SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Gastrointestinal toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Myelosuppression [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Hepatic toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Fluid retention [see WARNINGS AND PRECAUTIONS].

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.

Serious adverse reactions reported include anaphylactic shock [see CONTRAINDICATIONS], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatoxicity and rash.

Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%).

Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML

The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients. Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months, and a median dose intensity of 484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively.

Table 2 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population.

Table 2: Adverse Reactions (10% or greater) in patients with CML

In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.

Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population. 6

Table 3: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities In the Phase 1/2 Clinical Study, Safety Population

Additional Data from Multiple Clinical Trials

The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Blood and Lymphatic System Disorders: 1% and less than 10% - febrile neutropenia

Cardiac Disorders: 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis

Ear and Labyrinth Disorders: 1% and less than 10% - tinnitus

Gastrointestinal Disorders: 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage^a

General Disorders and Administrative Site Conditions: 1% and less than 10% - chest pain^b, pain

Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity^c, abnormal hepatic function^d; 0.1% and less than 1% - liver injury

Immune System Disorders: 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock

Infections and Infestations: 1% and less than 10% - pneumonia^e, influenza, bronchitis

Investigations: 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine

Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration

Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% - myalgia

Nervous System Disorders: 1% and less than 10% - dysgeusia

Renal and Urinary Disorders: 1% and less than 10% - acute renal failure, renal failure7

Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension

Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption

REFERENCES

^a Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage

^b Chest pain includes the following preferred terms: chest pain, chest discomfort

^c Hepatotoxicity includes the following preferred terms: hepatoxicity, toxic hepatitis, cytolytic hepatitis

^d Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder

^e Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia

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