Side Effects of Gleevec (imatinib)

Gleevec (imatinib) is a kinase inhibitor used to treat chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). 

Kinase inhibitors prevent tumors from growing by reducing the action of proteins that control cell division, growth and survival. These proteins are usually present in larger quantities or are more active in cancer cells. By reducing the activity of these proteins, growth and survival of cancer cells are reduced. 

Common side effects of Gleevec include

• fluid retention,
• headache,
• diarrhea,
• loss of appetite,
• weakness,
• nausea and vomiting,
• abdominal distention,
• swelling of arms and legs,
• rash,
• itching,
• fever,
• dizziness, and
• muscle pain.

Serious side effects of Gleevec include fever associated with reduced white blood cells, reduced platelets, reduced red blood cell counts, infection, stomach or intestinal bleeding, bleeding in the brain, heart failure, reduced liver function, and fluid in the lungs.

Drug interactions of Gleevec include ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, and grapefruit juice because these drugs reduce the breakdown of Gleevec by the liver, increasing the blood concentration of Gleevec, which may increase the occurrence of adverse effects. 

Carbamazepine, phenobarbital, rifampin, phenytoin, fosphenytoin, primidone, and St John's wort decrease the blood concentration of Gleevec resulting in decreased blood levels and possibly reduced effect. 

Gleevec increases the blood concentration of simvastatin by reducing the activity of enzymes that break down simvastatin in the liver. This may increase the side effects of simvastatin. 

Gleevec may interact with other drugs that are broken down in a similar way as simvastatin. 

Gleevec is harmful to a fetus and should not be used during pregnancy. Gleevec is excreted in breast milk. Nursing mothers should either discontinue Gleevec or stop breastfeeding.

Common side effects include:

• fluid retention,
• headache,
• diarrhea,
• loss of appetite,
• weakness,
• nausea and vomiting,
• abdominal distention,
• swelling of arms and legs,
• rash,
• itching,
• fever,
• dizziness, and
• muscle pain.

Serious side effects include:

• fever associated with reduced white blood cells,
• reduced platelets
• reduced red blood cell counts,
• infection,
• stomach or intestinal bleeding,
• bleeding in the brain,
• heart failure,
• reduced liver function, and
• fluid in the lungs.

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

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

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. 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⁾

Table 3: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP in the Gleevec Versus nilotinib Study (greater than or equal to 10% in Gleevec 400 mg once-daily or nilotinib 300 mg twice-daily groups) 60-Month Analysis^a

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⁾

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)

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

Table 7: Laboratory Abnormalities in Other CML Clinical Trials

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 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

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

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

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. 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

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

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⁾

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⁾

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 vasculitiss

Gastrointestinal DisordersGastrointestinal 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, 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.

Agents Inducing CYP3A Metabolism

• Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

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.

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 .

Interactions With Drugs Metabolized By CYP2D6

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