BOSULIF (bosutinib) tablet Warnings And Precautions

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Serious Warnings and Precautions
  • Drug interactions with inhibitors or inducers of CYP3A4. The concomitant use of BOSULIF with strong 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 strong 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 strong 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. Seven (1.2%) of the patients experienced QTcF increases from baseline exceeding 60 ms. Patients with uncontrolled or significant cardiovascular disease, including QT interval prolongation, at baseline were excluded by protocol criteria from the clinical trials (see ADVERSE REACTIONS).

In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, there was 1 patient (0.4%) in the bosutinib treatment group and 0 patients in the imatinib treatment group who experienced corrected QT by the Fridericia method (QTcF) interval of greater than 500 msec.

In a Phase 3 study of newly diagnosed Ph+ CP CML patients treated with bosutinib 500 mg, 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 productsand 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 13.5% of patients in the Phase 1/ 2 study, with Grade 3 or 4 cardiac-related events reported in 5.4% of patients. Pericardial effusion (3.7%), atrial fibrillation (2.5%) (Grade 3 or 4 in 0.9%), cardiac failure congestive (2.3%), and tachycardia (1.8%) were most commonly reported. The following Grade 3 or 4 events of acute myocardial infarction (0.5%), cardiac failure and coronary artery disease (1% of patients each), coronary artery stenosis (0.4%), left ventricular dysfunction (0.4%), and pulmonary edema (0.2%) were reported in the phase 1/2 study. In the Phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, 5.2 % of patients in the BOSULIF arm experienced cardiac events (0. 7% of patients with Grade 3 or 4) versus 5.3% of patients in the imatinib arm ( 1.1% with Grade 3 or 4). Electrocardiogram QT prolonged (1.5%), Atrial fibrillation (1.1%) and Sinus bradycardia (1.5%) were most commonly reported. The following Grade 3 or 4 events of angina (0.4%), atrial fibrillation (0.4%), supraventricular tachycardia (0.4%), coronary artery disease (0.4%), coronary artety occlusion (0.4%), acute coronary syndrome (0.4%) and pericardial effusion (0.4%) were reported.

In a Phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 500 mg, 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 Phase 3 clinical trial of 268 patients with newly-diagnosed CML in the bosutinib treatment group, 1 patient (0.4%) experienced severe fluid retention of Grade 3 pericardial effusion.

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 26 patients (4.9%). Twenty-four patients had a Grade 3 or 4 effusion (22 patients had Grade 3 or 4 pleural effusions [3.8%] and 7  patients [1%] had a Grade 3 or 4 pericardial effusion). Edema TEAEs were reported in 114  (20.0%) subjects, most commonly, edema peripheral in 56 (9.8%) and weight increased in 24 (4.2%) subjects. Eight subjects reported SAEs: pulmonary edema (3 subjects), edema (2  subjects), angioedema, circumoral edema, and edema peripheral (one subject each). One subject died due to pulmonary edema.

In a Phase 3 study in patients newly diagnosed with CP CML treated with BOSULIF 500 mg, 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, 88.4% of patients treated with BOSULIF experienced events of gastrointestinal toxicity. Diarrhea, nausea and vomiting were reported in 82%, 47% and 39% of subjects, respectively. Overall, 8% of patients experienced severe Grade 3 /4 diarrhea and 2.1% of patients had SAEs of diarrhea. The median time of onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days.

In the Phase 3 clinical trial in patients with newly-diagnosed Ph+ CML treated with BOSULIF 400 mg, diarrhea, nausea and vomiting were reported in 70%, 35% and 18% of subjects, respectively. Overall, 8% of patients experienced severe Grade 3 /4 diarrhea and 1.1% of patients had SAEs of diarrhea. The median time to onset for diarrhea (all grades) was 3 days and the median duration per event was 3 days.

In newly diagnosed CML CP patients treated with BOSULIF 500 mg, 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. Myelosuppression events reported in 58% of subjects treated with BOSULIF in the Phase 1 /2 study. The most common treatment-emergent adverse events were thrombocytopenia (41%), anemia (30%) and neutropenia (19%). Myelosuppression events reported in 45.5% of subjects treated with BOSULIF in the Phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg. The most common treatment-emergent adverse events were thrombocytopenia (23.9%), anemia (17.9%), and platelet count decreased (12.3%). 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 22.5% of patients. Thirty two (5.6%) patients had SAEs. Hemorrhage events included duodenal ulcer hemorrhage, eye hemorrhage, gastrointestinal hemorrhage, hematochezia, menorrhagia, operative hemorrhage, pericardial hemorrhage, rectal hemorrhage, retroperitoneal hemorrhage, subarachnoid hemorrhage, vaginal hemorrhage, and cerebral hemorrhage. There were four deaths associated with haemorrhagic events (gastrointestinal hemorrhage, subarachnoid hemorrhage, intraventricular hemorrhage and cerebral hemorrhage in one subject each). In the phase 3 study, treatment-emergent adverse events of any severity grade related to bleeding events were commonly reported in 15.3% of patients. Four patients (1.5%) patients had SAEs (uterine hemorrhage, post procedural hemorrhage, hematuria, and implant site hematoma) none of which were fatal.

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 (alanine aminotransferase [ALT ], aspartate aminotransferase [AST ]).

In the 268 patients from the safety population in the Phase 3 clinical trial in patients with newly-diagnosed CML in the bosutinib treatment group, the incidence of ALT elevation was 31% and AST elevation was 23%. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, 79% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 32 and 43 days, respectively, and the median duration was 20 and 15 days, respectively.

In the 570 patients from the safety population from the single arm phase 1/2 study, adverse events associated with liver function were reported in 146 (25.6%) patients overall. 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 21 days. Eighteen (3.2%) patients discontinued BOSULIF due to liver function-related events.

In clinical studies with patient with cancer, 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 breast cancer 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 (4.9%) and amylase (1.2%) and Grade 3 or 4 acute pancreatitis (0.8%) 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). In the phase 3 study, Grade 3 or 4 elevation in serum lipase (9.7%) and amylase (1.5%) and Grade 3 or 4 acute pancreatitis (0.4%) has been observed with BOSULIF.

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 0.7% of subjects in the Phase 1/2 study had Grade 3 or 4 cellulitis. BOSULIF may predispose patients who are immunocompromised or older patients to bacterial, fungal, viral or protozoan infections. In the Phase 1/2 study, 53% of patients had events of infection (13.5% Grade 3/4). Eighty (14.0%) patients had SAEs, some of which were fatal. Seven patients died due to infection events, 4 patients died due to pneumonia and 1 patient each died due to fungal infection, bacteremia, sepsis.

In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, infection was reported less frequently in the bosutinib arm (44.4%) than in the imatinib arm (47.2%). 0.4% of subjects had Grade 3 or 4 cellulitis. Nine patients had Grade 3 or 4 infection (3.4%) and thirteen (4.9%) patients had SAEs, none of which were fatal.

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%).

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 in the phase 1/2 clinical study only. In the phase 3 study in patients newly diagnosed with CP CML, hypersensitivity events were reported in 5 patients (1.9%) in the bosutinib arm, of which none were serious.

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). In a rat pre- and postnatal development study, there were reduced number of pups born, decreased postnatal survival (including increased incidence of total litter loss), and decreased growth of offspring after birth (see TOXICOLOGY, Developmental Toxicity). 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 and for at least 1 month after the final dose. 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. In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, there was 1 patient (0.4%) with Grade 3 tumour lysis syndrome. 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 in newly diagnosed CML CP patients treated with BOSULIF 500 mg, 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.

In the Phase 3 study in newly diagnosed CML CP patients treated with BOSULIF 400 mg, the frequency of fractures (including hand, foot, ankle, radius, rib, spinal and tooth) was 2.8% in the BOSULIF arm with each event reported once. There were no reports of Grade 3 or 4 fractures.

In addition, hypophosphataemia (including blood phosphorus decreased) was reported in 6 patients (2.3%) treated with BOSULIF and 17 patients (6.4%) treated with imatinib.

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. Renal TEAEs were reported in 76 (13.3%) patients, most common events were blood creatinine increased in 8.8% of patients and renal failure in 3.0% of patients. Thirteen (2.3%) patients had SAEs and 1 patient died due to acute kidney injury. 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. In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, Renal TEAEs were reported in 19 (7.1%) patients, most common events were blood creatinine increased in 5.6%, acute kidney injury in 0.7 % and Renal Impairment in 0.7%.

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 serious respiratory disorders including dyspnoea, pleural effusion, respiratory failure, acute pulmonary edema, pulmonary hypertension, pneumonitis, and interstitial lung disease. In the phase 3 study in patients newly diagnosed with CP CML treated with bosutinib 400 mg, respiratory disorders were reported in 67 (25%) patients with the following Grade 3 or 4 events dyspnoea (0.4%), pneumothorax (0.4%) and respiratory failure (0.4%).

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): The type and frequency of TEAEs of was generally similar between younger (<65 years) vs. older (> 65 years) subjects. The overall frequency of AEs leading to discontinuation was higher in older subjects, however the type of AEs leading to discontinuation was similar.

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 (8.2%) 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).