ASH Clinical News March 2017 | Seite 4

BOSULIF ® ( bosutinib ) tablets for oral use

Initial U . S . Approval : 2012

Brief summary of Prescribing Information

INDICATIONS AND USAGE

BOSULIF is indicated for the treatment of adult patients with chronic , accelerated , or blast phase Philadelphia chromosome – positive ( Ph +) chronic myelogenous leukemia ( CML ) with resistance or intolerance to prior therapy .

DOSAGE AND ADMINISTRATION

Recommended Dosing : The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food . Continue treatment with BOSULIF until disease progression or patient intolerance . If a dose is missed beyond 12 hours , the patient should skip the dose and take the usual prescribed dose on the following day . Dose Escalation : Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response ( CHR ) by week 8 or a complete cytogenetic response ( CCyR ) by week 12 , who did not have Grade 3 or higher adverse reactions , and who are currently taking 500 mg daily . Dose Adjustments for Non-Hematologic Adverse Reactions : Elevated liver transaminases : If elevations in liver transaminases greater than 5 x institutional upper limit of normal ( ULN ) occur , withhold BOSULIF until recovery to less than or equal to 2.5 x ULN and resume at 400 mg once daily thereafter . If recovery takes longer than 4 weeks , discontinue BOSULIF . If transaminase elevations greater than or equal to 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN and alkaline phosphatase less than 2 x ULN ( Hy ’ s law case definition ), discontinue BOSULIF . Diarrhea : For NCI CTCAE Grade 3-4 diarrhea ( increase of greater than or equal to 7 stools / day over baseline / pretreatment ), withhold BOSULIF until recovery to Grade less than or equal to 1 . BOSULIF may be resumed at 400 mg once daily . For other clinically significant , moderate or severe non-hematological toxicity : Withhold BOSULIF until the toxicity has resolved , then consider resuming BOSULIF at 400 mg once daily . If clinically appropriate , consider re-escalating the dose of BOSULIF to 500 mg once daily . Dose Adjustments for Myelosuppression : Dose reductions for severe or persistent neutropenia and thrombocytopenia are as follows : If absolute neutrophil count ( ANC ) is less than 1000x10 6 / L or platelets are less than 50,000x10 6 / L : Withhold BOSULIF until ANC is greater than or equal to 1000x10 6 / L and platelets are greater than or equal to 50,000x10 6 / L . Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks . If blood counts remain low for greater than 2 weeks , upon recovery , reduce dose by 100 mg and resume treatment . If cytopenia recurs , reduce the dose by an additional 100 mg upon recovery and resume treatment . Doses less than 300 mg / day have not been evaluated . Concomitant Use With CYP3A Inhibitors : Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected ( strong CYP3A inhibitors include boceprevir , clarithromycin , conivaptan , indinavir , itraconazole , ketoconazole , lopinavir / ritonavir , mibefradil , nefazodone , nelfinavir , posaconazole , ritonavir , saquinavir , telaprevir , telithromycin , and voriconazole . Moderate CYP3A inhibitors include amprenavir , aprepitant , atazanavir , ciprofloxacin , crizotinib , darunavir / ritonavir , diltiazem , erythromycin , fluconazole , fosamprenavir , grapefruit products , imatinib , and verapamil ). Concomitant Use With CYP3A Inducers : Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected ( strong CYP3A inducers include carbamazepine , phenytoin , rifampin , and St . John ’ s Wort . Moderate CYP3A inducers include bosentan , efavirenz , etravirine , modafinil , and nafcillin ). Hepatic Impairment : In patients with mild ( Child-Pugh A ), moderate ( Child-Pugh B ), or severe ( Child-Pugh C ) hepatic impairment , the recommended dose of BOSULIF is 200 mg daily . Renal Impairment : If creatinine clearance ( CrCL ) is 30 to 50 mL / min , the recommended starting dose of BOSULIF is 400 mg daily . If CrCL is < 30 mL / min , the recommended starting dose of BOSULIF is 300 mg daily .

CONTRAINDICATIONS

History of hypersensitivity to BOSULIF . Reactions have included anaphylaxis . Anaphylactic shock occurred in less than 0.2 % of treated patients in clinical trials .

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 single-arm Phase 1 / 2 clinical trial , the median time to onset for diarrhea ( all grades ) was 2 days and the median duration per event was 1 day . Among the patients who experienced diarrhea , the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 ( range 1-221 ). 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 : One case consistent with 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 . This case represented 1 out of 1209 patients in BOSULIF clinical trials . In the 546 patients from the safety population , the incidence of ALT elevation was 17 % and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST . 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 30 and 33 days , respectively , and the median duration for each was 21 days . Perform hepatic enzyme tests monthly for the first three 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 single-arm , Phase 1 / 2 clinical trial in 546 patients with CML treated with prior therapy , severe fluid retention was reported in 14 patients ( 3 %). Specifically , 9 patients had a Grade 3 or 4 pleural effusion , 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions , 1 patient experienced Grade 3 peripheral and pulmonary edema , and 1 patient had a 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 table identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the global Ph + Leukemia studies . The median duration of therapy with BOSULIF was approximately 17 months ( range , 0.03 to 95 ) for patients in these studies .

Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies ( n = 818 )*

Baseline

Follow Up

Renal Function Status n Normal Mild

Mild to Moderate n (%) n (%) Moderate to Severe

Severe n (%) n (%) n (%)

Normal 274 53 ( 19 ) 174 ( 64 ) 30 ( 11 ) 14 ( 5 ) 1 (< 1 ) 1 (< 1 ) Mild 438 10 ( 2 ) 170 ( 39 ) 177 ( 40 ) 63 ( 14 ) 14 ( 3 ) 2 ( 1 ) Mild to Moderate 79 0 4 ( 5 ) 28 ( 35 ) 37 ( 47 ) 10 ( 13 ) 0 Moderate to Severe 24 0 1 ( 4 ) 1 ( 4 ) 6 ( 25 ) 15 ( 63 ) 1 ( 4 ) Severe 1 0 0 0 0 0 1 ( 100 ) Total 816 63 ( 8 ) 349 ( 43 ) 236 ( 29 ) 120 ( 15 ) 40 ( 5 ) 5 ( 1 )

Notes : Grading is based on Modification in Diet in Renal Disease method ( MDRD ). 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 818 patients , eGFR was missing in 5 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 : There are no adequate and well controlled studies of BOSULIF in pregnant women . BOSULIF can cause fetal harm when administered to a pregnant woman . Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg / day . Females of reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF . If this drug is used during pregnancy , or if the patient becomes pregnant while taking this drug , the patient should be apprised of the potential hazard to the fetus .

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 of any toxicity grade reported for greater than 20 % of patients in the Phase 1 / 2 safety population ( n = 546 ) were diarrhea ( 82 %), nausea ( 46 %), thrombocytopenia ( 41 %), vomiting ( 39 %), abdominal pain ( 37 %), rash ( 35 %), anemia ( 27 %), pyrexia ( 26 %), and fatigue ( 24 %). Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph + Chronic Phase ( CP ), Accelerated Phase ( AP ), and Blast Phase ( BP ) CML : The single-arm , Phase 1 / 2 clinical trial enrolled patients with Ph + chronic , accelerated , or blast phase chronic myelogenous leukemia ( CML ) with resistance or intolerance to prior therapy . The safety population ( received at least 1 dose of BOSULIF ) included 546 CML patients . Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months and a median dose intensity of 484 mg / day ; 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg / day ; and 140 patients with advanced phase CML , including 76 patients with AP CML and 64 patients with BP CML . In the patients with AP CML and BP CML , the median duration of BOSULIF treatment was 10 months and 3 months , respectively . The median dose intensity was 483 mg / day and 500 mg / day in the AP CML and BP CML cohorts , respectively .

Adverse Reactions ( 10 % or Greater ) in Patients with CML in Study 1

All Grades (%)

Chronic Phase CML N = 406

Grade 3 / 4 (%)

Advanced Phase CML N = 140

All Grades (%)

Kidney Failure n (%)

Grade 3 / 4 (%)