IMATINIB MESYLATE tablet, film coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

IMATINIB MESYLATE (UNII: 8A1O1M485B) (IMATINIB - UNII:BKJ8M8G5HI)

Available from:

American Health Packaging

INN (International Name):

IMATINIB MESYLATE

Composition:

IMATINIB 100 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. None. Risk Summary Imatinib mesylate can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day. Risk Summary Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from imatinib mesylate, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose. Human Data Based on data from 3 breastfeeding women taking imatinib mesylate, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Human postmarketing reports and animal studies have shown imatinib mesylate to be harmful to the developing fetus [see Use in Specific Populations (8.1)]. Pregnancy Testing Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib mesylate. Contraception Females Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1 % pregnancy rates) when using imatinib mesylate during treatment and for fourteen days after stopping treatment with imatinib mesylate [see Use in Specific Populations (8.1)]. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13) ]. The safety and effectiveness of imatinib mesylate have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2, 14.4)]. There are no data in children under 1 year of age. In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1) ]. The efficacy of imatinib mesylate was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of imatinib mesylate was similar in patients older than 65 years and younger patients. The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, the imatinib C max and area under curve (AUC) increased by 63% and 45% and the CGP74588 C max and AUC increased by 56% and 55%, relative to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Reduce the dose by 25% for patients with severe hepatic impairment [see Dosage and Administration (2.12)]. Abbreviation: SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); ULN, upper limit of normal for the institution. The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2- fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2.12)]. Renal Dysfunction Renal Function Tests Mild CrCL = 40 to 59 mL/min Moderate CrCL = 20 to 39 mL/min Severe CrCL = less than 20 mL/min Abbreviation: CrCL, creatinine clearance.

Product summary:

Each film-coated tablet contains 100 mg or 400 mg of imatinib free base. Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature]. Protect from moisture. FOR YOUR PROTECTION: Do not use if blister is torn or broken. Do not crush imatinib mesylate tablets. Avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, wash thoroughly as outlined in the references. Avoid exposure to crushed tablets.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

IMATINIB MESYLATE- IMATINIB MESYLATE TABLET, FILM COATED
AMERICAN HEALTH PACKAGING
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
IMATINIB MESYLATE
TABLETS SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
IMATINIB MESYLATE
TABLETS.
IMATINIB MESYLATE TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2001
INDICATIONS AND USAGE
Imatinib mesylate is a kinase inhibitor indicated for the treatment
of:
Newly diagnosed adult and pediatric patients with Philadelphia
chromosome positive chronic myeloid
leukemia (Ph+ CML) in chronic phase. (1.1)
Patients with Philadelphia chromosome positive chronic myeloid
leukemia (Ph+ CML) in blast crisis
(BC), accelerated phase (AP), or in chronic phase (CP) after failure
of interferon-alpha therapy. (1.2)
Adult patients with relapsed or refractory Philadelphia chromosome
positive acute lymphoblastic
leukemia (Ph+ ALL). (1.3)
Pediatric patients with newly diagnosed Philadelphia chromosome
positive acute lymphoblastic
leukemia (Ph+ ALL) in combination with chemotherapy. (1.4)
Adult patients with myelodysplastic/myeloproliferative diseases
(MDS/MPD) associated with platelet-
derived growth factor receptor (PDGFR) gene re-arrangements. (1.5)
Adult patients with aggressive systemic mastocytosis (ASM) without the
D816V c-Kit mutation or with c-
Kit mutational status unknown. (1.6)
Adult patients with hypereosinophilic syndrome (HES) and/or chronic
eosinophilic leukemia (CEL) who
have the FIP1L1-PDGFRα fusion kinase (mutational analysis or
fluorescence in situ hybridization [FISH]
demonstration of CHIC2 allele deletion) and for patients with HES
and/or CEL who are FIP1L1‑-PDGFRα
fusion kinase negative or unknown. (1.7)
Adult patients with unresectable, recurrent and/or metastatic
dermatofibrosarcoma protuberans
(DFSP). (1.8)
Patients with Kit (CD117) positive unresectable and/or metastatic
malignant gastrointestinal stromal
tumors (GIST). (1.9)
Adjuvant treatment of adult patients following resection of Kit
(CD117)