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Gleevec

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Gleevec

Side Effects
Interactions

SIDE EFFECTS

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

Chronic Myeloid Leukemia

The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% 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 for newly diagnosed CML, Table 3 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]. 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. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.

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 and 3.

Table 2 : Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial ( ≥ 10% of Gleevec Treated Patients)1

Preferred Term All Grades CTC Grades 3/4
Gleevec
N=551
(%)
IFN+Ara-C
N=533
(%)
Gleevec
N=551
(%)

IFN+Ara-C
N=533
(%)

Fluid Retention 61.7 11.1 2.5 0.9
- Superficial Edema 59.9 9.6 1.5 0.4
- Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6
Nausea 49.5 61.5 1.3 5.1
Muscle Cramps 49.2 11.8 2.2 0.2
Musculoskeletal Pain 47.0 44.8 5.4 8.6
Diarrhea 45.4 43.3 3.3 3.2
Rash and Related Terms 40.1 26.1 2.9 2.4
Fatigue 38.8 67.0 1.8 25.1
Headache 37.0 43.3 0.5 3.8
Joint Pain 31.4 38.1 2.5 7.7
Abdominal Pain 36.5 25.9 4.2 3.9
Nasopharyngitis 30.5 8.8 0 0.4
Hemorrhage 28.9 21.2 1.8 1.7
- GI Hemorrhage 1.6 1.1 0.5 0.2
- CNS Hemorrhage 0.2 0.4 0 0.4
Myalgia 24.1 38.8 1.5 8.3
Vomiting 22.5 27.8 2.0 3.4
Dyspepsia 18.9 8.3 0 0.8
Cough 20.0 23.1 0.2 0.6
Pharyngolaryngeal Pain 18.1 11.4 0.2 0
Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4
Dizziness 19.4 24.4 0.9 3.8
Pyrexia 17.8 42.6 0.9 3.0
Weight Increased 15.6 2.6 2.0 0.4
Insomnia 14.7 18.6 0 2.3
Depression 14.9 35.8 0.5 13.1
Influenza 13.8 6.2 0.2 0.2
Bone Pain 11.3 15.6 1.6 3.4
Constipation 11.4 14.4 0.7 0.2
Sinusitis 11.4 6.0 0.2 0.2
1All adverse reactions occurring in ≥ 10% of Gleevec treated patients are listed regardless of suspected relationship to treatment.
2Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Table 3 : Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials ( ≥ 10% of All Patients in any Trial)1

Preferred Term Myeloid Blast Crisis
(n=260) %
Accelerated Phase
(n=235) %
Chronic Phase, IFN Failure
(n=532) %
All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Fluid Retention 72 11 76 6 69 4
-Superficial Edema 66 6 74 3 67 2
-Other Fluid Retention Reactions2 22 6 15 4 7 2
Nausea 71 5 73 5 63 3
Muscle Cramps 28 1 47 0.4 62 2
Vomiting 54 4 58 3 36 2
Diarrhea 43 4 57 5 48 3
Hemorrhage 53 19 49 11 30 2
- CNS Hemorrhage 9 7 3 3 2 1
- GI Hemorrhage 8 4 6 5 2 0.4
Musculoskeletal Pain 42 9 49 9 38 2
Fatigue 30 4 46 4 48 1
Skin Rash 36 5 47 5 47 3
Pyrexia 41 7 41 8 21 2
Arthralgia 25 5 34 6 40 1
Headache 27 5 32 2 36 0.6
Abdominal Pain 30 6 33 4 32 1
Weight Increased 5 1 17 5 32 7
Cough 14 0.8 27 0.9 20 0
Dyspepsia 12 0 22 0 27 0
Myalgia 9 0 24 2 27 0.2
Nasopharyngitis 10 0 17 0 22 0.2
Asthenia 18 5 21 5 15 0.2
Dyspnea 15 4 21 7 12 0.9
Upper Respiratory Tract Infection 3 0 12 0.4 19 0
Anorexia 14 2 17 2 7 0
Night Sweats 13 0.8 17 1 14 0.2
Constipation 16 2 16 0.9 9 0.4
Dizziness 12 0.4 13 0 16 0.2
Pharyngitis 10 0 12 0 15 0
Insomnia 10 0 14 0 14 0.2
Pruritus 8 1 14 0.9 14 0.8
Hypokalemia 13 4 9 2 6 0.8
Pneumonia 13 7 10 7 4 1
Anxiety 8 0.8 12 0 8 0.4
Liver Toxicity 10 5 12 6 6 3
Rigors 10 0 12 0.4 10 0
Chest Pain 7 2 10 0.4 11 0.8
Influenza 0.8 0.4 6 0 11 0.2
Sinusitis 4 0.4 11 0.4 9 0.4
1All adverse reactions occurring in ≥ 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 Toxicity

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥ 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 4 and 5). 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 in rare cases require permanent discontinuation of treatment.

Table 4 : Lab Abnormalities in Newly Diagnosed CML Clinical Trial

CTC Grades Gleevec
N=551 %
IFN+Ara−C
N=533 %
Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters*
- Neutropenia* 13.1 3.6 20.8 4.5
- Thrombocytopenia* 8.5 0.4 15.9 0.6
- Anemia 3.3 1.1 4.1 0.2
Biochemistry Parameters
- Elevated Creatinine 0 0 0.4 0
- Elevated Bilirubin 0.9 0.2 0.2 0
- Elevated Alkaline Phosphatase 0.2 0 0.8 0
- Elevated SGOT /SGPT 4.7 0.5 7.1 0.4
*p < 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)

Table 5 : Lab Abnormalities in Other CML Clinical Trials

CTC Grades1 Myeloid Blast Crisis
(n=260) 600 mg n=223 400 mg n=37 %
Accelerated Phase
(n=235) 600 mg n=158 400 mg n=77 %
Chronic Phase, IFN Failure
(n=532) 400 mg %
Grade 3 Grade 4 Grade 3 Grade 4 Grade Grade 4
Hematology Parameters
- Neutropenia 16 48 23 36 3 27 9
- Thrombocytopenia 30 33 31 13 21 < 1
- Anemia 42 11 34 7 6 1
Biochemistry Parameters
- Elevated Creatinine 1.5 0 1.3 0 0.2 0
- Elevated Bilirubin 3.8 0 2.1 0 0.6 0
- Elevated Alkaline Phosphatase 4.6 0 5.5 0.4 0.2 0
- Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0
- Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0
1CTC Grades: neutropenia (Grade 3 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10-50 x 109/L, Grade 4 < 10 x 109/L), anemia (hemoglobin ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 6 x ULN), elevated bilirubin (Grade 3 > 3-10 x ULN, Grade 4 > 10 x ULN), elevated alkaline phosphatase (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN), elevated SGOT or SGPT (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN)

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) 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. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.

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 ( < 750/μL) and thrombocytopenia ( < 75,000/ μL) 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 6.

Table 6 : Adverse Reactions Reported More Frequently in Patients Treated with Study Drug ( > 5%) or in Cycles with Study Drug ( > 1%)

Adverse Event Per Patient Incidence Ph+ALL With Gleevec
N = 92
Per Patient Incidence Ph- ALL No Gleevec
N = 65
Per Patient Per Cycle Incidence With Gleevec*
N = 778
Per Patient Per Cycle Incidence No Gleevec**
N = 647
Grade 3 and 4 Adverse Events
Nausea and/or Vomiting 15 (16%) 6 (9%) 28 (4%) 8 (1%)
Hypokalemia 31 (34%) 16 (25%) 72 (9%) 32(5%)
Pneumonitis 7 (8%) 1 (1%) 7(1%) 1( < 1%)
Pleural effusion 6 (7%) 0 6 (1%) 0
Abdominal Pain 8 (9%) 2 (3%) 9 (1%) 3( < 1%)
Anorexia 10 (11%) 3 (5%) 19 (2%) 4 (1%)
Hemorrhage 11 (12%) 4 (6%) 17 (2%) 8 (1%)
Hypoxia 8 (9%) 2 (3%) 12 (2%) 2 ( < 1%)
Myalgia 5 (5%) 0 4 (1%) 1 ( < 1%)
Stomatitis 15 (16%) 8 (12%) 22 (3%) 14 (2%)
Diarrhea 8 (9%) 3 (5%) 12 (2%) 3 ( < 1%)
Rash / Skin Disorder 4 (4%) 0 5 (1%) 0
Infection 49 (53%) 32 (49%) 131 (17%) 92 (14%)
Hepatic (transaminase and/or bilirubin) 52 (57%) 38 (58%) 172 (22%) 113 (17%)
Hypotension 10 (11%) 5 (8%) 16 (2%) 6 (1%)
Myelosuppression
Neutropenia ( < 750/μL) 92 (100%) 63 (97%) 556 (71%) 218 (34%)
Thrombocytopenia ( < 75,000/μL) 90 (92%) 63 (97%) 431 (55%) 329 (51%)
* Defined as the frequency of 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 ( ≥ 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, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe 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 7.

Table 7 : Adverse Reactions Regardless of Relationship to Study Drug Reported (More than One Patient) in MPD Patients in the Phase 2 Study ( ≥ 10% All Patients) All Grades

Preferred Term N=7
n (%)
Nausea 4 (57.1)
Diarrhea 3 (42.9)
Anemia 2 (28.6)
Fatigue 2 (28.6)
Muscle Cramp 3 (42.9)
Arthralgia 2 (28.6)
Periorbital Edema 2 (28.6)

Aggressive Systemic Mastocytosis

All 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 gastrointestinal, 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 8.

Table 8 : Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study ( ≥ 10% All Patients) All Grades

Preferred term N=12
n (%)
Nausea 5 (41.7)
Diarrhea 3 (25.0)
Vomiting 3 (25.0)
Periorbital Edema 4 (33.3)
Face Edema 2 (16.7)
Rash 3 (25.0)
Fatigue 5 (41.7)
Edema Peripheral 4 (33.3)
Pyrexia 2 (16.7)
Eye Edema 4 (33.3)
Lacrimation Increased 3 (25.0)
Dyspnea Exertional 2 (16.7)
Anemia 3 (25.0)
Rhinitis 2 (16.7)
Anorexia 2 (16.7)

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the phase 2 study are presented in Table 9.

Table 9 : Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study

CTC Grades1 N=12
Grade 3 Grade 4
Hematology Parameters
- Anemia 17% 0%
- Thrombocytopenia 17% 0%
- Neutropenia 0% 8%
Biochemistry Parameters
- Elevated Creatinine 0% 8%
1CTC Grades: neutropenia (Grade 3 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10 - 50 x 109/L, Grade 4 < 10 x 109/L), anemia (Grade 3 ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 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]. Severe (CTC Grade 3/4) 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 10.

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 10 : Number (%) of Patients with Adverse Reactions Regardless of Relationship to Study Drug where Frequency is ≥ 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials

  Imatinib 400 mg
N=818
Imatinib 800 mg
N=822
All Grades % Grades 3/4/5% All Grades % Grades 3/4/5%
Reported or Specified Term Edema 76.7 9.0 86.1 13.1
Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2
Nausea 58.1 9.0 64.5 7.8
Abdominal pain/cramping 57.2 13.8 55.2 11.8
Diarrhea 56.2 8.1 58.2 8.6
Rash/desquamation 38.1 7.6 49.8 8.9
Vomiting 37.4 9.2 40.6 7.5
Myalgia 32.2 5.6 30.2 3.8
Anemia 32.0 4.9 34.8 6.4
Anorexia 31.1 6.6 35.8 4.7
Other GI toxicity 25.2 8.1 28.1 6.6
Headache 22.0 5.7 19.7 3.6
Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0
Other dermatology /skin toxicity 17.6 5.9 20.1 5.7
Leukopenia 17.0 0.7 19.6 1.6
Other constitutional symptoms 16.7 6.4 15.2 4.4
Cough 16.1 4.5 14.5 3.2
Infection (without neutropenia) 15.5 6.6 16.5 5.6
Pruritus 15.4 5.4 18.9 4.3
Other neurological toxicity 15.0 6.4 15.2 4.9
Constipation 14.8 5.1 14.4 4.1
Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2
Arthralgia (joint pain) 13.6 4.8 12.3 3.0
Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6
Fever in absence of neutropenia (ANC < 1.0 x 109/L) 13.2 4.9 12.9 3.4
Sweating 12.7 4.6 8.5 2.8
Other hemorrhage 12.3 6.7 13.3 6.1
Weight gain 12.0 1.0 10.6 0.6
Alopecia 11.9 4.3 14.8 3.2
Dyspepsia/heartburn 11.5 0.6 10.9 0.5
Neutropenia/ granulocytopenia 11.5 3.1 16.1 4.1
Rigors/chills 11.0 4.6 10.2 3.0
Dizziness/ lightheadedness 11.0 4.8 10.0 2.8
Creatinine increase 10.8 0.4 10.1 0.6
Flatulence 10.0 0.2 10.1 0.1
Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3
Lymphopenia 6.0 0.7 10.1 1.9

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 11.

Table 11 : Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial

CTC Grades1 400 mg
(n=73) %
600 mg
(n=74)
Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters
- Anemia 3 0 8 1
- Thrombocytopenia 0 0 1 0
- Neutropenia 7 3 8 3
Biochemistry Parameters
- Elevated Creatinine 0 0 3 0
- Reduced Albumin 3 0 4 0
- Elevated Bilirubin 1 0 1 3
- Elevated Alkaline Phosphatase 0 0 3 0
- Elevated SGOT (AST) 4 0 3 3
- Elevated SGPT (ALT) 6 0 7 1
1CTC Grades: neutropenia (Grade 3 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10 - 50 x 109/L, Grade 4 < 10 x 109/L), anemia (Grade 3 ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 6 x ULN), elevated bilirubin (Grade 3 > 3-10 x ULN, Grade 4 > 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN), albumin (Grade 3 < 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, gastrointestinal 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 12 (Study 1) and Table 13 (Study 2). There were no deaths attributable to Gleevec treatment in either trial.

Table 12: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 ( ≥ 5% of Gleevec Treated Patients)1

Preferred Term All CTC Grades CTC Grade 3 and above
Gleevec
(n=337) %
Placebo
(n=345) %
Gleevec
(n=337) %
Placebo
(n=345) %
Diarrhea 59.3 29.3 3.0 1.4
Fatigue 57.0 40.9 2.1 1.2
Nausea 53.1 27.8 2.4 1.2
Periorbital Edema 47.2 14.5 1.2 0
Hemoglobin Decreased 46.9 27.0 0.6 0
Peripheral Edema 26.7 14.8 0.3 0
Rash (Exfoliative) 26.1 12.8 2.7 0
Vomiting 25.5 13.9 2.4 0.6
Abdominal Pain 21.1 22.3 3.0 1.4
Headache 19.3 20.3 0.6 0
Dyspepsia 17.2 13.0 0.9 0
Anorexia 16.9 8.7 0.3 0
Weight Increased 16.9 11.6 0.3 0
Liver enzymes (ALT) Increased 16.6 13.0 2.7 0
Muscle spasms 16.3 3.3 0 0
Neutrophil Count Decreased 16.0 6.1 3.3 0.9
Arthralgia 15.1 14.5 0 0.3
White Blood Cell Count Decreased 14.5 4.3 0.6 0.3
Constipation 12.8 17.7 0 0.3
Dizziness 12.5 10.7 0 0.3
Liver Enzymes (AST) Increased 12.2 7.5 2.1 0
Myalgia 12.2 11.6 0 0.3
Blood Creatinine Increased 11.6 5.8 0 0.3
Cough 11.0 11.3 0 0
Pruritus 11.0 7.8 0.9 0
Weight Decreased 10.1 5.2 0 0
Hyperglycemia 9.8 11.3 0.6 1.7
Insomnia 9.8 7.2 0.9 0
Lacrimation Increased 9.8 3.8 0 0
Alopecia 9.5 6.7 0 0
Flatulence 8.9 9.6 0 0
Rash 8.9 5.2 0.9 0
Abdominal Distension 7.4 6.4 0.3 0.3
Back Pain 7.4 8.1 0.6 0
Pain in Extremity 7.4 7.2 0.3 0
Hypokalemia 7.1 2.0 0.9 0.6
Depression 6.8 6.4 0.9 0.6
Facial Edema 6.8 1.2 0.3 0
Blood Alkaline Phosphatase Increased 6.5 7.5 0 0
Dry skin 6.5 5.2 0 0
Dysgeusia 6.5 2.9 0 0
Abdominal Pain Upper 6.2 6.4 0.3 0
Neuropathy Peripheral 5.9 6.4 0 0
Hypocalcemia 5.6 1.7 0.3 0
Leukopenia 5.0 2.6 0.3 0
Platelet Count Decreased 5.0 3.5 0 0
Stomatitis 5.0 1.7 0.6 0
Upper Respiratory Tract Infection 5.0 3.5 0 0
Vision Blurred 5.0 2.3 0 0
1All adverse reactions occurring in ≥ 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 13: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades ( ≥ 5% of Gleevec Treated Patients) Study 21

Preferred Term All CTC Grades CTC Grades 3 and above
Gleevec12 Months
(N=194) %
Gleevec36 Months
(N=198) %
Gleevec12 Months
(N=194) %
Gleevec36 Months
(N=198) %
Patients with at least one AE 99.0 100.0 20.1 32.8
Hemoglobin decreased 72.2 80.3 0.5 0.5
Periorbital edema 59.3 74.2 0.5 1.0
Blood lactate dehydrogenase increased 43.3 60.1 0 0
Diarrhea 43.8 54.0 0.5 2.0
Nausea 44.8 51.0 1.5 0.5
Muscle spasms 30.9 49.0 0.5 1.0
Fatigue 48.5 48.5 1.0 0.5
White blood cell count decreased 34.5 47.0 2.1 3.0
Pain 25.8 45.5 1.0 3.0
Blood creatinine increased 30.4 44.4 0 0
Edema peripheral 33.0 40.9 0.5 1.0
Dermatitis 29.4 38.9 2.1 1.5
Aspartate aminotransferase increased 30.9 37.9 1.5 3.0
Alanine aminotransferase increased 28.9 34.3 2.1 3.0
Neutrophil count decreased 24.2 33.3 4.6 5.1
Hypoproteinemia 23.7 31.8 0 0
Infection 13.9 27.8 1.5 2.5
Weight increased 13.4 26.8 0 0.5
Pruritus 12.9 25.8 0 0
Flatulence 19.1 24.7 1.0 0.5
Vomiting 10.8 22.2 0.5 1.0
Dyspepsia 17.5 21.7 0.5 1.0
Hypoalbuminemia 11.9 21.2 0 0
Edema 10.8 19.7 0 0.5
Abdominal distension 11.9 19.2 0.5 0
Headache 8.2 18.2 0 0
Lacrimation increased 18.0 17.7 0 0
Arthralgia 8.8 17.2 0 1.0
Blood alkaline phosphatase increased 10.8 16.7 0 0.5
Dyspnea 6.2 16.2 0.5 1.5
Myalgia 9.3 15.2 0 1.0
Platelet count decreased 11.3 14.1 0 0
Blood bilirubin increased 11.3 13.1 0 0
Dysgeusia 9.3 12.6 0 0
Paresthesia 5.2 12.1 0 0.5
Vision blurred 10.8 11.1 1.0 0.5
Alopecia 11.3 10.6 0 0
Decreased appetite 9.8 10.1 0 0
Constipation 8.8 9.6 0 0
Pyrexia 6.2 9.6 0 0
Depression 3.1 8.1 0 0
Abdominal pain 2.6 7.6 0 0
Conjunctivitis 5.2 7.6 0 0
Photosensitivity reaction 3.6 7.1 0 0
Dizziness 4.6 6.6 0.5 0
Hemorrhage 3.1 6.6 0 0
Dry skin 6.7 6.1 0.5 0
Nasopharyngitis 1.0 6.1 0 0.5
Palpitations 5.2 5.1 0 0
1All adverse reactions occurring in ≥ 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.

Additional Data From Multiple Clinical Trials

The following adverse reactions have been reported during clinical trials of Gleevec.

Cardiac Disorders

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

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

Vascular Disorders

Estimated 1%-10%: flushing, hemorrhage

Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, subdural hematoma

Clinical Laboratory Tests

Estimated 0.1%-1%: blood CPK increased, blood LDH increased

Estimated 0.01%-0.1%: blood amylase increased

Dermatologic

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

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

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, erythema multiforme, leucocytoclastic vasculitis

Digestive

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

Hematologic

Estimated 1%-10%: pancytopenia, febrile neutropenia

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

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

Hepatobiliary

Estimated 0.1%-1%: hepatitis, jaundice

Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1

Hypersensitivity

Estimated 0.01%-0.1%: angioedema

Infections

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

Estimated 0.01%-0.1%: fungal infection

Metabolic and Nutritional

Estimated 1%-10%: weight decreased

Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia

Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia

Musculoskeletal

Estimated 1%-10%: joint swelling

Estimated 0.1%-1%: joint and muscle stiffness

Estimated 0.01%-0.1%: muscular weakness, arthritis

Nervous System/Psychiatric

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 pressure1, confusional state, convulsions, optic neuritis

Renal

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

Reproductive

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

Respiratory

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

Special Senses

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

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

Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract

1Including some fatalities

Postmarketing Experience

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.

Nervous system disorders: cerebral edema1

Eye disorders: vitreous hemorrhage

Cardiac disorders: pericarditis, cardiac tamponade1

Vascular disorders: thrombosis/embolism, anaphylactic shock

Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease

Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see WARNINGS AND PRECAUTIONS], diverticulitis

Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children

Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

1Including some fatalities

Read the Gleevec (imatinib mesylate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Agents Inducing CYP3A Metabolism

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.

Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED's decreased by 73% compared to patients not receiving EIAED.

Concomitant administration of Gleevec and St. John's Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers [see DOSAGE AND ADMINISTRATION].

Agents Inhibiting CYP3A Metabolism

There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.

Interactions With Drugs Metabolized By CYP3A4

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., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).

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 instead of warfarin.

Interactions With Drugs Metabolized by CYP2D6

Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

Interaction With Acetaminophen

In vitro, Gleevec inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 μM). Co-administration of Gleevec (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Gleevec pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Gleevec at doses > 400 mg/day or the chronic use of concomitant acetaminophen and Gleevec.

Read the Gleevec Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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