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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 ). 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 .

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 4 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 ]). Two cases 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 ) have occurred without alternative causes . This represented 2 out of 1711 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 68 % and AST elevation was 56 %. Of patients who experienced transaminase elevations of any grade , 73 % experienced their first event within the first 3 months . The median time to onset of increased ALT and AST was 29 and 56 days , respectively , and the median duration was 19 and 15 days , respectively . Among the 546 patients in a singlearm study in patients with CML who were resistant or intolerant to prior therapy , the incidence of ALT elevation was 53 % and AST elevation was 47 %. Sixty percent of 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 81 % experienced their first event within the first 3 months . The median time to onset of increased ALT and AST was 22 and 29 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 .

Cardiovascular Toxicity : BOSULIF can cause cardiovascular toxicity , including cardiac failure , left ventricular dysfunction , and cardiac ischemic events . Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors , including previous medical history of cardiac failure . Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors , including history of diabetes , body mass index greater than 30 , hypertension , and vascular disorders . In a randomized study with newly diagnosed CML , cardiac failure occurred in 1.9 % of patients treated with BOSULIF compared to 0.8 % of patients treated with imatinib . Cardiac ischemic events occurred in 4.9 % of patients treated with BOSULIF compared to 0.8 % of patients treated with imatinib . In a single-arm study in patients with CML who were resistant or intolerant to prior therapy , cardiac failure was observed in 5.3 % of patients and cardiac ischemic events were observed in 4.9 % of patients treated with BOSULIF . Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated . Interrupt , 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 , 3 patients ( 1.1 %) experienced severe fluid retention of Grade 3 , 1 patient experienced Grade 3 pericardial effusion , and 2 patients experienced Grade 3 pleural 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 30 patients ( 6 %). Some patients experienced more than one fluid retention event . Specifically , 24 patients experienced Grade 3 or 4 pleural effusions , 9 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 24 months ( range , 0.03 to 155 ) for patients in these studies .

Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies ( N = 1372 )*

Baseline Follow-Up

Renal Function Status

N

Normal n (%)

Mild n (%)

Mild to Moderate n (%)

Moderate to Severe n (%)

Severe n (%)

Kidney Failure n (%)

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 .

Embryo-Fetal Toxicity : Based on findings from animal studies and its mechanism of action , BOSULIF can cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drug-associated risk . In animal reproduction studies conducted in rats and rabbits , oral administration of bosutinib during organogenesis caused adverse developmental outcomes , including structural abnormalities , embryo-fetal mortality , and alterations to growth at maternal exposures ( AUC ) as low as 1.2 times the human exposure at the dose of 500 mg / day . 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 2 weeks 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 . The most common adverse reactions in ≥20 % of patients with newly diagnosed CP Ph + CML or CP , AP , or BP Ph + CML with resistance or intolerance to prior therapy ( N = 814 ) were diarrhea ( 80 %), rash ( 44 %), nausea ( 44 %), abdominal pain ( 43 %), vomiting ( 33 %), fatigue ( 33 %), hepatic dysfunction ( 33 %), respiratory tract infection ( 25 %), pyrexia ( 24 %), and headache ( 21 %). The most common laboratory abnormalities that worsened from baseline in ≥20 % of patients were creatinine increased ( 93 %), hemoglobin decreased ( 90 %), lymphocyte count decreased ( 72 %), platelets decreased ( 69 %), ALT increased ( 58 %), calcium decreased ( 53 %), white blood cell count decreased ( 52 %), absolute neutrophil count decreased ( 50 %), AST increased ( 50 %), glucose increased ( 46 %), phosphorus decreased ( 44 %), urate increased ( 41 %), alkaline phosphatase increased ( 40 %), lipase increased ( 36 %), creatine kinase increased ( 29 %), and amylase increased ( 24 %).

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 55 months ( range : 0.3 to 60 months ) and a median dose intensity of 394 mg / day . Serious adverse reactions occurred in 22 % of patients with newly diagnosed CP CML who received bosutinib . Serious adverse reactions reported in > 2 % of patients included hepatic dysfunction ( 4.1 %), pneumonia ( 3.4 %), coronary artery disease ( 3.4 %), and gastroenteritis ( 2.2 %). Fatal adverse reactions occurred in 3 patients ( 1.1 %) due to coronary artery disease ( 0.4 %), cardiac failure acute ( 0.4 %), and renal failure ( 0.4 %). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20 % of patients with newly diagnosed CP CML who received bosutinib . Adverse reactions which resulted in permanent discontinuation in > 2 % of patients included hepatic dysfunction ( 9 %). Dose modifications ( dose interruption or reductions ) of bosutinib due to an adverse reaction occurred in 68 % of patients with newly diagnosed CP CML . Adverse reactions which required dose interruptions or reductions in > 5 % of patients included hepatic dysfunction ( 27 %), thrombocytopenia ( 16 %), diarrhea ( 16 %), lipase increased ( 10 %), neutropenia ( 7 %), abdominal pain ( 6 %), rash ( 5 %).

The most common adverse reactions , in > 20 % of bosutinib-treated patients with newly diagnosed CML ( N = 268 ) were diarrhea ( 75 %), hepatic dysfunction ( 45 %), rash ( 40 %), abdominal pain ( 39 %), nausea ( 37 %), fatigue ( 33 %), respiratory tract infection ( 27 %), headache ( 22 %), and vomiting ( 21 %). The most common laboratory abnormalities that worsened from baseline in ≥20 % of patients were creatinine increased ( 94 %), hemoglobin decreased ( 89 %), lymphocyte count decreased ( 84 %), ALT increased ( 68 %), platelet count decreased ( 68 %), glucose increased ( 57 %), AST increased ( 56 %), calcium decreased ( 55 %), phosphorus decreased ( 54 %), lipase increased ( 53 %), white blood cell count decreased ( 50 %), absolute neutrophil count decreased ( 42 %), alkaline phosphatase increased ( 41 %), creatine kinase increased ( 36 %), and amylase increased ( 32 %).

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 ( 75 / 9 vs 40 / 1 ); hepatic dysfunction ^a ( 45 / 27 vs 15 / 4 ); rash ^b ( 40 / 2 vs 30 / 2 ); abdominal pain ^c ( 39 / 2 vs 27 / 1 ); nausea ( 37 / 0 vs 42 / 0 ); fatigue ^d ( 33 / 1 vs 30 /< 1 ); respiratory tract infection ^e ( 27 / 1 vs 25 /< 1 ); headache ( 22 / 1 vs 15 / 1 ); vomiting ( 21 / 1 vs 20 / 0 ); arthralgia ( 18 / 1 vs 18 /< 1 ); pyrexia ( 17 / 1 vs 11 / 0 ); edema ^f ( 15 / 0 vs 46 / 2 ); constipation ( 13 / 0 vs 6 / 0 ); back pain ( 12 /< 1 vs 9 /< 1 ); pruritus ( 11 /< 1 vs 4 / 0 ); cough ( 11 / 0 vs 10 / 0 ); dyspnea ( 11 / 1 vs 6 / 1 ); decreased appetite ( 11 /< 1 vs 6 / 0 ); hypertension ^g ( 10 / 5 vs 11 / 5 ).

a

Hepatic dysfunction includes the preferred terms : Alanine aminotransferase increased , Aspartate aminotransferase , Aspartate aminotransferase increased , Bilirubin conjugated increased , Blood alkaline phosphatase increased , Blood bilirubin increased , Drug-induced liver injury , Gamma-glutamyltransferase increased , Hepatic enzyme increased , Hepatic steatosis , Hepatitis , Hepatitis toxic , Hepatocellular injury , Hepatotoxicity , Hyperbilirubinemia , Jaundice , Liver disorder , Liver function test increased , Ocular icterus , Transaminases increased . b

Rash includes the following preferred terms : Acne , Blister , Dermatitis , Dermatitis acneiform , Dermatitis bullous , Dermatitis exfoliative generalized , Drug reaction with eosinophilia and systemic symptoms , Dyshidrotic eczema , Eczema , Eczema asteatotic , Erythema , Erythema nodosum , Genital rash , Lichen planus , Perivascular dermatitis , Photosensitivity reaction , Psoriasis , Rash , Rash erythematous , Rash macular , Rash maculopapular , Rash papular , Rash pruritic , Rash pustular , Rash vesicular , Seborrheic keratosis , Skin discoloration , Skin exfoliation , Skin hypopigmentation , Skin irritation , Skin lesion , Stasis dermatitis . c

Abdominal pain includes the following preferred terms : Abdominal discomfort , Abdominal pain , Abdominal pain lower , Abdominal pain upper , Abdominal tenderness , Dyspepsia , Epigastric discomfort , Gastrointestinal pain .

d

Fatigue includes the following preferred terms : Asthenia , Fatigue , Malaise . e

Respiratory tract infection includes the following preferred terms : Nasopharyngitis , Respiratory tract congestion , Respiratory tract infection , Respiratory tract infection viral , Upper respiratory tract infection . f

Edema includes the following preferred terms : Eye edema , Eyelid edema , Face edema , Edema , Edema peripheral , Orbital edema , Periorbital edema , Periorbital swelling , Peripheral swelling , Swelling , Swelling face , Swelling of eyelid , Swollen tongue .

g

Hypertension includes the preferred terms : Blood pressure systolic increased , Hypertension , Hypertensive crisis , Hypertensive heart disease , Retinopathy hypertensive .

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

Laboratory Abnormalities ≥20 % That Worsened From Baseline in Patients With Newly Diagnosed CML in the BOSULIF 400 mg Study Based on a Minimum of 57 Months of Follow-Up ( bosutinib [ all grades / grade 3 / 4 ] vs imatinib [ all grades / grade 3 / 4 ]): Hematology parameters were platelet count decreased ( 68 / 14 vs 60 / 6 ); absolute neutrophil count decreased ( 42 / 9 vs 65 / 20 ); hemoglobin decreased ( 89 / 9 vs 90 / 7 ); white blood cell count decreased ( 50 / 6 vs 70 / 8 ); lymphocyte count decreased ( 84 / 12 vs 82 / 14 ). Biochemistry parameters were serum glutamic-pyruvic transaminase ( SGPT )/ ALT increased ( 68 / 26 vs 28 / 3 ); serum glutamic-oxaloacetic transaminase ( SGOT )/ AST increased ( 56 / 13 vs 29 / 3.4 ); lipase increased ( 53 / 19 vs 35 / 8 ); phosphorus decreased ( 54 / 9 vs 69 / 21 ); amylase increased ( 32 / 3.4 vs 18 / 2.3 ); alkaline phosphatase increased ( 41 / 0 vs 43 / 0.4 ); calcium decreased ( 55 / 1.5 vs 57 / 1.1 ); glucose increased ( 57 / 3 vs 65 / 3.4 ); creatine kinase increased ( 36 / 3 vs 65 / 5 ); creatinine increased ( 94 / 1.1 vs 98 / 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 ( range : 0.2 to 155 months ), and a median dose intensity of 437 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 ( range : 0.2 to 148 months ) and a median dose intensity of 427 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 ( range : 0.1 to 140 months ) and 3 months ( range : 0.03 to 71 months ), respectively . The median dose intensity was 406 mg / day and 456 mg / day in the AP CML and BP CML cohorts , respectively . Serious adverse reactions occurred in 30 % of patients in the safety population of the single-arm trial in patients with CML ( N = 546 ) who were resistant or intolerant to prior therapy . Serious adverse reactions reported in > 2 % of patients included pneumonia ( 7 %), pleural effusion ( 6 %), pyrexia ( 3.7 %), coronary artery disease ( 3.5 %), dyspnea ( 2.6 %), rash ( 2.2 %), thrombocytopenia ( 2 %), abdominal pain ( 2 %), and diarrhea ( 2 %). Fatal adverse reactions occurred in 12 patients ( 2.2 %) due to coronary artery disease ( 0.9 %), pneumonia ( 0.4 %), respiratory failure ( 0.4 %), gastrointestinal hemorrhage ( 0.2 %), acute kidney injury ( 0.2 %), and acute pulmonary edema ( 0.2 %).