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Gleevec (Imatinib Mesylate) - Warnings and Precautions

 
 



WARNINGS AND PRECAUTIONS

Fluid Retention and Edema

Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)]. 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 1.5% 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) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

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. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.12)].

Severe Congestive Heart Failure and Left Ventricular Dysfunction

Severe congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. 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 Gleevec interruption and/or dose reduction [see Dosage and Administration (2.12)].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

Hemorrhage

In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. Patients should therefore be monitored for gastrointestinal symptoms at the start of therapy. 

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.

Hypereosinophilic Cardiac Toxicity

In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/ myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

Dermatologic Toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. 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.

Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

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 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.

Embryo-fetal Toxicity

Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Sexually active female patients of reproductive potential taking Gleevec should use highly effective contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Children and Adolescents

Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended [see Adverse Reactions (6.13)].

Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Gleevec. 

Driving and Using Machinery

Reports of motor vehicle accidents have been received in patients receiving Gleevec. While most of these reports are not suspected to be caused by Gleevec, patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Gleevec. Therefore, caution should be recommended when driving a car or operating machinery.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.11)].

Risk Summary

Gleevec can cause fetal harm when administered to a pregnant woman. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken Gleevec. Imatinib was teratogenic in animals. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data

Imatinib mesylate was teratogenic in rats when administered orally during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human 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 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).

Nursing Mothers

Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, 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. Because of the potential for serious adverse reactions in nursing infants from Gleevec, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Gleevec safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and Ph+ ALL. There are no data in children under 1 year of age.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs. 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.

Geriatric Use

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. 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 Warnings and Precautions (5.1)]. The efficacy of Gleevec 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 Gleevec was similar in patients older than 65 years and younger patients.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 14) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.11)].

Table 14 Liver Function Classification
Liver Function Test Normal
(n=14)
Mild
(n=30)
Moderate
(n=20)
Severe
(n=20)
Total Bilirubin ≤ULN >1.0-1.5x ULN >1.5-3x ULN >3-10x ULN
SGOT
≤ULN >ULN (can be normal if Total Bilirubin is >ULN) Any Any
ULN=upper limit of normal for the institution

Renal Impairment

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 15) 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. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.11)].

Table 15 Renal Function Classification
Renal Dysfunction Renal Function Tests
Mild CrCL = 40-59 mL/min
Moderate CrCL = 20-39 mL/min
Severe CrCL = <20 mL/min
CrCL = Creatinine Clearance

Page last updated: 2014-12-22

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