacy of this product in the Chinese pediatric population are limited, and there is currently no clinical experience with its use in children under 3 years of age.

Geriatric Use: Age-related reductions in creatinine clearance do not appear to have a significant effect on the pharmacokinetics of imatinib mesylate. Elderly patients or patients with a history of cardiac disease undergoing treatment with this product should first undergo an assessment of their Left Ventricular Ejection Fraction (LVEF). During treatment, if a patient develops significant symptoms of heart failure, a comprehensive examination should be performed, and appropriate treatment administered based on the clinical symptoms.

Product Specifications

Product Name: Gleevec | Imatinib Mesylate Tablets (Imatinib Veenat) 100mg / 120 Capsules

Common Name: Gleevec

Active Ingredient: Imatinib Mesylate (Imatinib) 100mg

Dosage Form: Capsules

Specification: 120 capsules per bottle

Manufacturer: Natco Pharma

Indications: Used for the treatment of patients with Chronic Myeloid Leukemia (CML) in the blast phase, accelerated phase, or chronic phase following failure of alpha-interferon therapy; and for patients with unresectable or metastatic malignant Gastrointestinal Stromal Tumors (GIST).

Dosage and Administration: Starting Dose: For patients with CML in the blast phase and accelerated phase, the recommended dose of Imatinib Mesylate is 600 mg/day. For patients in the chronic phase following failure of interferon therapy, as well as patients with unresectable or metastatic malignant GIST, the recommended dose is 400 mg/day. Both regimens are administered orally once daily. The medication should be taken with a meal and a large glass of water; treatment should be continued as long as the therapy remains effective.

Provided that blood counts permit and no severe adverse drug reactions occur, the dosage may be considered for escalation from 400 mg/day to 600 mg/day, or from 600 mg/day to 800 mg/day (administered as 400 mg twice daily) under the following circumstances: disease progression; failure to achieve a satisfactory hematologic response after at least 3 months of treatment; or the loss of a previously achieved hematologic response.