GLEEVEC Film coated tablet Ref.[10821] Active ingredients: Imatinib

5.1 Fluid Retention and Edema

Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)]. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher Gleevec dose and age greater than 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 (6.1)]. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving Gleevec and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the Gleevec arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

5.2 Hematologic Toxicity

Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 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 (2.14)].

5.3 Congestive Heart Failure and Left Ventricular Dysfunction

Congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 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. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared Gleevec and nilotinib, cardiac failure was observed in 1.1% of patient in the Gleevec arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

5.4 Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.1)]. 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. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.13)]. 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.

5.5 Hemorrhage

In a trial of Gleevec versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade ¾ hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade ¾ hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade ¾ hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Gleevec arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the Gleevec arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

5.6 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 GI perforation.

5.7 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. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec at the initiation of therapy.

5.8 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 rechallenge. Several foreign postmarketing 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.

5.9 Hypothyroidism

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

5.10 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 (BSA) . 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 BSA. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Gleevec and for 14 days after stopping Gleevec. 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 a fetus [see Use in Specific Populations (8.1)].

5.11 Growth Retardation in 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, monitor growth in children under Gleevec treatment [see Adverse Reactions (6.1)].

5.12 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. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Gleevec.

5.13 Impairments Related to Driving and Using Machinery

Motor vehicle accidents have been reported in patients receiving Gleevec. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Gleevec. Recommend caution when driving a car or operating machinery.

5.14 Renal Toxicity

A decline in renal function may occur in patients receiving Gleevec. Median estimated glomerular filtration rate (eGFR) values in patients on Gleevec 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m² (N=1190) to 75 mL/min/1.73 m² at 12 months (N=1082) and 69 mL/min/1.73 m² at 60 months (N=549). Evaluate renal function prior to initiating Gleevec and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema [see Warnings and Precautions (5.1)]
• Hematologic Toxicity [see Warnings and Precautions (5.2)]
• Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hemorrhage [see Warnings and Precautions (5.5)]
• Gastrointestinal Disorders [see Warnings and Precautions (5.6)]
• Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7)]
• Dermatologic Toxicities [see Warnings and Precautions (5.8)]
• Hypothyroidism [see Warnings and Precautions (5.9)]
• Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.12)]
• Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13)]
• Renal Toxicity [see Warnings and Precautions (5.14)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chronic Myeloid Leukemia

The majority of Gleevec-treated patients experienced adverse reactions at some time. Gleevec was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec versus IFN+Ara-C, and in 12.5% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and nilotinib. Gleevec was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis.

The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.13)]. The frequency of severe superficial edema was 1.5%-6%.

A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec-treated patients are shown in Tables 2, 3, and 4.

Table 2. Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Gleevec versus IFN+Ara-C Study (greater than or equal to 10% of Gleevec-treated patients)⁽¹⁾:

Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha.
^* NCI Common Terminology Criteria for Adverse Events, version 3.0.
⁽¹⁾ All adverse reactions occurring in greater than or equal to10% of Gleevec-treated patients are listed regardless of suspected relationship to treatment.
⁽²⁾ Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Table 3. Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Gleevec versus nilotinib Study (greater than or equal to 10% in Gleevec 400 mg once daily or nilotinib 300 mg twice daily groups) 60-Month Analysis^a:

Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase.
^a Excluding laboratory abnormalities.
^b NCI Common Terminology Criteria for Adverse Events, version 3.0.

Table 4. Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (greater than or equal to 10% of all patients in any trial)¹:

Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha.
¹ All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment.
² Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Hematologic and Biochemistry Laboratory Abnormalities

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but may require permanent discontinuation of treatment.

Table 5. Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Gleevec versus IFN+Ara-C):

Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
^* p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups).

Table 6. Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Gleevec versus nilotinib):

Abbreviations: CML, chronic myeloid leukemia; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
^* NCI Common Terminology Criteria for Adverse Events, version 3.0.

Table 7. Laboratory Abnormalities in Other CML Clinical Trials:

Abbreviations: CML, chronic myeloid leukemia; CTC, common terminology criteria; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
¹ CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 × 10⁹/L, Grade 4 less than 0.5 × 10 ⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 × 10 ⁹/L, Grade 4 less than 10 × 10⁹/L), anemia (hemoglobin greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN).

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Adverse Reactions in Pediatric Population

Single-Agent Therapy

The overall safety profile of pediatric patients treated with Gleevec in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade ¾ events across all types of adverse reactions was 75%; the events with the highest Grade ¾ incidence in CML pediatric patients were mainly related to myelosuppression.

In Combination with Multi-Agent Chemotherapy:

Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive Gleevec and treated in 5 successive cohorts. Gleevec exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of Gleevec given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive Gleevec. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Gleevec. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Gleevec, and 647 without Gleevec. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included Gleevec are presented in Table 8.

Table 8. Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (greater than 5%) or in Cycles With Study Drug (greater than 1%):

Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia.
^* Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included Gleevec (includes patients with Ph+ ALL that received cycles with Gleevec).
^** Defined as the frequency of AEs per patient per treatment cycles that did not include Gleevec (includes patients with Ph+ ALL that received cycles without Gleevec as well as all patients with Ph- ALL who did not receive Gleevec in any treatment cycle).

Adverse Reactions in Other Subpopulations

In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade ½ superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

Acute Lymphoblastic Leukemia

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade ¾ events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.

Myelodysplastic/Myeloproliferative Diseases

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the Phase 2 study, are shown in Table 9.

Table 9. Adverse Reactions Regardless of Relationship to Study Drug Reported (more than one patient) in MPD Patients in the Phase 2 Study (greater than or equal to 10% all patients) All Grades:

Abbreviation: MPD, Myeloproliferative Disease.

Aggressive Systemic Mastocytosis

All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued Gleevec due to drug-related adverse reactions or abnormal laboratory values.

Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Gleevec observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.

Dermatofibrosarcoma Protuberans

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the Phase 2 study are shown in Table 10.

Table 10. Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (greater than or equal to 10% all patients) All Grades:

Abbreviation: DFSP, dermatofibrosarcoma protuberans.

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the Phase 2 study are presented in Table 11.

Table 11. Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study:

Abbreviation: CTC, common terminology criteria.
¹ CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 × 10⁹/L, Grade 4 less than 0.5 × 10⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 × 10⁹/L, Grade 4 less than 10 × 10⁹/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN).

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

In the Phase 3 trials, the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.13)]. Severe (CTC Grade ¾) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 12.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 12. Number () of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10 in any One Group (full analysis set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials:

Abbreviations: ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors.

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.

Table 13. Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial:

Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
¹ CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 × 10⁹/L, Grade 4 less than 0.5 × 10⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 × 10⁹/L, Grade 4 less than 10 × 10⁹/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L).

Adjuvant Treatment of GIST

In Study 1, the majority of both Gleevec and placebo-treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST-treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo-treated patients, respectively. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.

In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Gleevec 12-month, and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to Gleevec treatment in either trial.

Table 14. Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (greater than or equal to 5% of Gleevec-treated patients)⁽¹⁾:

Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
^* NCI Common Terminology Criteria for Adverse Events, version 3.0.
¹ All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

Table 15. Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and ¾ Grades (greater than or equal to 5% of Gleevec-treated patients) Study 2¹:

Abbreviations: AE, adverse event; CTC, common terminology criteria.
¹ All adverse reactions occurring in greater than or equal to5% of patients are listed regardless of suspected relationship to treatment.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

Adverse Reactions from Multiple Clinical Trials

Cardiac Disorders:

Estimated 1%-10%: palpitations, pericardial effusion

Estimated 0.1%-1%: congestive cardiac failure, tachycardia, pulmonary edema

Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris

Vascular Disorders:

Estimated 1%-10%: flushing, hemorrhage

Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma

Investigations:

Estimated 1%-10%: blood creatine phosphokinase (CPK) increased, blood amylase increased

Estimated 0.1%-1%: blood lactate dehydrogenase (LDH) increased

Skin and Subcutaneous Tissue Disorders:

Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura

Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme

Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis

Gastrointestinal Disorders:

Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis

Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis

Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease

General Disorders and Administration-Site Conditions:

Estimated 1%-10%: weakness, anasarca, chills

Estimated 0.1%-1%: malaise

Blood and Lymphatic System Disorders:

Estimated 1%-10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia

Estimated 0.1%-1%: thrombocythemia, bone marrow depression, lymphadenopathy

Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia

Hepatobiliary Disorders:

Estimated 0.1%-1%: hepatitis, jaundice

Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis ¹

Immune System Disorders:

Estimated 0.01%-0.1%: angioedema

Infections and Infestations:

Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis

Estimated 0.01%-0.1%: fungal infection

Metabolism and Nutrition Disorders:

Estimated 1%-10%: weight decreased, decreased appetite

Estimated 0.1%-1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia

Musculoskeletal and Connective Tissue Disorders:

Estimated 1%-10%: joint swelling

Estimated 0.1%-1%: joint and muscle stiffness, muscular weakness, arthritis

Nervous System/Psychiatric Disorders:

Estimated 1%-10%: paresthesia, hypesthesia

Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor

Estimated 0.01%-0.1%: increased intracranial pressure ¹, confusional state, convulsions, optic neuritis

Renal and Urinary Disorders:

Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain

Reproductive System and Breast Disorders:

Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema

Respiratory, Thoracic and Mediastinal Disorders:

Estimated 1%-10%: epistaxis

Estimated 0.1%-1%: pleural effusion

Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage

Endocrine Disorders:

Estimated 0.1%-1%: hypothyroidism, hyperthyroidism

Eye, Ear, and Labyrinth Disorders:

Estimated 1%-10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye

Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract

Estimated 0.01%-0.1%: papilledema¹, glaucoma

¹Including some fatalities.

The following additional adverse reactions have been identified during post approval use of Gleevec. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: thrombotic microangiopathy

Cardiac Disorders: pericarditis, cardiac tamponade¹

Eye Disorders: vitreous hemorrhage

Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation¹ [see Warnings and Precautions (5.6)], diverticulitis, gastric antral vascular ectasia

Infections: hepatitis B virus reactivation¹

Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain)

Nervous System Disorders: cerebral edema¹

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure¹, interstitial lung disease

Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria

Vascular Disorders: thrombosis/embolism, anaphylactic shock

¹ Including some fatalities.

7.1 Agents Inducing CYP3A Metabolism

Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3)].

7.2 Agents Inhibiting CYP3A Metabolism

Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3)].

7.3 Interactions With Drugs Metabolized by CYP3A4

Gleevec will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window.

Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology (12.3)].

7.4 Interactions With Drugs Metabolized by CYP2D6

Use caution when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

Risk Summary

Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Gleevec in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to Gleevec 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 Gleevec. 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%-4% and of miscarriage is 15%-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 numbers 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 Gleevec, 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 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.

Pregnancy Testing

Human postmarketing reports and animal studies have shown Gleevec to be harmful to the developing fetus. Test pregnancy status in females with reproductive potential prior to the initiation of treatment with Gleevec.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Gleevec during treatment and for fourteen days after stopping treatment with Gleevec [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 Gleevec 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 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.

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)].

Table 17. Renal Function Classification:

Abbreviation: CrCL, creatinine clearance.

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)].

Table 16. Liver Function Classification:

Abbreviation: SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); ULN, upper limit of normal for the institution.