Imatinib Mesylate (Page 3 of 10)

5.4 Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with imatinib [see Adverse Reactions (6.1)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with imatinib interruption and/or dose reduction [see Dosage and Administration (2.13)]. When imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage

In a trial of imatinib versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral(3 patients) or both(1 patient).Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

5.6 Gastrointestinal Disorders

Imatinib is sometimes associated with GI irritation. Imatinib should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.

5.7 Hypereosinophilic Cardiac Toxicity

In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1 mg/kg to 2 mg/kg) for one to two weeks concomitantly with imatinib at the initiation of therapy.

5.8 Dermatologic Toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib therapy after resolution or improvement of the bullous reaction. In these instances, imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

5.9 Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib. Monitor TSH levels in such patients.

5.10 Embryo-Fetal Toxicity

Imatinib can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib and for 14 days after stopping imatinib. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.11 Growth Retardation in Children and Adolescents

Growth retardation has been reported in children and pre-adolescents receiving imatinib. The long term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, monitor growth in children under imatinib treatment [see Adverse Reactions (6.1)].

5.12 Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML,GIST, ALL and eosinophilic leukemia receiving imatinib. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib.

5.13 Impairments Related to Driving and Using Machinery

Motor vehicle accidents have been reported in patients receiving imatinib. Advise patients that they may experience side effects such as dizziness, blurred vision or somnolence during treatment with imatinib. Recommend caution when driving a car or operating machinery.

5.14 Renal Toxicity

A decline in renal function may occur in patients receiving imatinib. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 ml/min/1.73m2 (N=1190) to 75 ml/min/1.73m2 at 12 months (N=1082) and 69 ml/min/1.73m2 at 60 months (N=549). Evaluate renal function prior to initiating imatinib and monitor during therapy, with attention to risk factors for renal dysfunction such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

6 ADVERSE REACTIONS

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

  • Fluid Retention and Edema [see Warnings and Precautions (5.1)]
  • Hematologic Toxicity [see Warnings and Precautions (5.2)]
  • Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]
  • Hepatotoxicity [see Warnings and Precautions (5.4)]
  • Hemorrhage [see Warnings and Precautions (5.5)]
  • Gastrointestinal Disorders [ see Warnings and Precautions (5.6)]
  • Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7)]
  • Dermatologic Toxicities [see Warnings and Precautions (5.8)]
  • Hypothyroidism [see Warnings and Precautions (5.9)]
  • Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11)]
  • Tumor Lysis Syndrome [see Warnings and Precautions (5.12)]
  • Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13)]
  • Renal Toxicity [see Warnings and Precautions (5.14)]

6.1 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 imatinib-treated patients experienced adverse reactions at some time. imatinib was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib versus IFN+Ara-C, and in 12.5% of patients receiving imatinib in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib and nilotinib. Imatinib 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 imatinib [see Dosage and Administration (2.13)]. The frequency of severe superficial edema was 1.5% to 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 imatinib 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 imatinib 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 Imatinib versus IFN+Ara-C Study (greater than or equal to 10% of Imatinib-treated patients)(1)

Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha.

* NCI Common Terminology Criteria for Adverse Events, version 3

(1) All adverse reactions occurring in greater than or equal to 10% of imatinib 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.

All Grades CTC Grades 3/4
Imatinib IFN+Ara-C Imatinib IFN+Ara-C
Preferred Term N=551 (%) N=533 (%) N=551 (%) N=533 (%)
Fluid Retention 61.7 11.1 2.5 0.9
— Superficial Edema 59.9 9.6 1.5 0.4
— Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6
Nausea 49.5 61.5 1.3 5.1
Muscle Cramps 49.2 11.8 2.2 0.2
Musculoskeletal Pain 47 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 1.8 25.1
Headache 37 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 3.4
Dyspepsia 18.9 8.3 0 0.8
Cough 20 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
Weight Increased 15.6 2.6 2 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 0.2 0.2
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 Imatinib versus nilotinib Study (greater than or equal to 10% in Imatinib 400 mg once daily or nilotinib 300 mg twice daily groups) 60-Month Analysisa

Abbreviation: Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase.

a Excluding laboratory abnormalities

b NCI Common Terminology Criteria for Adverse Events, version 3

Patients With Newly Diagnosed Ph+ CML-CP
Imatinib 400 mg once daily nilotinib 300 mg twice daily Imatinib 400 mg once daily nilotinib 300 mg twice daily
N=280 N=279 N=280 N=279
Body System and Preferred Term All Grades (%) CTC Grades b 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
Abdominal pain 12 15 0 2
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
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)

Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha.

(1) All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment.

(2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

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

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-fold 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 weeks to 3 weeks, and from 2 weeks to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but may require permanent discontinuation of treatment.

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

Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).

*p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups).

Imatinib 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 (AST)/SGPT (ALT) 4.7 0.5 7.1 0.4
Table 6 Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib versus nilotinib)

Abbreviations: CML, chronic myeloid leukemia; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).

*NCI Common Terminology Criteria for Adverse Events, version 3

Imatinib nilotinib
400 mg 300 mg
once daily twice daily
N=280 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
Table 7 Laboratory Abnormalities in Other CML Clinical Trials

Abbreviations: CML, chronic myeloid leukemia; CTC, common terminology criteria; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).

1 CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 to 1 x 109 /L, Grade 4 less than 0.5 x 109 /L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 109 /L, Grade 4 less than 10 x 109 /L), anemia (hemoglobin greater than or equal to 65 to 80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3 to 6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3 to 10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5 to 20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5 to 20 x ULN, Grade 4 greater than 20 x ULN)

Myeloid Blast Crisis (n=260) Accelerated Phase (n=235) Chronic Phase, IFN Failure (n=532)
600 mg n=223 400 mg n=37 600 mg n=158 400 mg n=77 400 mg
% % %
CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters
− Neutropenia 16 48 23 36 27 9
− Thrombocytopenia 30 33 31 13 21 <1
− Anemia 42 11 34 7 6 1
Biochemistry Parameters
− Elevated creatinine 1.5 0 1.3 0 0.2 0
− Elevated bilirubin 3.8 0 2.1 0 0.6 0
− Elevated alkaline phosphatase 4.6 0 5.5 0.4 0.2 0
− Elevated SGOT (AST) 1.9 0 3 0 2.3 0
− Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0

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% 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 imatinib 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 imatinib and treated in 5 successive cohorts. Imatinib exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of imatinib 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 imatinib. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1,425 cycles of therapy, 778 with imatinib and 647 without imatinib. 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 imatinib 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%)

Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia.

* Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib (includes patients with Ph+ ALL that received cycles with imatinib)

** Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib (includes patients with Ph+ ALL that received cycles without imatinib as well as all patients with Ph- ALL who did not receive imatinib in any treatment cycle).

Adverse Event Grade 3 and 4 Adverse Events Per Patient Incidence Ph+ALL With Imatinib N=92 n (%) Per Patient Incidence Ph-ALL No Imatinib N=65 n (%) Per Patient Per Cycle Incidence With Imatinib* N=778 n (%) Per Patient Per Cycle Incidence No Imatinib ** N=647 n (%)
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)

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 imatinib.

Myelodysplastic/Myeloproliferative Diseases

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib for MDS/MPD in the Phase 2 study, are shown in Table 9.

Table 9Adverse 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

Abbreviation: MPD, Myeloproliferative Disease.

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 aggressive systemic mastocytosis (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 imatinib 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 imatinib observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, 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 imatinib 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

Abbreviation: DFSP, dermatofibrosarcoma protuberans.

Preferred Term N=12
n (%)
Nausea 5 (41.7)
Diarrhea 3 (25)
Vomiting 3 (25)
Periorbital edema 4 (33.3)
Face edema 2 (16.7)
Rash 3 (25)
Fatigue 5 (41.7)
Peripheral edema 4 (33.3)
Pyrexia 2 (16.7)
Eye edema 4 (33.3)
Lacrimation increased 3 (25)
Dyspnea exertional 2 (16.7)
Anemia 3 (25)
Rhinitis 2 (16.7)
Anorexia 2 (16.7)

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib 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

Abbreviation: CTC, common terminology criteria.

1 CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 to 1 x 109 /L, Grade 4 less than 0.5 x 109 /L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 109 /L, Grade 4 less than 10 x 109 /L), anemia (Grade 3 greater than or equal to 65 g/L to 80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3 to 6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN)

N=12
CTC Grades 1 Grade 3 % Grade 4 %
Hematology Parameters
— Anemia 17 0
— Thrombocytopenia 17 0
— Neutropenia 0 8
Biochemistry Parameters
— Elevated Creatinine 0 8

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

In the Phase 3 trials, the majority of imatinib 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 imatinib mesylate tablets [see Dosage and Administration (2.13)]. 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 imatinib 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 Term Imatinib 400 mg N = 818 Imatinib 800 mg N = 822
All Grades % Grades 3/4/5 % All Grades % Grades 3/4/5 %
Edema 76.7 9 86.1 13.1
Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2
Nausea 58.1 9 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 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 5.7 19.7 3.6
Other pain (excluding tumor related pain) 20.4 5.9 20.8 5
Other dermatology/skin toxicity 17.6 5.9 20.1 5.7
Leukopenia 17 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 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
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 1 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 4.6 10.2 3
Dizziness/lightheadedness 11 4.8 10 2.8
Creatinine increase 10.8 0.4 10.1 0.6
Flatulence 10 0.2 10.1 0.1
Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10 4.3
Lymphopenia 6 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

Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic- oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST);SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).

1 CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109 /L, Grade 4 less than 0.5x 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).

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 3 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

Adjuvant Treatment of GIST

In Study 1, the majority of both imatinib 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 imatinib and placebo-treated patients, respectively. Edema, GI 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 imatinib 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 imatinib are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib mesylate tablets treatment in either trial.

In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the imatinib 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 imatinib are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib 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 imatinib-treated patients)

Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic- oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).

*NCI Common Terminology Criteria for Adverse Events, version 3

(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.

Preferred Term All CTC Grades CTC Grade 3* and Above
Imatinib (n = 337) % Placebo (n = 345) % Imatinib (n = 337) % Placebo (n = 345) %
Diarrhea 59.3 29.3 3 1.4
Fatigue 57 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 0.6 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 1.4
Headache 19.3 20.3 0.6 0
Dyspepsia 17.2 13 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 2.7 0
Muscle spasms 16.3 3.3 0 0
Neutrophil count decreased 16 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 11.3 0 0
Pruritus 11 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 0.9 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 2.6 0.3 0
Platelet count decreased 5 3.5 0 0
Stomatitis 5 1.7 0.6 0
Upper respiratory tract infection 5 3.5 0 0
Vision blurred 5 2.3 0 0
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 imatinib -treated patients) Study 2(1)

Abbreviations: AE, adverse event; CTC, common terminology criteria.

(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.

Preferred Term All CTC Grades CTC Grades 3 and Above
imatinib 12 Months imatinib 36 Months imatinib 12 Months imatinib 36 Months
(n = 194)% (n = 198)% (n = 194)% (n = 198)%
Patients with at least one AE 99 100 20.1 32.8
Hemoglobin decreased 72.2 80.3 0.5 0.5
Periorbital edema 59.3 74.2 0.5 1
Blood lactate 43.3 60.1 0 0
dehydrogenase increased
Diarrhea 43.8 54 0.5 2
Nausea 44.8 5 1.5 0.5
Muscle spasms 30.9 49 0.5 1
Fatigue 48.5 48.5 1 0.5
White blood cell count decreased 34.5 47 2.1 3
Pain 25.8 45.5 1 3
Blood creatinine increased 30.4 44.4 0 0
Peripheral edema 33 40.9 0.5 1
Dermatitis 29.4 38.9 2.1 1.5
Aspartate aminotransferase increased 30.9 37.9 1.5 3
Alanine 28.9 34.3 2.1 3
aminotransferase increased
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 0.5
Vomiting 10.8 22.2 0.5 1
Dyspepsia 17.5 21.7 0.5 1
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 17.7 0 0
Arthralgia 8.8 17.2 0 1
Blood alkaline 10.8 16.7 0 0.5
phosphatase increased
Dyspnea 6.2 16.2 0.5 1.5
Myalgia 9.3 15.2 0 1
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 0.5
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 6.1 0 0.5
Palpitations 5.2 5.1 0 0

Adverse Reactions from Multiple Clinical Trials

Cardiac Disorders:

Estimated 1% to 10%: palpitations, pericardial effusion

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

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

Vascular Disorders:

Estimated 1% to 10%: flushing, hemorrhage

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

Investigations:

Estimated 1% to 10%: blood creatine phosphokinase CPK increased, blood amylase increased

Estimated 0.1% to 1%: blood lactate dehydrogenase LDH increased

Skin and Subcutaneous Tissue Disorders:

Estimated 1% to 10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura

Estimated 0.1% to 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, panniculitis (including erythema nodosum)

Estimated 0.01% to 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% to 10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis

Estimated 0.1% to 1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis

Estimated 0.01% to 0.1%: colitis, ileus, inflammatory bowel disease

General Disorders and Administration Site Conditions:

Estimated 1% to 10%: weakness, anasarca, chills

Estimated 0.1% to 1%: malaise

Blood and Lymphatic System Disorders:

Estimated 1% to 10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia Estimated 0.1% to 1%: thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0.01% to 0.1%: hemolytic anemia, aplastic anemia

Hepatobiliary Disorders:

Estimated 0.1% to 1%: hepatitis, jaundice

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

Immune System Disorders:

Estimated 0.01% to 0.1%: angioedema

Infections and Infestations:

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

Estimated 0.01% to 0.1%: fungal infection

Metabolism and Nutrition Disorders:

Estimated 1% to 10%: weight decreased, decreased appetite

Estimated 0.1% to 1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia

Musculoskeletal and Connective Tissue Disorders:

Estimated 1% to 10%: joint swelling

Estimated 0.1% to 1%: joint and muscle stiffness, muscular weakness, arthritis

Nervous System/Psychiatric Disorders:

Estimated 1% to 10%: paresthesia, hypesthesia

Estimated 0.1% to 1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor

Estimated 0.01% to 0.1%: increased intracranial pressure1 , confusional state, convulsions, optic neuritis

Renal and Urinary Disorders:

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

Reproductive System and Breast Disorders:

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

Respiratory, Thoracic and Mediastinal Disorders:

Estimated 1% to 10%: epistaxis

Estimated 0.1% to 1%: pleural effusion

Estimated 0.01% to 0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage

Endocrine Disorders:

Estimated 0.1%-1%: hypothyroidism, hyperthyroidism

Eye, Ear and Labyrinth Disorders:

Estimated 1% to 10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye

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

Estimated 0.01% to 0.1%: papilledema1 , glaucoma

1 Including some fatalities.

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