ASH Clinical News March 2017 | Page 5

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

All Grades (%)

Chronic Phase CML N = 406

Grade 3 / 4 (%)

Advanced Phase CML N = 140

All Grades (%)

Grade 3 / 4 (%)

Back pain 12 1 7 1 Asthenia 11 1 10 1 Pruritus 11 1 8 0 Dizziness 10 0 13 1 Dyspnea 10 1 19 6

Advanced phase ( AdvP ) CML includes patients with accelerated phase and blast phase CML

a . Abdominal pain includes the following preferred terms : abdominal pain , upper abdominal pain , lower abdominal pain , abdominal tenderness , gastrointestinal pain , abdominal discomfort

b . Rash includes the following preferred terms : rash , macular rash , pruritic rash , generalized rash , papular rash , maculo-papular rash

c . Fatigue includes the following preferred terms : fatigue , malaise d . Edema includes the following preferred terms : edema , peripheral edema , localized edema , face edema

e . Respiratory tract infection includes the following preferred terms : respiratory tract infection , upper respiratory tract infection , lower respiratory tract infection , viral upper respiratory tract infection , viral respiratory tract infection

In the single-arm , Phase 1 / 2 clinical trial , one patient ( 0.2 %) experienced QTcF interval of greater than 500 ms . Patients with uncontrolled or significant cardiovascular disease , including QT interval prolongation , were excluded by protocol .

Additional Adverse Reactions from Multiple Clinical Trials :

The following adverse reactions were reported in patients in clinical trials with BOSULIF ( less than 10 % of BOSULIF-treated patients ). They represent an evaluation of the adverse reaction data from 870 patients with Ph + leukemia who received at least 1 dose of single-agent BOSULIF . These adverse reactions are presented by system organ class and are ranked by frequency . These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category .

Blood and Lymphatic System Disorders : 1 % and less than 10 % - febrile neutropenia Cardiac Disorders : 1 % and less than 10 % - pericardial effusion ; 0.1 % and less than 1 % - pericarditis Ear and Labyrinth Disorders : 1 % and less than 10 % - tinnitus Gastrointestinal Disorders : 1 % and less than 10 % - gastritis ; 0.1 % and less than 1 % - acute pancreatitis , gastrointestinal hemorrhage a General Disorders and Administrative Site Conditions : 1 % and less than 10 % - chest pain , b pain Hepatobiliary Disorders : 1 % and less than 10 % - hepatotoxicity , c abnormal hepatic function d ; 0.1 % and less than 1 % - liver injury Immune System Disorders : 1 % and less than 10 % - drug hypersensitivity ; 0.1 % and less than 1 % - anaphylactic shock Infections and Infestations : 1 % and less than 10 % - pneumonia , e influenza , bronchitis Investigations : 1 % and less than 10 % - electrocardiogram QT prolonged , increased blood creatine phosphokinase , increased blood creatinine Metabolism and Nutrition Disorder : 1 % and less than 10 % - hyperkalemia , dehydration Musculoskeletal and Connective Tissue Disorder : 1 % and less than 10 % - myalgia Nervous System Disorders : 1 % and less than 10 % - dysgeusia Renal and Urinary Disorders : 1 % and less than 10 % - acute renal failure , renal failure Respiratory , Thoracic , and Mediastinal Disorders : 1 % and less than 10 % - pleural effusion ; 0.1 % and less than 1 % - acute pulmonary edema , respiratory failure , pulmonary hypertension Skin and Subcutaneous Disorders : 1 % and less than 10 % - urticaria , pruritus , acne ; 0.1 % and less than 1 % - erythema multiforme , exfoliative rash , drug eruption

a . Gastrointestinal hemorrhage includes the following preferred terms : gastrointestinal hemorrhage , gastric hemorrhage , upper gastrointestinal hemorrhage b . Chest pain includes the following preferred terms : chest pain , chest discomfort c . Hepatotoxicity includes the following preferred terms : hepatotoxicity , toxic hepatitis , cytolytic hepatitis d . Abnormal hepatic function includes the following preferred terms : abnormal hepatic function , liver disorder e . Pneumonia includes the following preferred terms : pneumonia , bronchopneumonia , lobar pneumonia , primary atypical pneumonia

DRUG INTERACTIONS

Drugs That May Increase Bosutinib Plasma Concentrations : CYP3A inhibitors : Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected . In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant ketoconazole ( strong CYP3A inhibitor ) increased bosutinib C max 5.2-fold and AUC 8.6-fold compared to BOSULIF alone . Drugs That May Decrease Bosutinib Plasma Concentrations : CYP3A Inducers : Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected . In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant rifampin ( strong CYP3A inducer ) decreased bosutinib C max by 86 % and AUC by 94 % compared to BOSULIF alone . Proton Pump Inhibitors : In a dedicated cross-over drug-interaction trial in healthy volunteers ( N = 24 ), concomitant lansoprazole ( PPI ) decreased bosutinib C max by 46 % and AUC by 26 % compared to BOSULIF alone . Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure . Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours .

USE IN SPECIFIC POPULATIONS

Pregnancy Category D : Based on its mechanism of action and findings in animals , BOSULIF can cause fetal harm when administered to a pregnant woman . Studies in animals showed reproductive toxicities . If BOSULIF is used during pregnancy , or if the patient becomes pregnant while taking BOSULIF , the patient should be apprised of the potential hazard to the fetus . Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats . Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1 , 3 , and 10 mg / kg / day . This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes . In a study conducted in rabbits , bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3 , 10 , and 30 mg / kg / day . At the maternally-toxic dose of 30 mg / kg / day of bosutinib , there were fetal anomalies ( fused sternebrae , and two fetuses had various visceral observations ), and an approximate 6 % decrease in fetal body weight . The dose of 30 mg / kg / day resulted in exposures ( AUC ) approximately 4 times those in humans at the 500 mg / day dose of bosutinib . Nursing Mothers : It is not known whether bosutinib is excreted in human milk . Bosutinib and / or its metabolites were excreted in the milk of lactating rats . Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF , a decision should be made whether to discontinue nursing or to discontinue the drug , taking into account the importance of the drug to the mother . Pediatric Use : The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established . Geriatric Use : In the Phase 1 / 2 clinical trial of BOSULIF in patients with Ph + CML , 20 % were age 65 and over , and 4 % were 75 and over . No overall differences in safety or effectiveness were observed between these patients and younger patients , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out . Hepatic Impairment : Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment . In a dedicated hepatic impairment trial , the exposure to bosutinib increased ( C max increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold ) in patients with hepatic impairment ( Child-Pugh classes A , B , and C ; N = 18 ) compared to matched healthy volunteers ( N = 9 ). Renal Impairment : Reduce the BOSULIF starting dose in patients with severe ( CrCL < 30 mL / min ) or moderate ( CrCL 30-50 mL / min ) renal impairment at baseline . For patients who have declining renal function while on BOSULIF who cannot tolerate a 500-mg dose , follow dose adjustment recommendations for toxicity . In a dedicated renal impairment trial , compared to subjects with normal renal function , the exposure ( AUC ) of bosutinib increased by 60 % and 35 % in subjects with CrCL < 30 mL / min and CrCL 30-50 mL / min , respectively , compared to subjects with normal renal function . BOSULIF has not been studied in patients undergoing hemodialysis .

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 .

PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling . Dosing and Administration : Instruct patients to take BOSULIF exactly as prescribed , not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor . If patients miss a dose beyond 12 hours , they should be advised to take the next scheduled dose at its regular time . A double dose should not be taken to make up for any missed dose . Advise patients to take BOSULIF with food . Patients should be advised : “ Do not crush or cut tablet . Do not touch or handle crushed or broken tablets .” Gastrointestinal Problems : Advise patients that they may experience diarrhea , nausea , vomiting , abdominal pain , or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms . Low Blood Cell Counts : Advise patients of the possibility of developing low blood cell counts and to immediately report fever , any suggestion of infection , or signs or symptoms suggestive of bleeding or easy bruising . Liver Problems : Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice . Fluid Retention : Advise patients of the possibility of developing fluid retention ( swelling , weight gain , or shortness of breath ) and to seek medical attention promptly if these symptoms arise . Renal Problems : Advise patients of the possibility of developing renal problems and to immediately report frequent urination , polyuria , or oliguria . Other Adverse Reactions : Advise patients that they may experience other adverse reactions such as respiratory tract infections , rash , fatigue , loss of appetite , headache , dizziness , back pain , arthralgia , or pruritus with BOSULIF and to seek medical attention if symptoms are significant . There is a possibility of anaphylactic shock . Pregnancy and Breast-feeding : Advise patients that BOSULIF can cause fetal harm when administered to a pregnant woman . Advise women of the potential hazard to the fetus and to avoid becoming pregnant . If BOSULIF is used during pregnancy , or if the patient becomes pregnant while taking BOSULIF , the patient should be apprised of the potential hazard to the fetus . 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 . Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with BOSULIF . Instruct patients to contact their physicians immediately if they become pregnant during treatment . Advise patients not to take BOSULIF treatment while pregnant or breast-feeding . If a patient wishes to restart breast-feeding after treatment , advise her to discuss the appropriate timing with her physician . Drug Interactions : Advise patients that BOSULIF and certain other medicines , including over-the-counter medications or herbal supplements ( such as St . John ’ s wort ), can interact with each other and may alter the effects of BOSULIF .

Rx only This brief summary is based on BOSULIF Prescribing Information LAB-0443-6.0 , revised April 2016 .

© 2016 Pfizer Inc . All rights reserved . May 2016

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