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Bosulif

"The U.S. Food and Drug Administration today approved Imbruvica (ibrutinib) to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of blood cancer.

MCL is a rare form of non-Hodgkin lymphoma and represents about 6 "...

Bosulif

SIDE EFFECTS

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

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%).

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

The single-arm Phase ½ 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 ½ CML safety population.

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

System Organ Class Preferred Term CP CML
N=406
n (%)
AdvP CML
N=140
n (%)
All CP and AdvP CML
N=546
n (%)
All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Gastrointestinal Disorders
  Diarrhea 342 (84) 38 (9) 107 (76) 7 (5) 449 (82) 45 (8)
  Nausea 186 (46) 5 (1) 66 (47) 3 (2) 252 (46) 8 (1)
  Abdominal Paina 162 (40) 6 (1) 41 (29) 7 (5) 203 (37) 13 (2)
  Vomiting 152 (37) 12 (3) 59 (42) 5 (4) 211 (39) 17 (3)
Blood and Lymphatic System Disorders
  Thrombocytopenia 163 (40) 105 (26) 59 (42) 52 (37) 222 (41) 157 (29)
  Anemia 94 (23) 35 (9) 52 (37) 37 (26) 146 (27) 72 (13)
  Neutropenia 65 (16) 43 (11) 26 (19) 25 (18) 91 (17) 68 (12)
General Disorders and Administrative Site Conditions
  Fatigueb 104 (26) 6 (1) 28 (20) 6 (4) 132 (24) 12 (2)
  Pyrexia    90 (22) 2 ( < 1) 51 (36) 4 (3) 141 (26) 6 (1)
  Edemac 56 (14) 1 ( < 1) 19 (14) 1 (1) 75 (14) 2 ( < 1)
  Asthenia 45 (11) 5 (1) 14 (10) 1 (1) 59 (11) 6 (1)
Infections and Infestations
  Respiratory tract infectiond 49 (12) 2 ( < 1) 14 (10) 0 63 (12) 2 ( < 1)
  Nasopharyngitis 47 (12) 0 7 (5) 0 54 (10) 0
Investigations
  Alanine aminotransferase increased 81 (20) 30 (7) 14(10) 7(5) 95(17) 37(7)
  Aspartate aminotransferase increased 64 (16) 15 (4) 15(11) 4 (3) 79(14) 19(3)
Metabolism and nutrition disorder
  Decreased appetite 53 (13) 3 (1) 19 (14) 0 72 (13) 3 (1)
Musculoskeletal and Connective Tissue Disorder
  Arthralgia 58 (14) 2 ( < 1) 18 (13) 0 76 (14) 2 ( < 1)
  Back pain 49 (12) 3 (1) 10 (7) 2 (1) 59 (11) 5 (1)
Nervous System Disorders
  Headache 82 (20) 3 (1) 25 (18) 6 (4) 107 (20) 9 (2)
  Dizziness 39 (10) 0 18 (13) 1 (1) 57 (10) 1 ( < 1)
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 41 (10) 4 (1) 26 (19) 8 (6) 67 (12) 12 (2)
  Cough 80(20) 0 30(21) 0 110(20) 0
Skin and Subcutaneous Disorders
  Rashe 140 (34) 32 (8) 49 (35) 6 (4) 189 (35) 38 (7)
  Pruritus 43 (11) 3 (1) 11 (8) 0 54 (10) 3 (1)
CP CML = Chronic Phase CML; AdvP CML = Advanced Phase CML (includes patients with Accelerated Phase and Blast Phase CML)
aAbdominal pain includes the following preferred terms: Abdominal pain, Abdominal pain upper, Abdominal pain lower, Abdominal tenderness, Gastrointestinal pain, Abdominal discomfort
bFatigue includes the following preferred terms: Fatigue, Malaise
cEdema includes the following preferred terms: Edema, Edema peripheral, Localized edema, Face edema
dRespiratory tract infection includes the following preferred terms: Respiratory tract infection, Upper respiratory tract infection, Lower respiratory tract infection, Viral upper respiratory tract infection, Respiratory tract infection viral
eRash includes the following preferred terms: Rash, Rash macular, Rash pruritic, Rash generalized, Rash papular, Rash maculo-papular

In the single-arm Phase ½ 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 ½ CML safety population.

Table 3: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities In the Phase ½ Clinical Study, Safety Population

  CP CML
N=406
n (%)
AdvP CML
N=140
n (%)
All CP and AdvP CML
N=546
n (%)
Hematology Parameters
  Platelet Count (Low) less than 50×109/L 102 (25) 80 (57) 182 (33)
  Absolute Neutrophil Count less than 1×109/L 74 (18) 52 (37) 126 (23)
  Hemoglobin (Low) less than 80 g/L 53 (13) 49 (35) 102 (19)
Biochemistry Parameters
  SGPT/ALT greater than 5.0×ULN 39 (10) 8 (6) 47 (9)
  SGOT/AST greater than 5.0×ULN 17 (4) 4 (3) 21 (4)
  Lipase greater than 2×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×ULN 3 (1) 2 (1) 5 (1)

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 hemorrhagea

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

Hepatobiliary Disorders: 1% and less than 10% -hepatotoxicityc, abnormal hepatic functiond; 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% -pneumoniae, 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 failure

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

aGastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage
bChest pain includes the following preferred terms: chest pain, chest discomfort
cHepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis
dAbnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder
ePneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia

Read the Bosulif (bosutinib tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Drugs That May Increase Bosutinib Plasma Concentrations

CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp 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

CYP3A Inducers

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.

Drugs That May Have Their Plasma Concentrations Altered By Bosutinib

Substrates of P-glycoprotein

An in vitro study suggests that BOSULIF may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin [see CLINICAL PHARMACOLOGY].

Read the Bosulif Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 10/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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Additional Bosulif Information

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