Adverse Drug Reaction Overview

The safety information provided in this section represents an assessment of the adverse reactions from 1521 patients who received at least 1 oral dose of single-agent BOSULIF in newly diagnosed Ph+ CP CML, CML resistant or intolerant to prior therapy, other Ph+ leukemias, and advanced malignant solid tumors.

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

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Newly Diagnosed Chronic Phase Ph+ CML

A total of 268 patients newly-diagnosed with CP CML received at least 1 dose of single-agent bosutinib 400 mg in a randomized Phase 3 clinical study. After a minimum of 12 months of follow-up, the median duration of therapy was 14.1 months (range: 0.3 to 24.7 months); the median dose intensity was 391.8 mg/day.

The most frequent adverse reactions reported for ≥20% of patients in the bosutinib treatment group were diarrhoea (70.1% of patients), nausea (35.1%), ALT increased (30.6%), thrombocytopenia (35.1%), abdominal pain (25.3%), and AST increased (22.8%).

The Grade 3 or Grade 4 adverse reactions reported for ≥5% of patients in the bosutinib treatment group were alanine aminotransferase increased (19.0%), lipase increased (9.7%), aspartate aminotransferase increased (9.7%), thrombocytopenia (9.0%), diarrhoea (7.8%), neutropenia (6.0%), and platelet count decreased (5.6%).

Table 1 below presents adverse reactions (all causality) of any toxicity and grades 3/4 very commonly reported (frequencies ≥10%) in the Phase 3 safety population.

Table 2 below presents adverse reactions (all causality) of any toxicity and grades 3/4 commonly reported (frequencies ≥ 1% to <10%) in the Phase 3 safety population.

In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, the median time of onset for diarrhea (all grades) in the bosutinib treatment group was 3 days, and the median duration of an event was 3 days. The median time of onset for either ALT or AST elevations (all grades) observed was 32 and 43 days, respectively, and the median duration was 20 and 15 days, respectively.

Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML and ALL Patients Resistant or Intolerant to Previous TKIs Treatment

The single-arm Phase 1/2 clinical study enrolled a total of 571 patients with Ph+ chronic (n=284), accelerated (n=79), or blast (n=64) phase chronic myelogenous leukemia (CML) and 24  patients with Ph+ acute lymphoblastic leukemia (ALL) who were resistant or intolerant to prior TKI therapy. The safety population (received at least 1 dose of BOSULIF) included 570  patients.

With the ≥ 4 years of follow up, the majority of BOSULIF-treated patients (99.5%) experienced at least one adverse event. The most common (incidence ≥ 30%) were diarrhea (81.6%), nausea (47.0%), thrombocytopenia (41.4%), vomiting (39.1%), abdominal pain (38.4%), rash (32.8%), and anemia (30.2%).

Overall, 77.9% of patients experienced severe, Grade 3 and 4 adverse events, and 44.2% of patients experienced serious adverse events (SAEs). The most common SAEs (>2% of subjects overall) were pneumonia (4.9%), pleural effusion (4.7%), pyrexia (3.3%), thrombocytopenia (2.5%), dyspnea (2.3%), disease progression, and diarrhea (2.1% each).

Overall, 134 (24%) of patients permanently discontinued bosutinib due to treatment-emerged adverse events (TEAEs). The most common TEAEs leading to discontinuation (≥ 2% of subjects overall) were thrombocytopenia (5.3%) and ALT increased (2.1%). Overall, 65.3% of subjects had at least one dose interruption due to adverse events. The most common TEAEs (≥ 4% of subjects) resulting in dose interruption were thrombocytopenia (21.6%), diarrhea (11.6%), rash (9.8%), neutropenia (8.1%), vomiting and pleural effusion (6.0% each), ALT increased (7.0%), AST increased (5.1%), and anemia (4.2%). Overall, 49% of subjects had ≥1 dose reduction due to TEAEs. The most common TEAEs (≥ 4% of subjects) resulting in reductions in bosutinib dose were thrombocytopenia (13.5%), rash (5.4%), and diarrhea (4.7%).

Table 3 below presents adverse reactions (all causality) of any toxicity and grades 3/4 very commonly reported (frequencies ≥10%) in the Phase 1/2 safety population.

Table 4 below presents adverse reactions (all causality) of any toxicity and grades 3/4 commonly reported (frequencies ≥ 1% to <10%) in the Phase 1/2 safety population.

In the single-arm Phase 1/2 clinical study, the median time of onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Based on adverse reactions reported, the median time of onset for either ALT or AST (all grades) elevations was 29 and 30 days, respectively, and the median duration for each was 18 days.

ECG Findings

In the Phase 1/ 2 clinical study, 1 patient (0.2%) experienced QTcF (corrected QT by the Fridericia method) intervals of greater than 500 ms. Seven (1.2%) of the patients experienced QTcF increases from baseline exceeding 60 ms. Patients with uncontrolled or significant cardiovascular disease, including QT interval prolongation, at baseline were excluded by protocol criteria from the clinical trials.

In the phase 3 study in patients newly diagnosed with CP CML treated with 400 mg, there was 1 patient in the bosutinib treatment group and 0 patients in the imatinib treatment group who experienced corrected QT by the Fridericia method (QTcF) interval of greater than 500 msec.

In a Phase 3 study of newly diagnosed Ph+ CP CML patients treated with 500 mg, 2 patients (0.8%) experienced QTcF interval greater than 500 ms in the BOSULIF treatment arm. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded from enrolling in this clinical study. In this study population, BOSULIF was associated with statistically significant decreases from baseline in heart rate of approximately 4 bpm at months 2 and 3.

Tabulated Summary of Adverse Reactions

The following adverse reactions in Table 5 were reported in patients in pooled clinical studies with BOSULIF. They represent an evaluation of the adverse reaction data from 1521 patients who received at least 1 dose of single-agent BOSULIF in newly diagnosed Ph+ CP CML, CML resistant or intolerant to prior therapy, other Ph+ leukemias, and advanced malignant solid tumors. These adverse reactions are presented by system organ class and by frequency. Frequency categories are defined as: very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), rare (≥0.01% to <0.1%), very rare (<0.01%), not known (cannot be estimated from the available data).

All treatment-emergent adverse events that were reported in BOSULIF pooled clinical studies, regardless of causality and frequency, are listed in Table 6 below.

Abnormal Hematologic and Clinical Chemistry Findings

Table 6 presents potential clinically relevant or severe abnormalities of routine hematological, or biochemistry laboratory values in the study patient population who received at least one dose of BOSULIF in the Phase 1/2 study.

Table 7 presents potential clinically relevant or severe abnormalities of routine hematological, or biochemistry laboratory values in the study patient population who received at least one dose of BOSULIF in the Phase 3 study.

Table 8 presents the median (90% CI) change in eGFR from baseline over time in patients with a baseline creatinine value in the Phase 1/2 study (see CLINICAL TRIALS).

Table 9 presents the median (90% CI) change in eGFR from baseline over time in patients with a baseline creatinine value in the Phase 3 study (see CLINICAL TRIALS).