Gleevec (Imatinib Mesylate) - Side Effects and Adverse Reactions

6 ADVERSE REACTIONS

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.

6.1 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 (2.10) ]. 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 Reported in Newly Diagnosed CML Clinical Trial (≥10% of Gleevec Treated Patients)⁽¹⁾

	All Grades		CTC Grades 3/4
	Gleevec	IFN+Ara−C	Gleevec	IFN+Ara−C
Preferred Term	N=551 (%)	N=533 (%)	N=551 (%)	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
(1)All adverse reactions occurring in ≥10% 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 Adverse Reactions Reported in Other CML Clinical Trials (≥10% of All Patients in any Trial)⁽¹⁾

	Myeloid Blast Crisis (n= 260)		Accelerated Phase (n=235)		Chronic Phase, IFN Failure (n=532)
	%		%		%
Preferred Term	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 Reactions (2)	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
(1) All 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.

6.2 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

	Gleevec N=551		IFN+Ara−C N=533
	%		%
CTC Grades	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

	Myeloid Blast Crisis (n=260)		Accelerated Phase (n=235)		Chronic Phase, IFN Failure (n=532)
	600 mg n=223 400 mg n=37		600 mg n=158 400 mg n=77		400 mg
	%		%		%
CTC Grades 1	Grade 3	Grade 4	Grade 3	Grade 4	Grade 3	Grade 4
Hematology Parameters
− Neutropenia	16	48	23	36	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)

6.3 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.

6.4 Adverse Reactions in Pediatric Population

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.

6.5 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 1/2 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.

6.6 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.

6.7 Myelody s plastic/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 6. 

Table 6 Adverse Reactions 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)

6.8 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.

6.9 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.

6.10 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 7. 

Table 7 Adverse Reactions 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 8.

Table 8 Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study

	N=12
CTC Grades 1	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),

6.11 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 (2.10) ]. 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 9.

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

Reported or Specified Term	Imatinib 400 mg N=818		Imatinib 800 mg N=822
	All Grades %	Grades 3/4/5 %	All Grades %	Grades 3/4/5 %
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 10.

Table 10 Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial

	400 mg (n=73)		600 mg (n=74)
	%		%
CTC Grades 1	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

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.

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 11.

Table 11: Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)⁽¹⁾

	All CTC Grades		CTC Grade 3 and above
	Gleevec (n=337)	Placebo (n=345)	Gleevec (n=337)	Placebo (n=345)
Preferred Term	%	%	%	%
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
( 1 )All 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.

6.12 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,

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

6.13 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 (5.6) ],   diverticulitis

Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis

rhabdomyolysis/myopathy

Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

¹Including some fatalities

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.

REPORTS OF SUSPECTED GLEEVEC SIDE EFFECTS / ADVERSE REACTIONS

Possible Gleevec side effects / adverse reactions in 46 year old male

Reported by a consumer/non-health professional from Germany on 2011-10-03

Patient: 46 year old male

Reactions: Chondropathy, Osteonecrosis, Osteoporosis

Suspect drug(s):
Gleevec

Other drugs received by patient: Ibuprofen; Exjade; Acetylsalicylic Acid SRT; Allopurinol

Possible Gleevec side effects / adverse reactions in 31 year old male

Reported by a health professional (non-physician/pharmacist) from China on 2011-10-03

Patient: 31 year old male

Reactions: Dyspnoea, Chronic Myeloid Leukaemia Transformation, Blast Crisis in Myelogenous Leukaemia, Hypoaesthesia, Gene Mutation Identification Test Positive, Cerebral Haemorrhage, Loss of Consciousness, Dizziness, Platelet Count Decreased, Vision Blurred, Bone Marrow Failure, Hemiplegia, Metastases TO Central Nervous System, Acute Myelomonocytic Leukaemia

Adverse event resulted in: death, hospitalization

Suspect drug(s):
Gleevec

Other drugs received by patient: Mitoxantrone; Vincristine; Cytarabine; Dexamethasone

Possible Gleevec side effects / adverse reactions in 68 year old male

Reported by a physician from Germany on 2011-10-03

Patient: 68 year old male

Reactions: Back Pain, Iron Deficiency, Epilepsy

Suspect drug(s):
Gleevec

Other drugs received by patient: Morphine