Gleevec

Last updated on RxList: 7/20/2020
Gleevec Side Effects Center

What Is Gleevec?

Gleevec (imatinib mesylate) is a kinase inhibitor that inhibits a protein signal that causes cancer cell proliferation used to treat patients with hematological malignancies or malignant sarcomas such as Philadelphia positive chronic myeloid leukemia, chronic myeloid leukemia in blast crisis, acute lymphoblastic leukemia, aggressive systemic mastocytosis, gastrointestinal stromal tumors, and other diseases. Gleevec is available in generic form.

What Are Side Effects of Gleevec?

Common side effects of Gleevec include:

Tell your doctor if you have serious side effects of Gleevec including:

  • severe blistering skin rashes,
  • yellowing skin and eyes (jaundice),
  • gastrointestinal bleeding,
  • weakness with shortness of breath,
  • severe headaches,
  • swelling,
  • severe flu-like symptoms
  • easy bruising or bleeding,
  • fast or pounding heartbeat,
  • extreme tiredness,
  • sudden or unexplained weight gain,
  • swelling (especially of lower legs/the area around eyes),
  • black or bloody stools,
  • dark urine, or
  • vomit that looks like coffee grounds.

Dosage for Gleevec

Gleevec is supplied in 100 or 400 mg tablets. The dose is quite variable and depends on the disease being treated, age of patient (some doses based on mg per kilogram weight (mg/Kg). Doses usually range between 100 to 800 mg per day; high doses are divided into lower mg levels but are taken twice a day. Because the tablets have iron in the coating, high doses should use the 400 mg tablets to avoid getting too much iron. Gleevec should be taken with water and food. Gleevec should not be crushed or come in direct contact with skin as serious rashes may develop.

What Drugs, Substances, or Supplements Interact with Gleevec?

Gleevec may interact with bosentan, conivaptan, cyclosporine, dexamethasone, digoxin, fentanyl, isoniazid, nefazodone,pimozide, sirolimus, tacrolimus, St. John's wort, theophylline, antibiotics, antifungals, barbiturates, blood thinners, cholesterol-lowering medicines, ergot medicines, heart or blood pressure medicines, heart rhythm medications, HIV/AIDS medicines, medicines to treat narcolepsy, or seizure medications. Tell your doctor all medications and supplements you use.

Gleevec During Pregnancy and Breastfeeding

It is not safe to use this drug while pregnant; breastfeeding studies are unavailable. Use in children under the age of 18 is infrequent; consultation with a specialist (such as a pediatric oncologist) is recommended. Many medical conditions and drugs affect the levels of Gleevec in patients, so patients are urged to be sure the treating doctor has a complete medical history and medication list before the drug is prescribed.

Additional Information

Our Gleevec Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Gleevec Consumer Information

Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning in your eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).

Call your doctor at once if you have:

  • fluid retention--shortness of breath (even while lying down), swelling, rapid weight gain;
  • kidney problems--little or no urination, swelling in your feet or ankles;
  • fluid build-up in the lungs--pain when you breathe, wheezing, gasping for breath, cough with foamy mucus;
  • liver problems--upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes);
  • low blood cell counts--fever, cold or flu symptoms, easy bruising, unusual bleeding, mouth sores, pale skin, unusual tiredness, feeling light-headed, cold hands and feet;
  • signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
  • signs of tumor cell breakdown--confusion, weakness, muscle cramps, nausea, vomiting, fast or slow heart rate, decreased urination, tingling in your hands and feet or around your mouth; or
  • thyroid symptoms--tiredness, dry skin, hair loss, constipation, depression, slow heart rate, weight gain, feeling more sensitive to cold temperatures.

Imatinib can affect growth in children and teenagers. Tell your doctor if your child is not growing at a normal rate while using this medicine.

Common side effects may include:

  • fluid retention;
  • nausea, vomiting, stomach pain, diarrhea;
  • joint or muscle pain;
  • skin rash; or
  • feeling tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Gleevec (Imatinib Mesylate)

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Gleevec Professional Information

SIDE EFFECTS

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

  • Fluid Retention and Edema [see WARNINGS AND PRECAUTIONS]
  • Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
  • Congestive Heart Failure and Left Ventricular Dysfunction [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Hemorrhage [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS]
  • Hypereosinophilic Cardiac Toxicity [see WARNINGS AND PRECAUTIONS]
  • Dermatologic Toxicities [see WARNINGS AND PRECAUTIONS]
  • Hypothyroidism [see WARNINGS AND PRECAUTIONS]
  • Growth Retardation in Children and Adolescents [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Impairments Related to Driving and Using Machinery [see WARNINGS AND PRECAUTIONS]
  • Renal Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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

Chronic Myeloid Leukemia

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

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

Preferred TermAll GradesCTC Grades 3/4
Gleevec
N = 551 (%)
IFN + Ara−C
N = 533 (%)
Gleevec
N = 551 (%)
IFN + Ara−C
N = 533 (%)
Fluid Retention61.711.12.50.9
  Superficial Edema59.99.61.50.4
Other Fluid Retention Reactions26.91.91.30.6
Nausea49.561.51.35.1
Muscle Cramps49.211.82.20.2
Musculoskeletal Pain47.044.85.48.6
Diarrhea45.443.33.33.2
Rash and Related Terms40.126.12.92.4
Fatigue38.867.01.825.1
Headache37.043.30.53.8
Joint Pain31.438.12.57.7
Abdominal Pain36.525.94.23.9
Nasopharyngitis30.58.800.4
Hemorrhage28.921.21.81.7
  GI Hemorrhage1.61.10.50.2
  CNS Hemorrhage0.20.400.4
Myalgia24.138.81.58.3
Vomiting22.527.82.03.4
Dyspepsia18.98.300.8
Cough20.023.10.20.6
Pharyngolaryngeal Pain18.111.40.20
Upper Respiratory Tract Infection21.28.40.20.4
Dizziness19.424.40.93.8
Pyrexia17.842.60.93.0
Weight Increased15.62.62.00.4
Insomnia14.718.602.3
Depression14.935.80.513.1
Influenza13.86.20.20.2
Bone Pain11.315.61.63.4
Constipation11.414.40.70.2
Sinusitis11.46.00.20.2
(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

Body System and Preferred TermPatients 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
All Grades (%)CTC Gradesb 3/4 (%)
Skin and subcutaneous tissue disordersRash19382<1
Pruritus7210<1
Alopecia71300
Dry skin61200
Gastrointestinal disordersNausea412222
Constipation8200<1
Diarrhea461941
Vomiting2715<1<1
Abdominal pain upper1418<11
Abdominal pain121502
Dyspepsia121000
Nervous system disordersHeadache2332<13
Dizziness1112<1<1
General disorders and administration site conditions FatigueFatigue202311
Pyrexia13140<1
Asthenia12140<1
Peripheral edema2090<1
Face edema14<1<10
Musculoskeletal and connective tissue disordersMyalgia1919<1<1
Arthralgia1722<1<1
Muscle spasms341210
Pain in extremity1615<1<1
Back pain171911
Respiratory, thoracic and mediastinal disordersCough131700
Oropharyngeal pain61200
Dyspnea611<12
Infections and infestationsNasopharyngitis212700
Upper respiratory tract infection14170<1
Influenza91300
Gastroenteritis107<10
Eye disordersEyelid edema191<10
Periorbital edema15<100
Psychiatric disordersInsomnia91100
Vascular disorderHypertension410<11
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)

Preferred TermMyeloid Blast Crisis
(n = 260)
%
Accelerated Phase
(n = 235)
%
Chronic Phase, IFN Failure
(n = 532)
%
All GradesGrade 3/4All GradesGrade 3/4All GradesGrade 3/4
Fluid Retention7211766694
  Superficial Edema666743672
  Other Fluid Retention Reactions(2)22615472
Nausea715735633
Muscle Cramps281470.4622
Vomiting544583362
Diarrhea434575483
Hemorrhage53194911302
  CNS Hemorrhage973321
  GI Hemorrhage846520.4
Musculoskeletal Pain429499382
Fatigue304464481
Skin Rash365475473
Pyrexia417418212
Arthralgia255346401
Headache275322360.6
Abdominal Pain306334321
Weight Increased51175327
Cough140.8270.9200
Dyspepsia120220270
Myalgia90242270.2
Nasopharyngitis100170220.2
Asthenia185215150.2
Dyspnea154217120.9
Upper Respiratory Tract Infection30120.4190
Anorexia14217270
Night Sweats130.8171140.2
Constipation162160.990.4
Dizziness120.4130160.2
Pharyngitis100120150
Insomnia100140140.2
Pruritus81140.9140.8
Hypokalemia1349260.8
Pneumonia13710741
Anxiety88.012080.4
Liver Toxicity10512663
Rigors100120.4100
Chest Pain72100.4110.8
Influenza0.80.460110.2
Sinusitis40.4110.490.4
(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 may require permanent discontinuation of treatment.

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

CTC GradesGleevec
N = 551 %
IFN+Ara−C
N = 533 %
Grade 3Grade 4Grade 3Grade 4
Hematology Parameters*
  Neutropenia*13.13.620.84.5
  Thrombocytopenia*8.50.415.90.6
  Anemia3.31.14.10.2
Biochemistry Parameters
  Elevated Creatinine000.40
  Elevated Bilirubin0.90.20.20
  Elevated Alkaline Phosphatase0.200.80
  Elevated SGOT/SGPT4.70.57.10.4
*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
Thrombocytopenia910
Neutropenia2212
Anemia64
Biochemistry Parameters
Elevated lipase49
Hyperglycemia<17
Hypophosphatemia108
Elevated bilirubin (total)<14
Elevated SGPT (ALT)34
Hyperkalemia12
Hyponatremia<11
Hypokalemia2<1
Elevated SGOT (AST)11
Decreased albumin<10
Hypocalcemia<1<1
Elevated alkaline phosphatase<10
Elevated creatinine<10
*NCI Common Terminology Criteria for Adverse Events, version 3.0.

Table 7: Laboratory Abnormalities in Other CML Clinical Trials

CTC Grades1Myeloid 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 3Grade 4Grade 3Grade 4Grade 3Grade 4
Hematology Parameters
  Neutropenia16482336279
  Thrombocytopenia3033311321<1
  Anemia421134761
Biochemistry Parameters
  Elevated Creatinine1.501.300.20
  Elevated Bilirubin3.802.100.60
  Elevated Alkaline Phosphatase4.605.50.40.20
  Elevated SGOT (AST)1.903.002.30
  Elevated SGPT (ALT)2.30.44.302.10
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%)

Adverse Event Grade 3 and 4 Adverse EventsPer Patient Incidence Ph+ALL With Gleevec
N = 92
n (%)
Per Patient Incidence Ph- ALL No Gleevec
N = 65
n (%)
Per Patient Per Cycle Incidence With Gleevec*
N = 778 n (%)
Per Patient Per Cycle Incidence
No Gleevec**
N = 647
n (%)
Nausea and/or Vomiting15 (16)6 (9)28 (4)8 (1)
Hypokalemia31 (34)16 (25)72 (9)32(5)
Pneumonitis7 (8)1 (1)7(1)1(<1)
Pleural effusion6 (7)06 (1)0
Abdominal Pain8 (9)2 (3)9 (1)3(<1)
Anorexia10 (11)3 (5)19 (2)4 (1)
Hemorrhage11 (12)4 (6)17 (2)8 (1)
Hypoxia8 (9)2 (3)12 (2)2 (<1)
Myalgia5 (5)04 (1)1 (<1)
Stomatitis15 (16)8 (12)22 (3)14 (2)
Diarrhea8 (9)3 (5)12 (2)3 (<1)
Rash / Skin Disorder4 (4)05 (1)0
Infection49 (53)32 (49)131 (17)92 (14)
Hepatic (transaminase and/or bilirubin)52 (57)38 (58)172 (22)113 (17)
Hypotension10 (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 TermN = 7
n (%)
Nausea4 (57.1)
Diarrhea3 (42.9)
Anemia2 (28.6)
Fatigue2 (28.6)
Muscle Cramp3 (42.9)
Arthralgia2 (28.6)
Periorbital Edema2 (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 termN = 12
n (%)
Nausea5 (41.7)
Diarrhea3 (25.0)
Vomiting3 (25.0)
Periorbital Edema4 (33.3)
Face Edema2 (16.7)
Rash3 (25.0)
Fatigue5 (41.7)
Edema Peripheral4 (33.3)
Pyrexia2 (16.7)
Eye Edema4 (33.3)
Lacrimation Increased3 (25.0)
Dyspnea Exertional2 (16.7)
Anemia3 (25.0)
Rhinitis2 (16.7)
Anorexia2 (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

CTC Grades1N = 12
Grade 3
%
Grade 4
%
Hematology Parameters
  Anemia170
  Thrombocytopenia170
  Neutropenia08
Biochemistry Parameters
  Elevated Creatinine08
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

Reported or Specified TermImatinib 400 mg
N = 818
Imatinib 800 mg
N = 822
All Grades
%
Grades 3/4/5
%
All Grades
%
Grades 3/4/5
%
Edema76.79.086.113.1
Fatigue/lethargy, malaise, asthenia69.311.774.912.2
Nausea58.19.064.57.8
Abdominal pain/cramping57.213.855.211.8
Diarrhea56.28.158.28.6
Rash/desquamation38.17.649.88.9
Vomiting37.49.240.67.5
Myalgia32.25.630.23.8
Anemia32.04.934.86.4
Anorexia31.16.635.84.7
Other GI toxicity25.28.128.16.6
Headache22.05.719.73.6
Other pain (excluding tumor related pain)20.45.920.85.0
Other dermatology/skin toxicity17.65.920.15.7
Leukopenia17.00.719.61.6
Other constitutional symptoms16.76.415.24.4
Cough16.14.514.53.2
Infection (without neutropenia)15.56.616.55.6
Pruritus15.45.418.94.3
Other neurological toxicity15.06.415.24.9
Constipation14.85.114.44.1
Other renal/genitourinary toxicity14.26.513.65.2
Arthralgia (joint pain)13.64.812.33.0
Dyspnea (shortness of breath)13.66.814.25.6
Fever in absence of neutropenia (ANC< 1.0 x
109/L)
13.24.912.93.4
Sweating12.74.68.52.8
Other hemorrhage12.36.713.36.1
Weight gain12.01.010.60.6
Alopecia11.94.314.83.2
Dyspepsia/heartburn11.50.610.90.5
Neutropenia/ granulocytopenia11.53.116.14.1
Rigors/chills11.04.610.23.0
Dizziness/lightheadedness11.04.810.02.8
Creatinine increase10.80.410.10.6
Flatulence10.00.210.10.1
Stomatitis/pharyngitis (oral/pharyngeal mucositis)9.25.410.04.3
Lymphopenia6.00.710.11.9

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

CTC Grades1400 mg
(n = 73)
%
600 mg
(n = 74)
%
Grade 3Grade 4Grade 3Grade 4
Hematology Parameters
  Anemia3081
  Thrombocytopenia0010
  Neutropenia7383
Biochemistry Parameters
  Elevated Creatinine0030
  Reduced Albumin3040
  Elevated Bilirubin1013
  Elevated Alkaline Phosphatase0030
  Elevated SGOT (AST)4033
  Elevated SGPT (ALT)6071
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)

Preferred TermAll CTC GradesCTC Grade 3 and Above
Gleevec
(N = 337)
%
Placebo
(N = 345)
%
Gleevec
(N = 337)
%
Placebo
(N = 345)
%
Diarrhea59.329.33.01.4
Fatigue57.040.92.11.2
Nausea53.127.82.41.2
Periorbital Edema47.214.51.20
Hemoglobin Decreased46.927.00.60
Peripheral Edema26.714.80.30
Rash (Exfoliative)26.112.82.70
Vomiting25.513.92.40.6
Abdominal Pain21.122.33.01.4
Headache19.320.30.60
Dyspepsia17.213.00.90
Anorexia16.98.70.30
Weight Increased16.911.60.30
Liver enzymes (ALT) Increased16.613.02.70
Muscle spasms16.33.300
Neutrophil Count Decreased16.06.13.30.9
Arthralgia15.114.500.3
White Blood Cell Count Decreased14.54.30.60.3
Constipation12.817.700.3
Dizziness12.510.700.3
Liver Enzymes (AST) Increased12.27.52.10
Myalgia12.211.600.3
Blood Creatinine Increased11.65.800.3
Cough11.011.300
Pruritus11.07.80.90
Weight Decreased10.15.200
Hyperglycemia9.811.30.61.7
Insomnia9.87.20.90
Lacrimation Increased9.83.800
Alopecia9.56.700
Flatulence8.99.600
Rash8.95.20.90
Abdominal Distension7.46.40.30.3
Back Pain7.48.10.60
Pain in Extremity7.47.20.30
Hypokalemia7.12.00.90.6
Depression6.86.40.90.6
Facial Edema6.81.20.30
Blood Alkaline Phosphatase Increased6.57.500
Dry skin6.55.200
Dysgeusia6.52.900
Abdominal Pain Upper6.26.40.30
Neuropathy Peripheral5.96.400
Hypocalcemia5.61.70.30
Leukopenia5.02.60.30
Platelet Count Decreased5.03.500
Stomatitis5.01.70.60
Upper Respiratory Tract Infection5.03.500
Vision Blurred5.02.300
(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)

Preferred TermAll CTC GradesCTC Grades 3 and Above
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 AE99.0100.020.132.8
Hemoglobin decreased72.280.30.50.5
Periorbital edema59.374.20.51.0
Blood lactate dehydrogenase increased43.360.100
Diarrhea43.854.00.52.0
Nausea44.851.01.50.5
Muscle spasms30.949.00.51.0
Fatigue48.548.51.00.5
White blood cell count decreased34.547.02.13.0
Pain25.845.51.03.0
Blood creatinine increased30.444.400
Edema peripheral33.040.90.51.0
Dermatitis29.438.92.11.5
Aspartate aminotransferase increased30.937.91.53.0
Alanine aminotransferase increased28.934.32.13.0
Neutrophil count decreased24.233.34.65.1
Hypoproteinemia23.731.800
Infection13.927.81.52.5
Weight increased13.426.800.5
Pruritus12.925.800
Flatulence19.124.71.00.5
Vomiting10.822.20.51.0
Dyspepsia17.521.70.51.0
Hypoalbuminemia11.921.200
Edema10.819.700.5
Abdominal distension11.919.20.50
Headache8.218.200
Lacrimation increased18.017.700
Arthralgia8.817.201.0
Blood alkaline phosphatase increased10.816.700.5
Dyspnea6.216.20.51.5
Myalgia9.315.201.0
Platelet count decreased11.314.100
Blood bilirubin increased11.313.100
Dysgeusia9.312.600
Paresthesia5.212.100.5
Vision blurred10.811.11.00.5
Alopecia11.310.600
Decreased appetite9.810.100
Constipation8.89.600
Pyrexia6.29.600
Depression3.18.100
Abdominal pain2.67.600
Conjunctivitis5.27.600
Photosensitivity reaction3.67.100
Dizziness4.66.60.50
Hemorrhage3.16.600
Dry skin6.76.10.50
Nasopharyngitis1.06.100.5
Palpitations5.25.100
(1)All adverse reactions occurring in greater than or equal to5% of patients are listed regardless of suspected relationship to treatment.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

Adverse Reactions From Multiple Clinical Trials

Cardiac Disorders

Estimated 1% - 10%: palpitations, pericardial effusion

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

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

Vascular Disorders

Estimated 1% - 10%: flushing, hemorrhage

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

Investigations

Estimated 1% - 10%: blood 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, eosinophilia

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

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

Hepatobiliary Disorders

Estimated 0.1% - 1%: hepatitis, jaundice

Estimated 0.01% - 0.1%: hepatic failure and hepatic 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 pressure , 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), pseudoporphyria

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

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Blood and Lymphatic System Disorders: thrombotic microangiopathy

1Including some fatalities.

Read the entire FDA prescribing information for Gleevec (Imatinib Mesylate)

© Gleevec Patient Information is supplied by Cerner Multum, Inc. and Gleevec Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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