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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].
- 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.
Serious adverse reactions reported include anaphylactic shock [see CONTRAINDICATIONS], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.
Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase ½ 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%) [see Clinical Studies].
Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
The single-arm Phase ½ clinical trial (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and with resistance or intolerance to prior therapy [see Clinical Studies]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients:
- 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.
- 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.
- 140 patients with advanced phase CML including 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 3 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase ½ CML safety population.
Table 3: Adverse Reactions (10% or Greater) in
Patients with CML in Study 1
|Chronic Phase CML
|Advanced Phase CML
|All Grades (%)||Grade 3/4 (%)||All Grades (%)||Grade 3/4 (%)|
|Increased aspartate aminotransferase||16||4||11||3|
|Respiratory tract infectione||12||< 1||10||0|
|Advanced Phase CML includes patients with Accelerated
Phase and Blast Phase CML
aAbdominal pain includes the following terms: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, gastrointestinal pain, abdominal discomfort
bRash includes the following terms: rash, macular rash, pruritic rash, generalized rash, popular rash, maculo-papular rash
cFatigue includes the following terms: fatigue, malaise
dEdema includes the following terms: edema, peripheral edema, localized edema, face edema
eRespiratory tract infection includes the following terms: respiratory tract infection, upper respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection, viral respiratory tract infection
In the single-arm Phase ½ clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 4 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase ½ CML safety population.
Table 4: Number (%) of Patients with Clinically
Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML
in Study 1, Safety Population
|Chronic Phase CML
|Advanced Phase CML
|All CP and AdvP CML
|Platelet Count (Low) less than 50 x109/L||102 (25)||80 (57)||182 (33)|
|Absolute Neutrophil Count less than 1 x 109/L||74 (18)||52 (37)||126 (23)|
|Hemoglobin (Low) less than 80 g/L||53 (13)||49 (35)||102 (19)|
|SGPT/ALT greater than 5.0 x ULN||39 (10)||8 (6)||47 (9)|
|SGOT/AST greater than 5.0 x ULN||17 (4)||4 (3)||21 (4)|
|Lipase greater than 2 x ULN||33 (8)||4 (3)||37 (7)|
|Phosphorus (Low) less than 0.6 mmol/L||30 (7)||10 (7)||40 (7)|
|Total Bilirubin greater than 3.0 x ULN||3 (1)||2 (1)||5 (1)|
Additional Adverse Reactions 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.
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 (includes gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage)
General Disorders and Administrative Site Conditions: 1% and less than 10% -chest pain (includes chest pain and chest discomfort), pain
Hepatobiliary Disorders: 1% and less than 10% -hepatotoxicity (includes hepatotoxicity, toxic hepatitis, and cytolytic hepatitis), abnormal hepatic function (includes abnormal hepatic function, liver disorder); 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
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 failure
Read the Bosulif (bosutinib tablets) Side Effects Center for a complete guide to possible side effects
Drugs That May Increase Bosutinib Plasma Concentrations
Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected [see DOSAGE AND ADMINISTRATION]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to BOSULIF alone [see CLINICAL PHARMACOLOGY].
Drugs That May Decrease Bosutinib Plasma Concentrations
Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected [see DOSAGE AND ADMINISTRATION]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to BOSULIF alone [see CLINICAL PHARMACOLOGY].
Proton Pump Inhibitors
In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to BOSULIF alone [see CLINICAL PHARMACOLOGY].
Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours.
Read the Bosulif Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/19/2016
Additional Bosulif Information
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