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BOSULIF (bosutinib)

Health Professional Information

BOSULIF (bosutinib tablets), indicated for,
  • the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior TKI therapy, and for whom subsequent treatment with imatinib, nilotinib and dasatinib is not clinically appropriate,
has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization.

Summary Product Information

Route of AdministrationDosage Form / StrengthClinically Relevant Nonmedicinal Ingredients
OralTablets 100 mg and 500 mgCoating: iron oxide yellow, iron oxide red.
Tablet:
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

BOSULIF* (bosutinib) is indicated for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior TKI therapy, and for whom subsequent treatment with imatinib, nilotinib and dasatinib is not clinically appropriate.

Market authorization with conditions is based on cytogenetic and hematologic response rates observed in a single-arm, Phase 1/ 2 study. Overall survival benefit has not been demonstrated.

BOSULIF should only be prescribed by a qualified healthcare professional who is experienced in the use of antineoplastic therapy and in the treatment of chronic myeloid leukemia.

Geriatrics (≥ 65 years of age): No clinically relevant age-related pharmacokinetic differences have been observed in the elderly.

Pediatrics (< 18 years of age): The safety and efficacy of BOSULIF in patients less than 18 years of age have not been evaluated. No data are available.

Contraindications

Do not use BOSULIF (bosutinib) in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Cases of Grade 3 or 4 drug hypersensitivity were reported in patients treated with BOSULIF. Two cases (less than 0.2%) of Grade 4 drug-related anaphylactic shock were reported in patients treated with BOSULIF (see ADVERSE REACTIONS). For a complete listing of ingredients, see the Dosage Forms, Composition and Packaging section of the product monograph.

Do not use BOSULIF in patients with a known history of long QT syndrome or with a persistent QT interval of >480 ms (see ADVERSE REACTIONS).

Do not use BOSULIF in cases of uncorrected hypokalemia or hypomagnesemia (see ADVERSE REACTIONS)

Do not use BOSULIF in hepatically impaired patients. Higher risk of QT prolongation has been seen in patients with declining hepatic function (see ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS, Special Populations, and ACTION AND CLINICAL PHARMACOLOGY, Other Considerations).

Warnings And Precautions

Serious Warnings and Precautions
  • Drug interactions with inhibitors or inducers of CYP3A4. The concomitant use of BOSULIF with potent or moderate CYP3A4 inhibitors or inducers should be avoided (see Warnings and Precautions, Drug Interactions, Serious Drug and Drug-Food Interactions and Dosage and Administration)
  • Gastrointestinal toxicity, including diarrhea (see Warnings and Precautions and Adverse Reactions)
  • Hepatic toxicity, including Hy’s Law case (see Warnings and Precautions and Adverse Reactions)
  • Cardiac failure, including fatal outcomes (see Warnings and Precautions and Adverse Reactions)
  • Fluid retention (including pleural effusion, pulmonary edema and pericardial effusion (see Warnings and Precautions and Adverse Reactions)
  • Hemorrhage (see Warnings and Precautions and Adverse Reactions)
  • QT interval prolongation (see Warnings and Precautions and Adverse Reactions)

General

CYP3A inhibitors:

Bosutinib exposure can be increased when administered concomitantly with CYP3A inhibitors. Avoid the concomitant use of potent or moderate CYP3A inhibitors (see DRUG INTERACTIONS, Serious Drug and Drug-Food Interactions).

CYP3A inducers:

Bosutinib exposure is decreased when administered concomitantly with CYP3A inducers. Avoid the concomitant use of potent or moderate CYP3A inducers (see DRUG INTERACTIONS, Drug-Drug Interactions).

Carcinogenesis and Mutagenesis

Cases of second primary malignancies have been reported in humans in clinical trials with BOSULIF (see ADVERSE REACTIONS).

In the 2-year rat carcinogenicity study, overall, no relevant bosutinib-related increase in neoplastic lesion was shown. Nonclinical studies showed that bosutinib was not genotoxic or mutagenic (see TOXICOLOGY).

Cardiovascular

In clinical studies, patients with uncontrolled or significant cardiac disease (e.g. recent myocardial infarction, congestive heart failure or unstable angina) were excluded.

QT Prolongation

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. Six (1.1%) 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 (see ADVERSE REACTIONS).

In the Phase 3 study of newly diagnosed Ph+ CP CML patients, two patients (0.8%) experienced QTcF interval greater than 500 ms in the BOSULIF treatment arm. 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 (see ADVERSE REACTIONS).

BOSULIF should be administered with caution to patients who have a history of or predisposition for QTc prolongation, who have uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, or who are taking medicinal products that are known to prolong the QT interval (e.g. anti-arrhythmic medicinal products and other substances that may prolong QT (see DRUG INTERACTIONS, Drug-Drug Interactions). The presence of hypokalaemia and hypomagnesaemia may further increase this effect.

Monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with BOSULIF and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to BOSULIF administration and should be monitored periodically during therapy (see CONTRAINDICATIONS).

Patients with hepatic impairment who are receiving treatment with BOSULIF are at higher risk of developing QT interval prolongation (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations).

Cardiac Toxicity

Cardiac-related TEAEs were reported in 10.2% of patients in the Phase 1/ 2 study, with Grade 3 or 4 cardiac-related events reported in 3.5% of patients. Atrial fibrillation (2.1%) (Grade 3 or 4 in 0.9%), cardiac failure congestive (1.8%), and tachycardia (1.8%) were most commonly reported. Grade 3 or 4 events of acute myocardial infarction, cardiac failure, and coronary artery disease were reported in 0.5% of patients each, as well as coronary artery stenosis (0.4%), left ventricular dysfunction (0.4%), and pulmonary edema (0.2%). In the Phase 3 study, 3.6% of patients in the BOSULIF arm experienced cardiac events (0.8% with Grade 3 or 4) versus 1.6% of patients in the imatinib arm (none with Grade 3 or 4).

Caution should be exercised in patients with a history of or predisposition to relevant cardiac disorders including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.

Fluid Retention

Treatment with BOSULIF is associated with fluid retention (pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema).

In the single-arm Phase 1/2 clinical study in 570 patients with Ph+ leukemias treated with prior therapy, severe (Grade 3 and 4) fluid retention was reported in 18 patients (3.2%). Sixteen patients had a Grade 3 or 4 effusion (13 patients had Grade 3 or 4 pleural effusions [2.3%] and 3 patients [0.5%] had a Grade 3 or 4 pericardial effusion). In the Phase 3 study, 3 patients (1.2%) experienced acute pulmonary edema or pulmonary edema (all grades) in the setting of either a pleural effusion or a pericardial effusion.

Patients should be weighed regularly and monitored for signs and symptoms of fluid retention, and managed using standard of care treatment, such as diuretics. In addition, these events can also be managed by withholding BOSULIF temporarily, dose reduction, and/or discontinuation of BOSULIF (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Gastrointestinal

Diarrhea and Vomiting

Patients with recent or ongoing clinically significant gastrointestinal disorder should use BOSULIF with caution and only after a careful benefit-risk assessment, as patients with recent or ongoing clinically significant gastrointestinal disorder (e.g. severe vomiting and/or diarrhea) were excluded from CML clinical studies. Treatment with BOSULIF is associated with events of diarrhea and vomiting. 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. Eighty-one percent (81%) of patients treated with BOSULIF experienced diarrhea, with 8.1% Grade 3/4.

In newly diagnosed CML CP patients, a higher rate of drug-related vomiting was reported in the BOSULIF-treated group (31.5%) relative to the imatinib-treated group (13.5%). In these CML CP patients, a higher rate of drug-related diarrhea was also observed in the Bosulif-treated group (65.7%) relative to imatinib-treated group (17.9%). Bosutinib patients who reported a treatment-emergent diarrhea, 45.8% have experienced an individual episode of diarrhea for more than 28 consecutive days. Patients with these events should be managed using standard of care treatment, including antidiarrheal medication, and/or fluid replacement. Since some antiemetics and antidiarrheals are associated with a risk of increased QT interval prolongation with the potential to induce “torsade de pointes”, concomitant treatment with these agents should be carefully considered. In addition, these events can also be managed by withholding BOSULIF temporarily, dose reduction, and/or discontinuation of BOSULIF (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Hematologic

Myelosuppression

Treatment with BOSULIF is associated with myelosuppression, defined as anemia, neutropenia, and thrombocytopenia. Patients with Ph+ leukemias who are receiving BOSULIF should have a complete blood count (including platelet count) performed weekly for the first month and then monthly thereafter, or as clinically indicated. Myelosuppression can be managed by withholding BOSULIF temporarily, dose reduction, and/or discontinuation of BOSULIF (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).

Hemorrhage

In the Phase 1/2 population, treatment-emergent adverse events of any severity grade related to bleeding events were commonly reported in 9.6% of patients. Hemorrhage events included duodenal ulcer hemorrhage, eye hemorrhage, gastrointestinal hemorrhage, operative hemorrhage, pericardial hemorrhage, rectal hemorrhage, retroperitoneal hemorrhage, subarachnoid hemorrhage, vaginal hemorrhage, and cerebral hemorrhage.

Patients with coagulation dysfunction/low platelet counts should be closely monitoring during treatment with BOSULIF.

Hepatic/Biliary and Pancreatic

Hepatotoxicity

Treatment with bosutinib is associated with elevations in serum transaminases (ALT, AST).

In the 570 patients from the safety population, the incidence of ALT elevation was 17% for all grades (of which 6% were maximum Grade 3/4) and AST elevation was 14 % for all grades (of which 3% were maximum Grade 3/4). Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 29 and 30 days, respectively, and the median duration for each was 18 days.

One case consistent with Hy’s Law and drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3 x ULN with total bilirubin greater than 2 x ULN and alkaline phosphatase less than 2 x ULN) occurred in a trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF.

Patients receiving BOSULIF should have monthly hepatic enzyme tests for the first three months of treatment, or as clinically indicated. Patients with transaminase elevations can be managed by withholding BOSULIF temporarily, dose reduction, and/or discontinuation of BOSULIF (see DOSAGE AND ADMINISTRATION, Dosing Considerations, Hepatic Impairment and ADVERSE REACTIONS).

Elevated Serum lipase /Amylase and Pancreatitis

Grade 3 or 4 elevation in serum lipase (3%) and amylase and Grade 3 or 4 acute pancreatitis has been observed with BOSULIF. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinib should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustment

Infections

Infections including fungal respiratory tract infection and nasopharyngitis, fungal pneumonia, pseudomonal sepsis, bacteraemia, urinary tract infections, and gastrointestinal infections occurred more frequently in newly diagnosed BOSULIF-treated CML CP patients (40.7%) relative to imatinib-treated CML CP patients (31.1%). Also Grade 3 or 4 cellulitis in 0.5% of subjects in the Phase 1 /2 study. BOSULIF may predispose patients who are immunocompromised or older patients to bacterial, fungal, viral or protozoan infections.

Immune

In the Phase 1/2 clinical study, hypogammaglobulinaemia was reported. Patients with immunocompromising diseases or risk factors for immunosuppression, such as patients with HIV, AIDS, or patients receiving immunosuppressive therapies, should be closely monitored for signs of immunotoxicity. Leukocytoclastic vasculitis occurred in 1 patient (0.3%) (see ADVERSE REACTIONS).

Hepatitis B virus reactivation

Reactivation of hepatitis B virus (HBV) has occurred in patients who are chronic carriers of this virus after receiving a Bcr-Abl tyrosine kinase inhibitor (TKI). Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or death.

Patients should be tested for hepatitis B infection before initiating treatment with BOSULIF. Patients currently on BOSULIF should have baseline testing for hepatitis B infection if clinically indicated, in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with BOSULIF should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Hypersensitivity

Cases of Grade 3 or 4 hypersensitivity, anaphylactic shock leading to hospitalization, and urticaria have been reported with BOSULIF. A potential source of hypersensitivity reactions may also be the excipients in the BOSULIF formulation (polyethylene glycol 3350, poloxamer 188, povidone, or other excipients (see CONTRAINDICATIONS).

Sexual Function/Reproduction

Fertility

Human studies on male patients receiving BOSULIF and its effect on male fertility and spermatogenesis have not been performed. Studies in rats showed that fertility was slightly decreased in male rats treated with bosutinib. Female rats had increased embryonic resorptions and decreases in implantations and viable embryos. The dose at which no adverse reproductive effects were observed in males and females resulted in exposures equal to 0.5 times and 0.2 times, respectively, the human exposure based on the clinical dose of 500 mg (based on unbound AUC in the respective species). BOSULIF has the potential to impair reproductive function and fertility in humans. Physicians should advise and counsel their male and female patients as appropriate (see Special Populations, Male Fertility and DETAILED PHARMACOLOGY).

Females of childbearing potential

Females of childbearing potential (i.e. females who are menstruating, amenorrheic from previous treatments, and/or perimenopausal) must be advised to use highly effective contraception during treatment with BOSULIF. If pregnancy does occur during treatment, BOSULIF should be stropped and the patients should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counselling.

Tumour Lysis Syndrome

In the Phase 1/2 study, there were 4 patients (0.7%) with tumour lysis syndrome, 2 of whom had Grade 3 or 4 severity. Renal function should be closely monitored and adequate hydration should be maintained if tumour lysis syndrome is considered a substantial risk.

Musculoskeletal

Changes in Bone Density

In the Phase 1/2 study, the frequency of fractures (including cervical, vertebral, clavicle, facial bones, foot, hand, humerus, rib, tooth, and upper limb) was reported to be 1.8%, with tooth fracture reported to be most common (0.4%). Grade 3 or 4 humerus fracture and rib fracture were reported in 0.2%, each (see ADVERSE DRUG REACTIONS). In the Phase 3 study, the frequency of fractures was 1.2% in the BOSULIF arm versus 0.4% in the imatinib arm. In addition, hypophosphataemia was reported in patients treated with BOSULIF.

Patients with endocrine abnormalities (e.g. hyperparathyroidism) and severe osteoporosis treated with BOSULIF could be at greater risk from the impact of bone mineralization abnormalities, and should be monitored closely for changes in bone and mineral abnormalities, including bone density (see Monitoring and Laboratory Tests).

Renal and Urinary

A decline over time in estimated glomerular filtration rate (eGFR) was observed in CML patients receiving BOSULIF (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings). For patients with advanced phase leukemia, there appeared to be a more significant decline in eGFR at the same time point. While on treatment, over half (55%) of patients had at least trace or positive protein detected on spot check urinalyses, compared to 21% at baseline. A total of 29 subjects (5%) in the study had a total of 35 adverse events (AEs) of renal failure/impairment (including renal failure acute, renal failure, renal failure chronic and renal impairment). Seven patients discontinued BOSULIF treatment due to an AE related to renal impairment, including two patients who underwent hemodialysis as a result of renal dysfunction. The reversibility of the eGFR decline following treatment interruption, dose reduction or treatment discontinuation is unclear, due to limited clinical data.

Monitor patients for renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have pre-existing renal compromise or risk factors for renal dysfunction (see Special Populations, Renal Impairment, below).

Respiratory

In the clinical studies, 2.3% of patients treated with BOSULIF reported respiratory disorders including dyspnoea, pleural effusion, respiratory failure, acute pulmonary edema, pulmonary hypertension, pneumonitis, and interstitial lung disease.

Skin

Stevens-Johnson syndrome has been rarely reported in the post-market setting. Discontinue BOSULIF should this condition be suspected.

Special Populations

Pregnant Women: BOSULIF is teratogenic and is transferred to breast milk. Based on its mechanism of action and findings of embryofetal toxicities in rabbits, BOSULIF can cause fetal harm when administered to a pregnant woman (see TOXICOLOGY). There are no adequate and well-controlled studies of BOSULIF in pregnant women. If BOSULIF is used during pregnancy, the patient should be advised of the potential serious risks to a developing fetus.

Nursing Women: An animal study demonstrated excretion of bosutinib-derived radioactivity in breast milk. Because many drugs are excreted in human milk and because a potential risk to the nursing infant cannot be excluded, women that are taking BOSULIF should not breast-feed or provide breast milk to infants (see TOXICOLOGY).

Male Patients: There is a potential risk to the developing fetus if exposed to BOSULIF through the semen of male patients, therefore physicians should advise their male patients to use highly effective contraception (including condom) during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy. The method of contraception should be used while the patient is taking BOSULIF, during interruption of BOSULIF treatment, and for at least 4 weeks after stopping BOSULIF. Physicians should advise their male patients to inform their female sexual partners (with childbearing potential) that they are taking BOSULIF and that there are risks to the developing fetus if exposed to their semen (see DETAILED PHARMACOLOGY).

Pediatrics (<18 years of age): The safety and efficacy of BOSULIF in patients less than 18 years of age have not been evaluated. No data are available.

Geriatrics (≥ 65 years of age): No clinically relevant age-related pharmacokinetic differences have been observed in the elderly. No specific dose recommendation is necessary in the elderly.

Renal Impairment: In a renal impairment study, bosutinib exposures were increased in patients with moderate or severe renal impairment. Reduced starting doses are recommended for patients with moderate and severe renal impairment, respectively (see DOSAGE AND ADMINISTRATION, Dosing Considerations, Renal Impairment and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment). The efficacy and safety of BOSULIF were not investigated in these patients, as those with reduced renal function (serum creatinine > 1.5 x ULN) were excluded from the Phase 1/ 2 and Phase 3 BOSULIF CML studies. Initiate BOSULIF therapy in these patients only when perceived benefits outweigh the potential risks. Patients should be closely monitored for renal function at baseline and during therapy (see WARNINGS AND PRECAUTIONS, Renal and Urinary).

Hypertension was reported at a common (5.0%) frequency in patients treated with BOSULIF (see ADVERSE REACTIONS). Patients with renal impairment who are receiving treatment with BOSULIF were at higher risk of developing hypertension. Among patients with renal insufficiency, the frequency of hypertension was greater than for patients without renal insufficiency (13.6% versus 5.8%, respectively).

Hepatic Impairment: Metabolism of bosutinib is mainly hepatic. Clinical studies have excluded patients with ALT and/or AST >2.5 (or >5, if related to disease) x ULN range and/or bilirubin >1.5 x ULN range. BOSULIF should not be used in hepatically impaired patients.

Higher risk of QT prolongation has been seen in patients with declining hepatic function. In a single-oral-dose study, higher bosutinib plasma levels with reduced clearance were reported in non-CML patients with mild, moderate or severe hepatic impairment (Child-Pugh class) at baseline, compared to matching healthy volunteers. Treatment-emergent QTc prolongation was observed in 50% of hepatically impaired patients (including all 6 patients with severe hepatic impairment) versus 11% of healthy volunteers; the frequency, magnitude and duration of QTc prolongation appeared to increase with severity of baseline hepatic impairment (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, Dosing considerations, ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Higher risk of QT prolongation has been seen in patients with declining hepatic function (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Sensitivity/Intolerance: Two cases (less than 0.2%) of Grade 4 drug-related anaphylactic shock were reported in patients treated with BOSULIF (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Leukocytoclastic vasculitis occurred in 1 patient (0.3%). Patients with hypersensitivity to excipients in BOSULIF, such as polyethylene glycol 3350, poloxamer 188, povidone, or other excipients, may be at risk.

Coagulation Dysfunction/Platelet Disorders: Patients with coagulation dysfunction /platelet disorders and who are taking BOSULIF may be at higher risk of bleeding events.

Serum Lipase / Pancreatitis: Elevated serum lipase, amylase and acute pancreatitis have been reported in patients treated with BOSULIF. Patients with previous history of pancreatitis may be at higher risk, so caution is recommended. In cases where lipase elevations are accompanied by abdominal symptoms, BOSULIF should be interrupted and appropriate diagnostic measures considered to rule out pancreatitis.

Monitoring and Laboratory Tests

Patients with Ph+ leukemias should have a complete blood count (including platelet counts) performed weekly for the first month then monthly thereafter, or as clinically indicated (see WARNINGS AND PRECAUTIONS, Hematologic).

Patients should have baseline and monthly liver function tests (including total bilirubin) and renal function tests for the first three months of treatment and periodically thereafter (see WARNINGS AND PRECAUTIONS, Hepatic).

Serum electrolytes (including phosphorus), calcium and magnesium, as well as serum lipase/amylase, should be monitored at baseline and frequently during treatment with BOSULIF, and as clinically indicated. Patients with endocrine abnormalities (e.g. hyperparathyroidism) and/or severe osteoporosis should be monitored closely for changes in bone and mineral abnormalities, including bone density (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Monitor patients for renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have pre-existing renal compromise or risk factors for renal dysfunction.

Adequate hydration should be maintained if tumour lysis syndrome is considered a substantial risk.

Patients should be weighed and monitored regularly for fluid retention and managed using standard of care treatment (see WARNINGS AND PRECAUTIONS, Fluid Retention).

Monitoring for an effect on the QTc interval is recommended and a baseline ECG is recommended prior to initiating therapy with BOSULIF and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to BOSULIF administration and should be monitored periodically during therapy (see WARNINGS AND PRECAUTIONS, QT/QTc Prolongation).

Adverse Reactions

Adverse Drug Reaction Overview

The safety information provided in this section represents an assessment of the adverse reactions from 1119 patients who received at least 1 oral dose of single-agent BOSULIF in Ph+ CML, other Ph+ leukemias, and advanced malignant solid tumors.

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.

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

The single-arm Phase 1/2 clinical study enrolled a total of 571 patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) who were resistant or intolerant to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 570 patients. Within the safety population, the 288 patients with Ph+ CP CML who were resistant or intolerant to imatinib had a median duration of BOSULIF treatment of 22 months, and a median dose intensity of 484 mg/day. There were 118 patients with Ph+ CP CML who were resistant or intolerant to ≥ 2 tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, and/or nilotinib. These patients had a median duration of BOSULIF treatment of 8 months; and a median dose intensity of 478 mg/day. There were 164 patients with Ph+ AP CML, BP CML, or ALL who were resistant or intolerant to at least imatinib. These patients had a median duration of BOSULIF treatment of 10 months, 3 months, and 1 month, respectively. The median dose intensities were 483 mg/day, 500 mg/day, and 500 mg/day in the AP CML, BP CML, and Ph+ ALL cohorts, respectively.

Adverse reactions of any toxicity grade reported for ≥20% of patients in the Phase 1/2 safety population were diarrhea (79.5% of which 7.7% were Grade 3/4), nausea (41.6% of which 1.1% were Grade 3/4), vomiting (34.4% of which 2.5% were Grade 3/4), abdominal pain (28.9% of which 0.7% were Grade 3/4), thrombocytopenia (35.1% of which 23.9% were Grade 3/4), and rash (27.9% of which 6.3% were Grade 3/4). Table 1 below presents adverse reactions of any toxicity and grades 3/4 very commonly reported (frequencies ≥10%) in the Phase 1/2 safety population.

Table 1:
Number (%) of CML and Ph+ALL Patients Receiving BOSULIF Reporting Very Common (≥10%) Frequencies
Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 1/2 Safety Population
 CP* Imatinib Resistant or Intolerant N=288CP* Resistant or Intolerant ≥2 TKIs N=118AP* CML, BP* CML, Ph+ ALL
Resistant or Intolerant to at least Imatinib N=164
System Organ Class
Preferred Term
All
Grades
n (%)
Grade 3/4
n (%)
All
Grades
n (%)
Grade
3/4
n (%)
All
Grades
n (%)
Grade
3/4
n (%)

Any Adverse Reactions

283 (98.3)

154 (53.5)

118 (100)

60 (50.8)

154 (93.9)

85 (51.8)

Blood and lymphatic system disorders      

   Thrombocytopenia

113 (39.2)

69 (24.0)

43 (36.4)

29 (24.6)

44 (26.8)

38 (23.2) 

   Anemia

47 (16.3)

21 (7.3)

17 (14.4)

3 (2.5)

30 (18.3)

14 (8.5)

   Neutropenia41 (14.2)23 (8.0)  20 (16.9)16 (13.6) 28 (17.1)26 (15.9)
   Leukopenia30 (10.4)

13 (4.5)

3 (2.5)

0

15 (9.1)

10 (6.1)

Nervous system disorders      
   Headache

22 (7.6)

0

16 (13.6)

1 (0.8)

10 (6.1)

0

Gastrointestinal disorders      
   Diarrhea

240 (83.3)

26 (9.0)

96 (81.4)

10 (8.5)

117 (71.3)

8 (4.9)

   Nausea

119 (41.3)

4 (1.4)

51 (43.2)

0

67 (40.9)

2 (1.2)

   Vomiting

94 (32.6)

8 (2.8)

38 (32.2)

1 (0.8)

64 (39.0)

5 (3.0)

   Abdominal pain

101 (35.1)

2 (0.7)

32 (27.1)

0

32 (19.5)

2 (1.2)

Skin and subcutaneous tissue disorders      
   Rash

89 (30.9)

25 (8.7)

26 (22.0)

5 (4.2)

44 (26.8)

6 (3.7)

   Pruritus

18 (6.3)

2 (0.7)

12 (10.2)

1 (0.8)

5 (3.0)

0

General disorders and administration site-conditions      
   Fatigue

44 (15.3)

3 (1.0)

22 (18.6)

1 (0.8)

16 (9.8)

3 (1.8)

Investigations      
   Alanine-aminotransferase increased

60 (20.8)

21 (7.3)

14 (11.9)

7 (5.9)

14 (8.5)

7 (4.3)

   Aspartate-aminotransferase increased

51 (17.7)

11 (3.8)

7 (5.9)

2 (1.7)

11 (6.7)

3 (1.8)

* CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase
Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
NOTE: Cluster terms used in the analysis are defined below.
Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain
Anaemia includes the following preferred terms: Anaemia, Haemoglobin decreased
Fatigue includes the following preferred terms: Fatigue, Malaise
Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased
Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased
Rash includes the following preferred terms: Rash, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic
Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia

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

Table 2:
Number (%) of CML and Ph+ALL Patients Receiving BOSULIF Reporting Common (≥ 1% to <10%)
Frequencies Adverse Reactions by All Grades and Grades 3 or 4 for the Phase 1/2 Safety Population
 CP* Imatinib Resistant or Intolerant N=288CP* Resistant or Intolerant ≥2 TKIs N=118AP* CML, BP* CML,
Ph+ ALL
Resistant or Intolerant
to at least Imatinib N=164
System Organ Class
Preferred Term
All
Grades
n (%)
Grade 3/4
n (%)
All
Grades
n (%)
Grade
3/4
n (%)
All
Grades
n (%)
Grade
3/4
n (%)

Infections and infestations

      

    Pneumonia

1 (0.3 )

1 (0.3 )

0

0

7 (4.3 )

3 (1.8 )

    Respiratory tract infection

1 (0.3 )

0

2 (1.7 )

0

2 (1.2 )

0

    Influenza

2 (0.7 )

0

2 (1.7 )

0

0

0

Blood and lymphatic system disorders 

Febrile Neutropenia

0

0

1 (0.8)

1 (0.8)

2 (1.2)

1 (0.6)

Immune system disorders

      

Drug hypersensitivity

3 (1.0)

2 (0.7)

4 (3.4)

1 (0.8)

1 (0.6)

0

Metabolism and nutrition disorders

      

    Decreased appetite

28 (9.7)

1 (0.3)

11 (9.3)

1 (0.8)

10 (6.1)

0

    Hypophosphataemia

7 (2.4)

3 (1.0)

3 (2.5)

0

3 (1.8)

2 (1.2)

    Dehydration

2 (0.7)

0

1 (0.8)

0

3 (1.8)

1 (0.6)

    Hyperkalaemia

2 (0.7)

1 (0.3)

3 (2.5)

0

1 (0.6)

0

Nervous system disorders

      

    Dizziness

13 (4.5)

0

6 (5.1)

0

6 (3.7)

0

    Dysgeusia

5 (1.7)

0

2 (1.7)

0

2 (1.2)

0

Cardiac disorders 

    Pericardial effusion

2 (0.7)

1 (0.3)

3 (2.5)

1 (0.8)

4 (2.4)

1 (0.6)

Respiratory, thoracic and mediastinal disorders

      

    Pleural effusion

8 (2.8)

1 (0.3)

9 (7.6)

1 (0.8)

9 (5.5)

5 (3.0)

    Dyspnoea

13 (4.5)

1 (0.3)

6 (5.1)

1 (0.8)

4 (2.4)

1 (0.6)

    Cough

7 (2.4)

0

1 (0.8)

0

2 (1.2)

0

    Respiratory failure

0

0

0

0

2 (1.2)

1 (0.6)

Gastrointestinal disorders

      

  Gastritis

4 (1.4)

0

1 (0.8)

0

4 (2.4)

1 (0.6)

Hepatobiliary disorders

      

    Hepatic function         abnormal

9 (3.1 )

5 (1.7 )

2 (1.7 )

2 (1.7 )

1 (0.6 )

0

    Hepatotoxicity

2 (0.7 )

0

2 (1.7 )

2 (1.7 )

1 (0.6 )

0

Skin and subcutaneous tissue disorders

      

    Acne

6 (2.1)

0

1 (0.8)

0

2 (1.2)

0

    Urticaria

5 (1.7)

0

3 (2.5)

1 (0.8)

1 (0.6)

1 (0.6)

Exfoliative rash

3 (1.0)

0

0

0

1 (0.6)

0

Musculoskeletal and connective tissue disorders

      

    Arthralgia

13 (4.5)

0

7 (5.9)

0

6 (3.7)

0

    Myalgia

9 (3.1)

0

5 (4.2)

1 (0.8)

7 (4.3)

2 (1.2)

    Back pain

3 (1.0)

0

2 (1.7)

0

1 (0.6)

0

Renal and urinary disorders

      

    Renal failure

0

0

1 (0.8)

0

2 (1.2)

0

General disorders and administration site conditions 

    Asthenia

23 (8.0 )

4 (1.4 )

4 (3.4 )

0

10 (6.1 )

0

    Pyrexia

19 (6.6 )

1 (0.3 )

4 (3.4 )

0

9 (5.5 )

2 (1.2 )

    Edema

16 (5.6 )

1 (0.3 )

9 (7.6 )

0

6 (3.7 )

0

    Pain

7 (2.4 )

0

2 (1.7 )

0

1 (0.6 )

0

    Chest pain

5 (1.7 )

0

1 (0.8 )

0

3 (1.8 )

0

Investigations 

    Lipase increased

15 (5.2)

10 (3.5)

7 (5.9)

4 (3.4)

2 (1.2)

1 (0.6)

    Blood creatinine         increased

5 (1.7)

0

7 (5.9)

0

4 (2.4)

0

    Blood bilirubin         increased

7 (2.4)

0

2 (1.7)

1 (0.8)

3 (1.8)

2 (1.2)

    Blood amylase         increased

7 (2.4)

3 (1.0)

4 (3.4)

0

2 (1.2)

1 (0.6)

    Blood creatine         phosphokinase         increased

7 (2.4)

3 (1.0)

1 (0.8)

0

0

0

    Gamma-        glutamyltransferase         increased

5 (1.7)

1 (0.3)

2 (1.7)

1 (0.8)

0

0

* CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase
Classifications of adverse events are based on the Medical Dictionary for Regulatory Activities (MedDRA).
Blood bilirubin increased includes the following preferred terms: Blood bilirubin increased, Hyperbilirubinaemia
Chest pain includes the following preferred terms: Chest discomfort, Chest pain
Edema includes the following preferred terms: Face oedema, Localised oedema, Oedema, Oedema peripheral
Electrocardiogram QT prolonged includes the following preferred terms: Electrocardiogram QT prolonged, Long QT syndrome
Hepatic function abnormal includes the following preferred terms: Hepatic function abnormal, Liver disorder
Hepatotoxicity includes the following preferred terms: Hepatitis toxic, Hepatotoxicity
Lipase increased includes the following preferred terms: Hyperlipasaemia, Lipase increased
Pneumonia includes the following preferred terms: Bronchopneumonia, Pneumonia, Pneumonia primary atypical
Rash includes the following preferred terms: Rash, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic
Respiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection

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. Six (1.1%) 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.

Tabulated Summary of Adverse Reactions

The following adverse reactions in Table 3 were reported in patients in pooled clinical studies with BOSULIF. They represent an evaluation of the adverse reaction data from 1119 patients who received at least 1 dose of single-agent BOSULIF in Ph+ CML, 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).

Table 3:
Adverse Reactions for BOSULIF
Pooled Safety
(Ph+ CML, other Ph+ leukemias, and advanced malignant solid tumors)
N=1119
Note: Preferred Terms shown in parenthesis were grouped to determine a more accurate frequency.

Infections and infestations

Very common                        

respiratory tract infection (including upper respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection, respiratory tract infection viral)

Common

pneumonia (including bronchopneumonia, primary atypical pneumonia),  influenza, bronchitis, nasopharyngitis

Blood and lymphatic system disorders

Very common

thrombocytopenia, anemia, neutropenia

Common

leucopenia

Uncommon

febrile neutropenia, granulocytopenia

Immune system disorders

Common

drug hypersensitivity

Uncommon

anaphylactic shock

Metabolism and nutrition disorders

Very common

decreased appetite

Common

hyperkalemia, hypophosphatemia, dehydration

Nervous system disorders

Very common

headache

Common

dizziness, dysgeusia

Ear and labyrinth disorders

Common

tinnitus

Cardiac disorders

Common

pericardial effusion

Uncommon

pericarditis

Vascular disorders

Common

hypertension (including blood pressure increased, essential hypertension, hypertensive crisis)

Respiratory, thoracic and mediastinal disorders

Very common

dyspnea

Common

pleural effusion

Uncommon

acute pulmonary edema, respiratory failure, pulmonary hypertension

Gastrointestinal disorders

Very common

diarrhea, vomiting, abdominal pain (including upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain), nausea

Common

gastritis, gastrointestinal hemorrhage (including gastric hemorrhage, upper gastrointestinal hemorrhage)

Uncommon

acute pancreatitis

Hepatobiliary disorders

Common

hepatotoxicity (including toxic hepatitis, cytolytic hepatitis), abnormal hepatic function (including liver disorder)

Uncommon

liver injury

Skin and subcutaneous tissue disorders

Very common

rash (including maculopapular rash, pruritic rash, generalized rash, papular rash)

Common

urticaria, pruritus, acne

Uncommon

erythema multiforme, exfoliative rash, drug eruption

Musculoskeletal and connective tissue disorders

Very common

arthralgia

Common

back pain, myalgia

Renal and urinary disorders

Common

acute renal failure, renal failure

Uncommon

renal impairment

General disorders and administration site conditions

Very common

fatigue (including malaise), pyrexia, edema (including face edema, localized edema, peripheral edema)

Common

asthenia, chest pain (including chest discomfort), pain

Investigations

Very common

increased alanine aminotransferase, increased aspartate aminotransferase

Common

increased lipase, increased blood amylase, increased gamma-glutamyltransferase, increased blood creatine phosphokinase, increased blood bilirubin, electrocardiogram QT prolonged, increased blood creatinine

All treatment-emergent adverse events that were reported in BOSULIF pooled clinical studies, regardless of causality and frequency, are listed in Table 4 below.

Table 4:
Adverse Events for BOSULIF
Pooled Safety
(Ph+ CML, other Ph+ leukemias, and advanced malignant solid tumors)
N=1119
SOCs: System Organ Classes based on MedDRA (Medical Dictionary for Regulatory Activities)

Infections and infestations

C. difficile colitis, Hepatitis A, pneumonia fungal, respiratory tract infection fungal, bacteremia, enterococcal sepsis, orchitis, pseudomonal sepsis, septic shock

Neoplasms benign and malignant (including cysts and polyps)

basal cell carcinoma, gastric cancer, keratoacanthoma, non-small lung cancer, squamous cell carcinoma, bladder cancer, malignant melanoma, metastatic neoplasm, rectal cancer recurrent

Metabolism and
nutrition disorders

 
hypogammglobulinaemia, hyperuricemia, hyperlipasemia,
hypermagnesemia, hypokalemia, decreased appetite, hyponatremia, diabetes mellitus, hypocalcemia, tumour lysis syndrome
Psychiatric disordersdissociative disorder, depression, confusional state, mental status changes

Nervous system disorders

cerebral hemorrhage, subarachnoid hemorrhage, hemicephalalgia, syncope, grand mal convulsion, somnolence, encephalopathy, encephalitis post varicella 

Cardiac disordersarterial occlusive disease, angina pectoris, atrial fibrillation, cardiac failure congestive, left ventricular dysfunction, palpitations,         arrhythmia, bradycardia, cardiac tamponade, coronary artery disease, coronary artery  stenosis, dilatation atrial, Long QT syndrome, myocardial infarction, supraventricular extrasystoles

Vascular disorders

hypertension, vasculitis, aortic stenosis, carotid arteriosclerosis, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

interstitial lung disease, pneumonitis, lung infiltration , acute respiratory failure,  pulmonary fibrosis, pulmonary embolism

Gastrointestinal disorders

diarrhea hemorrhagic, duodenal ulcer hemorrhage, sigmoiditis, melaena, rectal hemorrhage, retroperitoneal hemorrhage

Hepatobiliary
disorders

 
hyperbilirubinemia , cholangitis acute, cholelithiasis, cholecystitis

Skin and subcutaneous tissue disorders

erythematous, angioedema, photosensitivity reaction, alopecia, leukocytoclastic vasculitis, circumoral edema

Musculoskeletal and connective tissue

disorders                            

fractures ( including cervical, vertebral, clavicle, facial bones, foot, hand, humerus, rib, tooth, upper limb), spinal column stenosis

Renal and urinary

disorders

calculus bladder, tubulointerstitial nephritis, glomerulonephritis chronic, cystitis hemorrhagic, nephrolithiasis

Reproductive system

disorders

vaginal hemorrhage, breast hyperplasia, cervical dysplasia, vaginal dysplasia

General disorders and administration site conditions

serositis

Investigations

increased total bilirubin, increased blood bilirubin (conjugated), increased blood bilirubin (unconjugated), platelet count decreased, blood lactate dehydrogenase increased, blood phosphorus decreased, pancreatic enzymes increased, weight increased

Hemorrhage

(multiple SOCs)

subdural hemorrhage, cerebral hemorrhage, cerebral infarction, duodenal ulcer hemorrhage, eye hemorrhage, gastrointestinal hemorrhage, operative hemorrhage, pericardial hemorrhage, rectal hemorrhage, retroperitoneal hemorrhage, subarachnoid hemorrhage, vaginal hemorrhage, cerebral hemorrhage

ECG Findings

In the Phase 3 study of newly diagnosed Ph+ CP CML patients, 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.

Abnormal Hematologic and Clinical Chemistry Findings

Table 5 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 5:
Number (%) of Patients with Potential Clinically
Relevant or Severe
Grade 3 / 4 Laboratory Test Abnormalities
in the Phase 1/2 Clinical Study
*CP = Chronic Phase; AP = Accelerated Phase; BP = Blast Phase
 

CP* CML
Imatinib- Resistant or Intolerant 
N=288

n (%)

CP* CML
Resistant or Intolerant ≥2 TKIs
N=118

n (%)

AP* CML, BP* CML, Ph+ ALL
Resistant or
Intolerant to at least Imatinib
N=164

 n (%)

Hematology parameters

  

Platelet Count <50
X 109/L

70 (24.3%)

30 (25.4%)

98 (59.8%)

Absolute
Neutrophil Count
<1 X 109/L

49 (17%)

23 (19.5%)

64 (39%)

Hemoglobin (Low)

<80 g/L

39 (13.5%)

10 (8.5%)

56 (34.1%)

Biochemistry parameters
SGPT/ALT
>5.0 X ULN
30 (10.4%)8 (6.8%)8 (4.9%)
SGOT/AST
>5.0 X ULN
13 (4.5%)4 (3.4%)4 (2.4%)
Lipase
>2 X ULN
24 (8.3%)8 (6.8%)5 (3%)
Phosphorus (Low)
<0.6 mmol/L
25 (8.7%)3 (2.5%)13 (7.9%)
Total Bilirubin (High)
>3xULN
03 (2.5%)3 (1.8%)

Table 6 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 6: On-treatment eGFR Change from Baseline Over Time In Patients in the Phase 1/2 study

Time Point

(months)

Total

(N=569)

eGRF (mL/min/1.73 m2)

Median Change

(90% CI)

Baseline

569

NA

3

429

-5.29 (-6.26, -4.02)

12

290

-7.55 (-8.29, -4.89)

24

210

-8.54 (-10.07, -6.55)

36

185

-10.92 (-12.92, -8.62)

Drug Interactions

Serious Drug and Drug-Food Interactions
  • Potent and moderate CYP3A inhibitors increase BOSULIF exposure. Avoid concomitant use of these inhibitors.
  • Potent and moderate CYP3A inducers decrease BOSULIF exposure. Avoid concomitant use of these inducers.

Overview

In vitro studies with human liver microsomes indicated that the major CYP450 isozyme involved in the metabolism of bosutinib is CYP3A4. No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5. Flavin-containing monooxygenase enzymes (FMO1, FMO3, and FMO5) are capable of metabolizing bosutinib to its N-oxide metabolite.

Drug-Drug Interactions

Drugs That May Increase Bosutinib Plasma Concentrations

CYP3A inhibitors: Avoid the concomitant use of potent CYP3A inhibitors (e.g., including but not limited to ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, troleandomycin, clarithromycin, telithromycin, mibefradil, nefazodone, conivaptan), or moderate CYP3A inhibitors (e.g., including but not limited to fluconazole, darunavir, erythromycin, diltiazem, dronedarone, atazanavir, aprepitant, amprenavir, imatinib, verapamil, grapefruit products including star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4, tofisopam ciprofloxacin, cimetidine) with BOSULIF, as an increase in bosutinib plasma concentration is possible.

Use caution if mild CYP3A inhibitors are used concomitantly with BOSULIF.

Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended.

In a study of 24 healthy subjects in which five daily doses of 400 mg ketoconazole (a potent CYP3A inhibitor) were co-administered with a single dose of 100 mg of BOSULIF, ketoconazole increased BOSULIF Cmax by 5.2 (90% CI: [4.3, 6.2])-fold, and BOSULIF AUC in plasma by 8.6 (90% CI: [7.5, 9.9])-fold, as compared with administration of BOSULIF alone under fasting conditions.

In a study of 20 healthy subjects in which a single dose of 125 mg aprepitant (a moderate CYP3A inhibitor) was co-administered with a single dose of 500 mg BOSULIF, aprepitant increased bosutinib Cmax by 1.5 (90% CI= 1.3 to 1.8)-fold, and bosutinib AUC in plasma by 2.0 (90% CI = 1.7 to 2.4)-fold over a 5-day pharmacokinetic assessment period, as compared with administration of BOSULIF alone under fed conditions.

In vitro transporter studies demonstrated that bosutinib is a substrate for efflux transporters P-gp, BCRP and MRPs. Possible interactions with BOSULIF and concomitant drug efflux transporter substrates may occur.

Drugs That May Decrease Bosutinib Plasma Concentrations

CYP3A Inducers: Avoid the concomitant use of potent CYP3A inducers (e.g., including but not limited to rifampin, phenytoin, carbamazepine, St. John’s wort, rifabutin, phenobarbital), or moderate CYP3A inducers (e.g., including but not limited to bosentan, nafcillin, efavirenz, modafinil, etravirine) with BOSULIF.

Based on the large reduction in bosutinib exposure that occurred when BOSULIF was co-administered with rifampin (potent CYP3A inducer), increasing the dose of BOSULIF when co-administering with potent or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure.

Use caution if mild CYP3A inducers are used concomitantly with BOSULIF.

Following concomitant administration of a single dose of 500 mg of BOSULIF with six daily doses of 600 mg of rifampin in 24 healthy subjects, bosutinib exposure (Cmax and AUC in plasma) decreased to 14% (90%CI: [12.0, 16.0]) and to 6% (90%CI: [5.0, 7.0]), respectively, of the values when 500 mg of BOSULIF was administered alone in the fed state.

Proton Pump Inhibitors: Use caution when administering BOSULIF concomitantly with proton pump inhibitors (PPIs). Short-acting antacids should be considered as an alternative to PPIs, administration times of BOSULIF and antacids should be separated (e.g take BOSULIF in the morning, and antacids in the evening) whenever possible. BOSULIF displays pH-dependent aqueous solubility in vitro. When a single-oral dose of 400 mg of BOSULIF was co-administered with multiple-oral doses of 60 mg of lansoprazole (a PPI) in a study of 24 healthy fasting subjects, bosutinib Cmax and AUC decreased to 54% (90%CI: [42.0, 70.0]) and 74% (90%CI: [60.0, 90.0]), respectively, of the values seen when 400 mg of BOSULIF was given alone.

Drugs That May Have Their Plasma Concentration Altered By Bosutinib

Substrates of P-glycoprotein (P-gp): Caution should be used if BOSULIF is administered with drugs that are substrates of P-glycoprotein (P-gp). An in vitro study suggests that BOSULIF has the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin.

Substrates of CYP: An in vitro study indicates that clinical drug-drug interactions are unlikely to occur as a result of induction by BOSULIF on the metabolism of drugs that are substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4.

In vitro, bosutinib inhibited CYP2C19, CYP2D6, and CYP3A4/5 at concentrations that were 26- to 71-fold higher than the Cmax in humans at 500 mg once daily.

Anti-arrhythmic Medicines and Other Drugs That May Prolong QT:

Concomitant use of BOSULIF with another QT/QTc-prolonging drug is discouraged. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

  • Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide);
  • Class III antiarrhythmics (e.g., amiodarone, sotalol, dronedarone, ibutilide);
  • Class 1C antiarrhythmics (e.g., flecainide, propafenone);
  • antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone);
  • antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline);
  • opioids (e.g., methadone);
  • macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus);
  • quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
  • antimalarials (e.g., quinine, chloroquine);
  • azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
  • domperidone;
  • 5-hydroxytryptamine (5-HT)3 receptor antagonists (e.g., dolasetron, ondansetron);
  • tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib);
  • histone deacetylase inhibitors (e.g., vorinostat);
  • beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol). (See Warnings and Precautions, Cardiovascular, Action and Clinical Pharmacoogy, QT/QTc Prolongation)

The use of BOSULIF* is discouraged with drugs that can disrupt electrolyte levels, including, but not limited to, the following:

  • loop, thiazide, and related diuretics;
  • laxatives and enemas;
  • amphotericin B;
  • high dose corticosteroids.

The above lists of potentially interacting drugs are not comprehensive. Current information sources should be consulted for newly approved drugs that prolong the QT/QTc interval, inhibit metabolizing enzymes and/or transporters, or cause electrolyte disturbances, as well as for older drugs for which these effects have recently been established.

Drug-Food Interactions

Administration of BOSULIF with a meal increased BOSULIF Cmax 1.8- fold and AUC 1.7-fold, respectively at the dose of 400 mg in healthy subjects (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption and Special Populations). BOSULIF taken without a meal may decrease BOSULIF’s bioavailability.

Products and juices containing grapefruit, star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4, should be avoided at any time as they may increase BOSULIF plasma concentrations.

Drug-Herb Interactions

St. John’s Wort is a potent CYP3A4 inducer. Avoid the concomitant use of potent CYP3A inducers with BOSULIF as this may lead to decreased plasma concentrations of BOSULIF (see DRUG INTERACTIONS, Drug-Drug Interaction and DOSAGE AND ADMINISTRATION).

Drug-Lifestyle Interactions

Interactions between BOSULIF and laboratory tests have not been studied.

Drug-Lifestyle Interactions

Effects on ability to drive and use machinery

No studies on the effects of bosutinib on the ability to drive and operate machines have been performed. Patients experiencing dizziness or other undesirable effects with a potential impact on the ability to safely drive or use machines should refrain from these activities as long as these undesirable effects persist (see ADVERSE REACTIONS).

Alcohol

No studies have been performed on the potential interaction between bosutinib and alcohol consumption.

Dosage And Administration

Recommended Dose and Dosage Adjustment

The recommended dose and schedule of BOSULIF is 500 mg orally once daily, swallowed whole, with a meal. Do not take with grapefruit products and star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4 (see DRUG INTERACTIONS, Serious Drug and Drug-Food Interactions). Tablets should not be crushed or cut, and should not be dissolved in a liquid.

In the Phase 1/2 clinical trial, treatment with BOSULIF continued until disease progression or until it was no longer tolerated by the patient.

In the Phase 1/2 clinical trial, dose escalation to 600 mg once daily with food was allowed only in patients who failed to reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, at the recommended starting dosage, and who did not have Grade 3 or higher adverse reactions. Dose escalations are expected to result in greater toxicity.

Dose Adjustments for Non-Hematologic Adverse Reactions

Elevated liver transaminases: If elevations in liver transaminases >5 x institutional upper limit of normal (ULN) occur, BOSULIF should be interrupted until recovery to ≤2.5 x ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of BOSULIF should be considered. If transaminase elevations ≥3 x ULN occur concurrently with bilirubin elevations >2 x ULN and alkaline phosphatase <2 x ULN, BOSULIF should be discontinued.

Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of ≥7 stools/day over baseline/pretreatment), BOSULIF should be interrupted temporarily. Patients with these events should be managed using standard of care treatment, including antidiarrheal medication, and/or fluid replacement. BOSULIF may be resumed at 400 mg once daily upon recovery to grade ≤1.

If other clinically significant moderate or severe non-hematological toxicity develops, BOSULIF should be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If clinically appropriate, re-escalation of the dose to 500 mg once daily may be considered.

Dose Adjustments for Hematologic Adverse Reactions

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described below. Dose interruptions and/or reductions may be needed for hematologic toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 7).

Table 7: Dose Adjustments for Neutropenia and Thrombocytopenia
aAbsolute Neutrophil Count

ANCa <1.0x109/L
 

and/or


Platelets <50x109/L

Hold BOSULIF until ANC ≥1.0x109/L and platelets ≥50x109/L.
 

Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment.
 

If either of these cytopenias recurs, reduce dose by 100 mg upon recovery and resume treatment.
 

Doses less than 300 mg/day have not been evaluated.

Dosing Considerations

Concomitant Use With CYP3A Inhibitors

Avoid the concomitant use of potent or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is possible (see DRUG INTERACTIONS, Serious Drug and Drug-Food Interactions).

Concomitant Use With CYP3A Inducers

Avoid the concomitant use of potent or moderate CYP3A with BOSULIF. Based on the large reduction in bosutinib exposure that occurred when BOSULIF was co-administered with rifampin, increasing the dose of BOSULIF when co-administering with potent or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure (see DRUG INTERACTIONS, Drug-Drug Interactions).

Hepatic Impairment

BOSULIF is contraindicated in patients with hepatic impairment at baseline. (see CONTRAINDICATIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Hepatic Impairment).

Renal Impairment

In patients with moderate renal impairment [creatinine clearance (CrCL) 30 to 50 mL/min, estimated by the Cockroft-Gault formula], the recommended dose of bosutinib is 400 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

In patients with severe renal impairment (CrCL <30 mL/min, estimated by the Cockroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment)

The starting dose recommendation in patients with moderate or severe renal impairment was based on pharmacological modeling; the efficacy and safety of BOSULIF have not been investigated in these patients. Initiate BOSULIF therapy in these patients only when perceived benefits outweigh the potential risks. Patients should be closely monitored for renal function at baseline and during therapy (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

Missed Dose

If a dose is missed, the patient should not take an additional dose but take the usual prescribed dose on the following day.

Administration

For oral use.

Overdosage

Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

BOSULIF belongs to a pharmacologic class of drugs known as tyrosine kinase inhibitors. BOSULIF inhibits the activity of the oncogenic Bcr-Abl kinase that promotes CML, and Src-family of kinases such as Src, Lyn and Hck, which participate in Bcr-Abl signaling. Modeling studies indicate that BOSULIF binds the kinase domain of Bcr-Abl. BOSULIF also inhibits other kinases such as EPH, TEC and STE20 kinases. BOSULIF minimally inhibits PDGF receptor and c-Kit (protein-tyrosine kinase Kit).

BOSULIF exhibits potent anti-leukemic activity in imatinib-sensitive and resistant BCR-ABL-dependent leukemia cells. In in vitro studies, BOSULIF inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells. BOSULIF inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, except T315I. Bosutinib treatment reduced the size of CML tumors growing in nude mice and inhibited growth of murine myeloid tumors expressing imatinib-resistant forms of Bcr-Abl. BOSULIF also inhibits receptor tyrosine kinases c-Fms, EphA and B receptors, Trk-family kinases, Axl-family kinases, Tec-family kinases, some members of the ErbB-family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20-family and two calmodulin-dependent protein kinases.

Pharmacodynamics

QT/QTc Prolongation

The effect of single dose BOSULIF 500 mg administration on corrected QT interval (QTcF=QT/RR0.33) was evaluated in a two part study (Part A & Part B).

Part A was a randomized, double-blind (with respect to bosutinib), 3 period crossover in which healthy male subjects (N=58) received single doses of bosutinib 500 mg, placebo, or moxifloxacin 400 mg in the fed state. The maximum observed QTcF difference from placebo during treatment with bosutinib 500 mg was 2.46 msec (90% CI: [0.54, 4.38]) at 8 h. The results for Part A cannot be extrapolated to steady-state use of bosutinib because the maximal plasma concentrations achieved after the single 500 mg dose (mean Cmax 114±39.8 ng/mL) were only 42-57% of the maximal plasma concentrations observed in the target patient population receiving bosutinib 500 mg at steady-state (mean Cmax 200-273 ng/mL).

Part B was a randomized, double-blind (with respect to bosutinib), 2 period crossover in which healthy male subjects (N=54) were administered a single dose of test article (bosutinib 500 mg or placebo) concomitantly with ketoconazole in the fed state. On day -1, ketoconazole was administered as a single oral 400 mg dose in each period. On day 1, the subjects received bosutinib 500 mg or placebo concomitantly with 400 mg ketoconazole in the fed state. On days 2 and 3, subjects received single oral doses of 400 mg ketoconazole. Part B did not have a placebo only treatment arm or a drug-free baseline. The maximal mean difference in QTcF interval between ketoconazole plus bosutinib and ketoconazole plus placebo was 7.36 msec (90% CI: [5.09, 9.63]) at 8 h on day 1. The mean Cmax achieved after a single 500 mg dose of bosutinib in the presence of ketoconazole was 326±77.2 ng/mL.

Patients with hepatic impairment may be at increased risk of developing QT/QTc prolongation. In a single-oral-dose (200 mg) study in non-CML patients, treatment-emergent QTc prolongation was observed in 50% of hepatically impaired patients (Child-Pugh class A, B or C), versus 11% of matching healthy volunteers; the frequency, magnitude and duration of QTc prolongation appeared to increase with severity of hepatic impairment: all 6 patients with Child-Pugh C at baseline had QTc prolongation following treatment, versus 1/6 and 2/6 of patients of Child-Pugh A and B, respectively. Except for one patient who recorded QTc of 450 msec at day 1 predose, all other Child-Pugh C patients (n=5) had QTc prolongation starting 3 hours post-dose lasted from Day 4 and beyond. The greatest relative QTc increase over baseline was 48 msec in one patient with Child-Pugh C hepatic impairment. However, no QTc > 500 msec was reported for any volunteer in the study.

Pharmacokinetics

Table 8. Summary of BOSULIF’s Pharmacokinetic Parameters in CML Fed Patients at Steady-state after 15 Consecutive Days of 400, 500 and 600 mg Oral Dose
Data are mean (standard deviation) values.
a: n = 7
b: n = 9

Dose

(mg)

N

Cmax

(ng/mL)

t½

(h)

AUC0-24

(ng*h/mL)

Clearance (CL/F)

(L/h)

400

3

146 (20)

46.0 (32.3)

2720 (442)

150 (23)

500

3

200 (12)

21.7 (4.6)

3650 (425)

138 (17)

600

10

208 (73)

25.9 (24.9)a

3630 (1270)b

185 (66)b

Absorption: Absolute bioavailability of BOSULIF has not been established. Following administration of a single oral dose of BOSULIF (500 mg) with food in healthy subjects, absorption was relatively slow, with a median time-to-peak concentration (tmax) reached after 6 hours. The mean standard deviation (SD) Cmax value was 112 (29) ng/mL, and the mean (SD) AUC was 2740 (790) ng•h/mL. Food increased bosutinib Cmax 1.8-fold and bosutinib AUC 1.7-fold compared to the fasting state. After 15 consecutive daily doses of BOSULIF (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng•h/mL.

Bosutinib displays pH-dependent aqueous solubility in vitro. Lansoprazole decreases bosutinib exposure (see Drug-Drug Interactions).

Distribution: After administration of a single dose of BOSULIF (500 mg) with food to healthy subjects, bosutinib had a mean apparent volume of distribution (standard deviation) of 7,700 L (±2,940 L), suggesting that bosutinib is extensively distributed to extra-vascular tissue and/or with low oral bioavailability. In an animal study with rat, bosutinib did not cross the blood-brain barrier.

Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent.

Metabolism: In vitro studies with human liver microsomes indicated that the major CYP450 isozyme involved in the metabolism of bosutinib is CYP3A4. No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5. Flavin-containing monooxygenase enzymes (FMO1, FMO3, and FMO5) are capable of metabolizing bosutinib to its N-oxide metabolite. In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantly hepatic metabolism (by CYP3A4) in humans. Following administration of single or multiple doses of BOSULIF (400 mg or 500 mg) to humans, the major circulating metabolites appeared to be oxydechlorinated (M2) and N-desmethylated (M5) bosutinib, with bosutinib N-oxide (M6) as a minor circulating metabolite. The systemic exposure of N-desmethylated metabolite was 25% of the parent compound, while the oxydechlorinated metabolite was 19% of the parent compound. All three metabolites exhibited activity that was ≤ 5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferation assay. In feces, bosutinib and N-desmethyl bosutinib were the major drug-related components.

Elimination: In healthy subjects given a single-oral dose of BOSULIF (500 mg) with food, the mean (SD) terminal phase elimination half-life (t1/2) was 33.8 (7.7) hours, and the mean (SD) clearance (Cl/F) was 197 (57) L/h. In six healthy male subjects given a single oral dose of [14C] radiolabeled bosutinib, an average of 94.6% of the total administered radioactivity was recovered in 9 days; feces (91.3% of dose) was the major route of excretion, with 3.29% of the dose recovered in urine. Excretion was rapid, with 75% of the dose recovered within 96 hours. Excretion of unchanged bosutinib in urine was low, approximately 1% of the administered dose, in healthy subjects.

Linearity / Non-linearity: Both observed Cmax and AUC values of bosutinib increased with increasing dose in a linear fashion when single, ascending oral doses of 200- to 800 mg bosutinib were administered with food to healthy subjects. At steady state (reached in approximately 15 days), Cmax and AUC values of bosutinib increased in a less than dose proportional manner between 500 and 600 mg taken with food in CML patients in a dose escalation study (see Table 8). The interpretation of bosutinib dose proportionality finding at steady state may be limited by small number of subjects and high interindividual variability. Based on a population pharmacokinetic analysis in cancer patients, bosutinib is predicted to exhibit dose proportional increase over the dose range of 200 -600 mg with food.

OTHER CONSIDERATIONS:

Special Populations and Conditions

Pediatrics (<18 years of age): The safety and efficacy of BOSULIF in patients less than 18 years of age have not been evaluated. No data are available.

Geriatrics (≥ 65 years of age): No clinically relevant age-related pharmacokinetic differences have been observed in the elderly. No specific dose recommendation is necessary in the elderly.

Hepatic Impairment: Metabolism of bosutinib is mainly hepatic. Clinical studies have excluded patients with ALT and/or AST >2.5 (or >5, if related to disease) x ULN range and/or bilirubin >1.5 x ULN range.

In a single-oral-dose study, BOSULIF (200 mg) administered with food was evaluated in a cohort of 18 hepatically impaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of bosutinib in plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C; and bosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t1/2 of bosutinib increased 1.6-fold, 2.0-fold and 2.0-fold and CL/F decreased to 45, 50 and 52% in hepatic impaired patients (subjects (Child-Pugh classes A, B, and C) as compared to the healthy subjects (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Special Populations; DOSAGE AND ADMINISTRATION, Dosing Considerations; ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment: In a dedicated renal impairment trial, a single dose of Bosulif 200 mg was administered with food to 26 non-CML subjects with mild, moderate or severe renal impairment and to 8 matching healthy volunteers. Renal impairment was based on CrCl (calculated by Cockcroft-Gault formula) of <30 mL/min (severe renal impairment), 30 ≤ CrCl ≤50 mL/min (moderate renal impairment), or 50 <CrCl ≤80 mL/min (mild renal impairment). Subjects with moderate and severe renal impairment had an increase in AUC over healthy volunteers of 35 % (90%CI: [-1.0, 85.0]) and 60% (90%CI: [16.0, 121.0]), respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. Based on pharmacokinetic linearity, a daily dose of 400 mg in patients with moderate renal impairment and 300 mg in patients with severe renal impairment are predicted to result in an area under the concentration curve (AUC) that are 108% and 96%, respectively of the AUC seen in patients with normal renal function receiving 500 mg daily. The half-life (57, 55 and 57 hours) of bosutinib in subjects with mild, moderate and severe renal impairment was similar to its half-life (54 hours) in healthy subjects. CL/F values of bosutinib in healthy subjects and in subjects with mild, moderate and severe renal impairment were 3021, 2965, 2238 and 1892 mL/min.

Storage And Stability

Store at 25°C; excursions permitted to 15- 30°C.

Special Handling Instructions

Not Applicable.

Dosage Forms, Composition And Packaging

BOSULIF (bosutinib) 100 mg tablets:
Each 100 mg BOSULIF tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib.
Yellow, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “100” on the other.

Non-medicinal ingredients:
Microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.

BOSULIF (bosutinib) 500 mg tablets:
Each 500 mg BOSULIF tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib.
Red, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “500” on the other.

Non-medicinal ingredients:
Microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.

BOSULIF (bosutinib) tablets are available in the following packaging configurations (Table 9):

Table 9: Tablet Presentations
*White opaque 3-ply Polyvinyl chloride (PVC)/ACLAR/PVC blisters sealed with push-through foil backing

Tablet Strength (mg)

Package Configuration

Tablet Description

100 mg

120 tablets per bottle

Yellow, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “100” on the other.

28 tablets

(2 blister packs* with 14 tablets each)

500 mg

30 tablets per bottle

Red, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “500” on the other

28 tablets

(2 blister packs* with 14 tablets each)

 

Control #: 200815
24 February 2017

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