WARNINGS
Pregnancy
Women of childbearing potential should be advised to avoid becoming pregnant.
Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).
Male and female rats were exposed in utero to a maternal imatinib mesylate dose of 45 mg/kg (approximately one-half the maximum human dose of 800 mg) from Day 6 of gestation and through milk during the lactation period. These animals then received no imatinib exposure for nearly 2 months. Body weights were reduced from birth until terminal sacrifice in these rats. Although fertility was not affected, fetal loss was seen when these male and female animals were then mated.
There are no adequate and well-controlled studies in pregnant women. If Gleevec® (imatinib mesylate) is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Gleevec, the patient should be apprised of the potential hazard to the fetus.
PRECAUTIONS
General
Dermatologic Toxicities: Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec® (imatinib mesylate). In some cases reported during post- marketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.
Fluid Retention and Edema: Gleevec is often associated with edema and occasionally serious fluid retention (see ADVERSE REACTIONS). Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.1% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) events were reported in 0.7% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe superficial edema and severe fluid retention (pleural effusion, pulmonary edema and ascites) were reported in 1%-6% of patients taking Gleevec for GIST.
There have been post-marketing reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema in patients treated with Gleevec.
Gastrointestinal Disorders: Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.
Hemorrhage: In the newly diagnosed CML trial, 1.1% of patients had Grade 3/4 hemorrhage. In the GIST clinical trial, seven patients (5%), four in the 600-mg dose group and three in the 400-mg dose group, had a total of eight events of CTC Grade 3/4 - gastrointestinal (GI) bleeds (3 patients), intra-tumoral bleeds (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI bleeds.
Hematologic Toxicity: Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. (See DOSAGE AND ADMINISTRATION.)
Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur with Gleevec (see ADVERSE REACTIONS). Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Gleevec. (See DOSAGE AND ADMINISTRATION).
Hepatic Impairment: Comparable exposure was noted between each of the mildly and moderately hepatically-impaired patients and patients with normal hepatic function. However, patients with severe hepatic impairment tended to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function (See CLINICAL PHARMACOLOGY and DOSING AND ADMINISTRATION). Patients with severe hepatic impairment should be closely monitored.
Toxicities From Long -Term Use: It is important to consider potential toxicities suggested by animal studies, specifically, liver and kidney 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 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).
Drug Interactions
Drugs that May Alter Amatinib Plasma Concentrations
Drugs that may increase imatinib plasma concentrations:
Caution is recommended when administering Gleevec with inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations. There is a significant increase in exposure to imatinib when Gleevec is coadministered with ketoconazole (CYP3A4 inhibitor).
Drugs that may decrease imatinib plasma concentrations:
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or St. John’s Wort) may significantly reduce exposure to Gleevec. Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC(0-∞). In patients where rifampin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Drugs that May Have their Plasma Concentration Altered by Gleevec
Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.
In vitro, Gleevec inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that affect CYP3A4 activity. Systemic exposure to substrates of CYP2D6 is expected to be increased when coadministered with Gleevec. No specific studies have been performed and caution is recommended.
In vitro, Gleevec inhibits acetaminophen O-glucuronidation (Ki value of 58.5 µM) at therapeutic levels. Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec. No specific studies in humans have been performed and caution is recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The urogenital tract from a 2-year carcinogenicity study in rats receiving doses of 15, 30 and 60 mg/kg/day of imatinib mesylate showed renal adenomas/carcinomas, urinary bladder papillomas and papillomas/carcinomas of the preputial and clitoral gland. Evaluation of other organs in the rats is ongoing.
The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day (approximately 0.5 to 4 times the human daily exposure at 400 mg/day). The kidney adenoma/carcinoma and the urinary bladder papilloma were noted at 60 mg/kg/day. No tumors in the urogenital tract were observed at 15 mg/kg/day.
Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay.
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ≤20 mg/kg (one-fourth the maximum human dose of 800 mg). When female rats were dosed 14 days prior to mating and through to gestational Day 6, there was no effect on mating or on number of pregnant females.
In female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end of lactation, red vaginal discharge was noted on either gestational Day 14 or 15.
Pregnancy
Pregnancy Category D. (See WARNINGS.)
Nursing Mothers
It is not known whether imatinib mesylate or its metabolites are excreted in human milk. However, in lactating female rats administered 100 mg/kg, a dose approximately equal to the maximum clinical dose of 800 mg/day based on body surface area, imatinib and its metabolites were extensively excreted in milk. Concentration in milk was approximately three-fold higher than in plasma. It is estimated that approximately 1.5% of a maternal dose is excreted into milk, which is equivalent to a dose to the infant of 30% the maternal dose per unit body weight. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while taking Gleevec.
Pediatric Use
Gleevec safety and efficacy have been demonstrated only in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferon-alpha therapy. There are no data in children under 3 years of age.
Geriatric Use
In the CML clinical studies, approximately 40% of patients were older than 60 years and 10% were older than 70 years. In the study of patients with newly diagnosed CML, 22% of patients were 60 years of age or older. 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. (See PRECAUTIONS.) The efficacy of Gleevec was similar in older and younger patients.
In the GIST study, 29% of patients were older than 60 years and 10% of patients were older than 70 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.
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