February 22, 2017
Recommended Topic Related To:

Gleevec

"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy.

CLL is a rare blood and bone marrow disease"...

A A A

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.

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

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]. 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)

  All Grades CTC Grades 3/4
Preferred Term 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
(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 Analysisa

  Patients with Newly Diagnosed Ph+ CML-CP
Gleevec 400 mg once daily
N=280
nilotinib 300 mg twice daily
N=279
Gleevec 400 mg once daily
N=280
nilotinib 300 mg twice daily
N=279
Body System and Preferred Term All Grades (%) CTC Gradesb 3/4 (%)
Skin and subcutaneous tissue disorders Rash 19 38 2 <1
  Pruritus 7 21 0 <1
  Alopecia 7 13 0 0
  Dry skin 6 12 0 0
Gastrointestinal disorders Nausea 41 22 2 2
  Constipation 8 20 0 <1
  Diarrhea 46 19 4 1
  Vomiting 27 15 <1 <1
  Abdominal pain upper 14 18 <1 1
  Dyspepsia 12 10 0 0
Nervous system disorders Headache 23 32 <1 3
  Dizziness 11 12 <1 <1
General disorders and administration site conditions Fatigue 20 23 1 1
  Pyrexia 13 14 0 <1
  Asthenia 12 14 0 <1
  Peripheral edema 20 9 0 <1
  Face edema 14 <1 <1 0
Musculoskeletal and connective tissue disorders Myalgia 19 19 <1 <1
  Arthralgia 17 22 <1 <1
  Muscle spasms 34 12 1 0
  Pain in extremity 16 15 <1 <1
  Back pain 17 19 1 1
Respiratory, thoracic and mediastinal disorders Cough 13 17 0 0
  Oropharyngeal pain 6 12 0 0
  Dyspnea 6 11 <1 2
Infections and infestations Nasopharyngitis 21 27 0 0
  Upper respiratory tract infection 14 17 0 <1
  Influenza 9 13 0 0
  Gastroenteritis 10 7 <1 0
Eye disorders Eyelid edema 19 1 <1 0
  Periorbital edema 15 <1 0 0
Psychiatric disorders Insomnia 9 11 0 0
Vascular disorder Hypertension 4 10 <1 1
aExcluding laboratory abnormalities
bNCI 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)

  Myeloid Blast Crisis Accelerated Phase Chronic Phase, IFN Failure
(n=260)
%
(n=235)
%
(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 greater than or equal to10% 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 in rare cases require permanent discontinuation of treatment.

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

  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 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)

  Gleevec 400 mg once-daily
N=280
(%)
nilotinib 300 mg twice-daily
N=279
(%)
Hematologic Parameters    
Thrombocytopenia 9 10
Neutropenia 22 12
Anemia 6 4
Biochemistry Parameters    
Elevated lipase 4 9
Hyperglycemia <1 7
Hypophosphatemia 10 8
Elevated bilirubin (total) <1 4
Elevated SGPT (ALT) 3 4
Hyperkalemia 1 2
Hyponatremia <1 1
Hypokalemia 2 <1
Elevated SGOT (AST) 1 1
Decreased albumin <1 0
Hypocalcemia <1 <1
Elevated alkaline phosphatase <1 0
Elevated creatinine <1 0
*NCI Common Terminology Criteria for Adverse Events, version 3.0

Table 7: Laboratory 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 Grades1 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 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 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 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 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%)

  Per Patient Incidence Ph+ALL With Gleevec Per Patient Incidence Ph- ALL No Gleevec Per Patient Per Cycle Incidence With Gleevec* Per Patient Per Cycle Incidence No Gleevec**
Adverse Event N=92
n (%)
N=65
n (%)
N=778
n (%)
N=647
n (%)
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/mcL) 92 (100) 63 (97) 556 (71) 218 (34)
Thrombocytopenia (<75,000/mcL) 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 (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 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.

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 3/4 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

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 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

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 11.

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

  N=12
CTC Grades1 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 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 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]. 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 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

  Imatinib 400 mg
N=818
Imatinib 800 mg
N=822
Reported or Specified Term 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 13.

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

  400 mg
(n=73)
%
600 mg
(n=74)
%
CTC Grades1 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 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 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, 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 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)

  All CTC Grades CTC Grade 3 and above
Preferred Term 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
(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 3/4 Grades (greater than or equal to 5% of Gleevec Treated Patients) Study 2(1)

  All CTC Grades CTC Grades 3 and above
Preferred Term Gleevec
12 Months
(N=194)
%
Gleevec
36 Months
(N=198)
%
Gleevec
12 Months
(N=194)
%
Gleevec
36 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
(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.

Additional Data From Multiple Clinical Trials

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

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 CPK increased, blood amylase increased

Estimated 0.1%–1%: blood 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, eosinophila

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 necrosis1

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 pressure1, 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

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

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.

Infections: hepatitis B virus reactivation1

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, gastric antral vascular ectasia

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

Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see CLINICAL PHARMACOLOGY].

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].

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].

Interactions With Drugs Metabolized By CYP2D6

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

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/24/2016

Side Effects
Interactions

Gleevec - User Reviews

Gleevec User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Gleevec sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.