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BOSULIF ® ( bosutinib ) tablets for oral use

Initial U . S . Approval : 2012 Brief Summary of Prescribing Information

INDICATIONS AND USAGE BOSULIF ® ( bosutinib ) is indicated for the treatment of adult patients with newly diagnosed chronic phase ( CP ) Philadelphia chromosome – positive chronic myelogenous leukemia ( Ph + CML ). This indication is approved under accelerated approval based on molecular and cytogenetic response rates . Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow-up trial . BOSULIF is also indicated for the treatment of adult patients with CP , accelerated phase ( AP ), or blast phase ( BP ) Ph + CML with resistance or intolerance to prior therapy .

CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF . Reactions have included anaphylaxis . In the BOSULIF single-agent cancer studies , anaphylactic shock occurred in less than 0.2 % of treated patients .

WARNINGS AND PRECAUTIONS Gastrointestinal Toxicity : Diarrhea , nausea , vomiting , and abdominal pain occur with BOSULIF treatment . Monitor and manage patients using standards of care , including antidiarrheals , antiemetics , and fluid replacement . In the randomized clinical trial in patients with newly diagnosed Ph + CML , the median time to onset for diarrhea ( all grades ) was 3 days and the median duration per event was 3 days . Among 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy , the median time to onset for diarrhea ( all grades ) was 2 days and the median duration per event was 2 days . Among the patients who experienced diarrhea , the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 ( range 1-268 ). To manage gastrointestinal toxicity , withhold , dose reduce , or discontinue BOSULIF as necessary .

Myelosuppression : Thrombocytopenia , anemia , and neutropenia occur with BOSULIF treatment . Perform complete blood counts weekly for the first month of therapy and then monthly thereafter , or as clinically indicated . To manage myelosuppression , withhold , dose reduce , or discontinue BOSULIF as necessary .

Hepatic Toxicity : BOSULIF may cause elevations in serum transaminases ( alanine aminotransferase [ ALT ], aspartate aminotransferase [ AST ]). One case consistent with drug-induced liver injury ( defined as concurrent elevations in ALT or AST ≥3 x the upper limit of normal ( ULN ) with total bilirubin > 2 x ULN and alkaline phosphatase < 2 x ULN ) occurred without alternative causes in a breast cancer ( a disease for which BOSULIF is not indicated ) trial of BOSULIF in combination with letrozole . The patient recovered fully following discontinuation of BOSULIF . This case represented 1 out of 1611 patients in BOSULIF clinical trials . In the 268 patients from the safety population in the randomized clinical trial in patients with newly diagnosed CML in the BOSULIF treatment group , the incidence of ALT elevation was 31 % and AST elevation was 23 %. 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 . Among the 546 patients in a single-arm study in patients with CML who were resistant or intolerant than 2 x ULN ( 35 / 13.1 vs 16 / 6.0 ); phosphorus ( low ) less than 0.6 mmol / L ( 12 / 4.5 vs 45 / 17.0 ); total bilirubin to prior therapy , the incidence of ALT elevation was 18 % and AST elevation was 15 %. Print-only Twenty percent of content greater than 3.0 x ULN ( 3 / 1.1 vs 2 / 0.8 ); amylase greater than 2 x ULN ( 6 / 2.2 vs 4 / 1.5 ); creatinine greater the patients experienced an increase in either ALT or AST . Most cases of transaminase elevations in this study 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 35 and 33 days , respectively , and the median duration for each was 21 days . Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated . In patients with transaminase elevations , monitor liver enzymes more frequently . Withhold , dose reduce , or discontinue BOSULIF as necessary .

Fluid Retention : Fluid retention occurs with BOSULIF and may manifest as pericardial effusion , pleural effusion , pulmonary edema , and / or peripheral edema . In the randomized clinical trial of 268 patients with newly diagnosed CML in the BOSULIF treatment group , 1 patient ( 0.4 %) experienced severe fluid retention of Grade 3 pericardial effusion . Among 546 patients in a single-arm study in patients with Ph + CML who were resistant or intolerant to prior therapy , Grade 3 or 4 fluid retention was reported in 26 patients ( 5 %). Some patients experienced more than one fluid retention event . Specifically , 21 patients experienced Grade 3 or 4 pleural effusions , 7 patients experienced Grade 3 or Grade 4 pericardial effusions , and 6 patients experienced Grade 3 edema . Monitor and manage patients using standards of care . Interrupt , dose reduce , or discontinue BOSULIF as necessary .

Renal Toxicity : An on-treatment decline in estimated glomerular filtration rate ( eGFR ) has occurred in patients treated with BOSULIF . The following table identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the pooled leukemia studies regardless of line of therapy . The median duration of therapy with BOSULIF was approximately 14 months ( range , 0.03 to 123 ) for patients in these studies .

Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies ( N = 1272 )*

Baseline

Follow-Up

Renal Function Status

N

Normal n (%)

Mild n (%)

Mild to Moderate n (%)

Moderate to Severe n (%)

Severe n (%)

Kidney Failure n (%)

Notes : Grading is based on Modification in Diet in Renal Disease method ( MDRD ). Kidney Disease : Improving Global Outcomes ( KDIGO ) Classification by eGFR : Normal : greater than or equal to 90 , Mild : 60 to less than 90 , Mild to Moderate : 45 to less than 60 , Moderate to Severe : 30 to less than 45 , Severe : 15 to less than 30 , Kidney Failure : less than 15 mL / min / 1.73 m 2 .

* Among the 1272 patients , eGFR was missing in 9 patients at baseline or on-therapy . There were no patients with kidney failure at baseline .

Monitor renal function at baseline and during therapy with BOSULIF , with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction . Consider dose adjustment in patients with baseline and treatment-emergent renal impairment .

Embryofetal Toxicity : Based on findings from animal studies and its mechanism of action , BOSULIF can cause fetal harm when administered to a pregnant woman . In animal reproduction studies conducted in rats and rabbits , oral administration of bosutinib caused adverse developmental outcomes . Administration of bosutinib to rats prior to fertilization until gestation day ( GD ) 7 caused increased embryonic resorptions at maternal exposures ( AUC ) approximately 0.5 and 0.4 times the human exposure at the recommended doses of 400 and 500 mg / day , respectively , and decreased implantations and reduced number of viable embryos at maternal exposures approximately 1.8 and 1.3 times the human exposure at the recommended doses of 400 or 500 mg / day , respectively . Administration of bosutinib to pregnant rabbits during organogenesis caused fetal anomalies ( fused sternebrae , and 2 fetuses had various visceral observations ), and an approximate 6 % decrease in fetal body weight at maternal exposures ( AUC ) approximately 2.3 and 1.7 times the human exposure at the recommended doses of 400 and 500 mg / day , respectively . Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose .

ADVERSE REACTIONS Clinical Trials Experience : Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Serious adverse reactions reported include anaphylactic shock , myelosuppression , gastrointestinal toxicity ( diarrhea ), fluid retention , hepatotoxicity , and rash .

Adverse Reactions in Patients with Newly Diagnosed CP CML : The clinical trial randomized and treated 533 patients with newly diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents ( Newly Diagnosed CP CML Study ). The safety population ( received at least 1 dose of BOSULIF ) included 268 patients with newly diagnosed CP CML that had a median duration of BOSULIF treatment of 14.1 months ( range : 0.3 to 24.7 months ) and a median dose intensity of 391.8 mg / day . Adverse reactions reported for ≥20 % of BOSULIF patients with newly diagnosed CML ( N = 268 ) were diarrhea ( 70 %), nausea ( 35 %), thrombocytopenia ( 35 %), rash ( 34 %), increased ALT ( 31 %), abdominal pain ( 25 %), and increased AST ( 23 %).

Adverse reactions with ≥10 % incidence in patients with newly diagnosed CML who received BOSULIF 400 mg ( N = 268 ) vs imatinib 400 mg ( N = 265 ) ( BOSULIF all grades [%]/ Grade 3-4 [%] vs imatinib ) were diarrhea ( 70 / 8 vs 34 /< 1 ); nausea ( 35 / 0 vs 38 / 0 ); thrombocytopenia a ( 35 / 14 vs 20 / 6 ); rash b ( 34 / 1 vs 21 / 2 ); ALT increased ( 31 / 19 vs 6 / 2 ); abdominal pain c ( 25 / 2 vs 15 /< 1 ); AST increased ( 23 / 10 vs 6 / 2 ); anemia d ( 19 / 3 vs 19 / 5 ); headache ( 19 / 1 vs 13 / 1 ); fatigue e ( 19 /< 1 vs 19 / 0 ); vomiting ( 18 / 1 vs 16 / 0 ); lipase increased f ( 13 / 10 vs 8 / 5 ); pyrexia ( 13 /< 1 vs 8 / 0 ); respiratory tract infection g ( 12 /< 1 vs 12 /< 1 ); neutropenia h ( 11 / 7 vs 21 / 12 ); arthralgia ( 11 /< 1 vs 13 / 0 ); asthenia ( 11 / 0 vs 6 / 0 ); appetite decreased ( 10 /< 1 vs 6 / 0 ).

In the randomized study in patients with newly diagnosed CP CML , one patient in the group treated with BOSULIF experienced a Grade 3 QTc prolongation (> 500 msec ). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol .

Clinically Relevant or Grade 3 / 4 Laboratory Test Abnormalities ( n /%) in Patients with Newly Diagnosed CML Administered BOSULIF 400 mg ( N = 268 ) vs Imatinib 400 mg ( N = 265 ), Safety Population : Hematology parameters were platelet count ( low ) less than 50 x 10 9 / L ( 38 / 14.2 vs 17 / 6.4 ); absolute neutrophil count less than 1 x 10 9 / L ( 24 / 9.0 vs 49 / 18.5 ); hemoglobin ( low ) less than 80 g / L ( 19 / 7.1 vs 15 / 5.7 ); white blood cell count ( low ) less than 2 x 10 9 / L ( 15 / 5.6 vs 20 / 7.5 ). Biochemistry parameters were serum glutamic-pyruvic transaminase ( SGPT )/ ALT greater than 5.0 x ULN ( 62 / 23.1 vs 7 / 2.6 ); serum glutamic-oxaloacetic transaminase ( SGOT )/ AST greater than 5.0 x ULN ( 32 / 11.9 vs 8 / 3.0 ); lipase greater

than 3.0 x baseline ; greater than 3.0 x ULN ( 0 vs 2 / 0.8 ). Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph + CP , AP , and BP CML : The single-arm clinical trial enrolled patients with Ph + CP , AP , or BP CML and with resistance or intolerance to prior therapy . The safety population ( received at least 1 dose of BOSULIF ) included 546 CML patients : 284 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months and a median dose intensity of 442 mg / day ; 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 442 mg / day ; and 143 patients with advanced phase ( AdvP ) CML , including 79 patients with AP CML and 64 patients with BP CML . In the patients with AP CML and BP CML , the median duration of BOSULIF treatment was 10 months and 3 months , respectively . The median dose intensity was 425 mg / day and 456 mg / day in the AP CML and BP CML cohorts , respectively . Adverse reactions of any toxicity grade reported for greater than or equal to 20 % of patients in the safety population of the single-arm trial in patients with CP CML ( N = 546 ) who were resistant or intolerant to prior therapy were diarrhea ( 85 %), nausea ( 47 %), abdominal pain ( 42 %), rash ( 42 %), thrombocytopenia ( 40 %), vomiting ( 37 %), anemia ( 27 %), fatigue ( 26 %), pyrexia ( 23 %), cough ( 22 %), headache ( 21 %), ALT increased ( 20 %), and edema ( 20 %).

Adverse reactions ( all grades [%]/ Grade 3 / 4 [%]) with ≥10 % incidence in patients with CP CML who were resistant or intolerant to prior therapy in the single-arm trial ( N = 403 ) based on a minimum of 48 months of follow-up were diarrhea ( 85 / 9 ), nausea ( 47 / 1 ), abdominal pain c ( 42 / 2 ), rash b ( 42 / 9 ), thrombocytopenia a ( 40 / 26 ), vomiting ( 37 / 3 ), anemia d ( 27 / 11 ), fatigue e ( 26 / 2 ), pyrexia ( 23 /< 1 ), cough ( 22 / 0 ), headache ( 21 /< 1 ), ALT increased ( 20 / 8 ), neutropenia h ( 18 / 12 ), arthralgia ( 17 /< 1 ), AST increased ( 16 / 3 ), edema i ( 20 / 1 ), respiratory tract infection g ( 15 /< 1 ), decreased appetite ( 14 /< 1 ), back pain ( 13 /< 1 ), nasopharyngitis ( 13 / 0 ), asthenia ( 13 / 2 ), pleural effusion ( 12 / 4 ), dyspnea ( 12 / 2 ), pruritus ( 12 /< 1 ), dizziness ( 11 / 0 ), leukopenia j ( 10 / 4 ), blood creatinine increased ( 10 /< 1 ), influenza ( 10 /< 1 ), chest pain k ( 7 / 1 ).

Adverse reactions ( all grades [%]/ Grade 3 / 4 [%]) with ≥10 % incidence in patients with AdvP CML who were resistant or intolerant to prior therapy in the single-arm trial ( N = 143 ) based on a minimum of 48 months of follow-up were diarrhea ( 76 / 4 ), nausea ( 48 / 2 ), abdominal pain c ( 31 / 6 ), rash b ( 38 / 5 ), thrombocytopenia a ( 45 / 39 ), vomiting ( 43 / 3 ), anemia d ( 38 / 27 ), fatigue e ( 21 / 5 ), pyrexia ( 37 / 2 ), cough ( 22 / 0 ), headache ( 17 / 4 ), ALT increased ( 10 / 5 ), neutropenia h ( 22 / 20 ), arthralgia ( 14 / 0 ), AST increased ( 11 / 3 ), edema i ( 17 / 2 ), respiratory tract infection g ( 10 / 0 ), decreased appetite ( 13 / 0 ), back pain ( 8 / 1 ), nasopharyngitis ( 6 / 0 ), asthenia ( 10 /< 1 ), pleural effusion ( 9 / 4 ), dyspnea ( 20 / 6 ), pruritus ( 7 / 0 ), dizziness ( 13 /< 1 ), leukopenia j ( 15 / 12 ), blood creatinine increased ( 6 /< 1 ), influenza ( 3 / 0 ), chest pain k ( 12 / 1 ).