Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22 % of patients with CML who were resistant or intolerant to prior therapy . Adverse reactions which resulted in permanent discontinuation in > 2 % of patients included thrombocytopenia ( 6 %), hepatic dysfunction ( 3.3 %), and neutropenia ( 2 %). Dose modifications ( dose interruption or reductions ) of bosutinib due to an adverse reaction occurred in 66 % of patients with CML who were resistant or intolerant to prior therapy . Adverse reactions which required dose interruptions or reductions in > 5 % of patients included thrombocytopenia ( 24 %), diarrhea ( 14 %), rash ( 13 %), hepatic dysfunction ( 10 %), neutropenia ( 9 %), pleural effusion ( 8 %), vomiting ( 7 %), anemia ( 6 %), and abdominal pain ( 6 %). The most common adverse reactions , in ≥20 % 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 were diarrhea ( 83 %), nausea ( 47 %), rash ( 46 %), abdominal pain ( 45 %), vomiting ( 39 %), fatigue ( 33 %), pyrexia ( 28 %), hepatic dysfunction ( 27 %), respiratory tract infection ( 24 %), cough ( 23 %), and headache ( 21 %).
The most common laboratory abnormalities that worsened from baseline in ≥20 % were creatinine increased ( 93 %), hemoglobin decreased ( 91 %), lymphocyte decreased ( 80 %), platelets decreased ( 69 %), absolute neutrophil count ( 54 %), ALT increased ( 53 %), calcium decreased ( 53 %), white blood cell count decreased ( 52 %), urate increased ( 48 %), AST increased ( 47 %), phosphorus decreased ( 39 %), alkaline phosphatase increased ( 39 %), lipase increased ( 28 %), magnesium increased ( 25 %), potassium decreased ( 24 %), potassium increased ( 23 %).
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 long-term follow-up ( based on a minimum of 105 months ) were diarrhea ( 85 / 10 ), abdominal pain a ( 49 / 2 ), rash b ( 48 / 9 ), nausea ( 47 / 1 ), vomiting
( 38 / 3 ), fatigue ( 35 / 3 ), hepatic dysfunction c ( 29 / 11 ), respiratory tract infection d ( 27 /< 1 ), pyrexia ( 25 / 1 ), cough ( 24 / 0 ), headache ( 21 / 1 ), edema e ( 19 /< 1 ), arthralgia ( 19 / 1 ), constipation ( 15 /< 1 ), pleural effusion ( 14 / 4 ), back pain
( 14 / 1 ), decreased appetite ( 14 / 1 ), pruritus ( 12 / 1 ), dyspnea ( 12 / 2 ), influenza f ( 11 / 1 ), dizziness ( 11 / 0 ), hypertension g ( 11 / 3 ), pneumonia h ( 10 / 4 ).
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 long-term follow-up were diarrhea ( 76 / 4 ), nausea ( 48 / 2 ), vomiting ( 43 / 3 ), rash b ( 42 / 5 ), pyrexia ( 37 / 3 ), abdominal pain a ( 36 / 7 ), fatigue ( 27 / 6 ), cough ( 22 / 0 ), hepatic dysfunction c ( 21 / 10 ), dyspnea ( 20 / 6 ), pneumonia h ( 18 / 12 ), headache ( 18 / 4 ), constipation ( 17 / 1 ), edema e ( 17 / 1 ), respiratory tract infection d ( 17 / 0 ), arthralgia ( 15 / 0 ), dizziness ( 14 / 1 ),
decreased appetite ( 14 / 0 ), chest pain i ( 12 / 1 ).
a
Abdominal pain includes the following preferred terms : Abdominal discomfort , Abdominal pain , Abdominal pain lower , Abdominal pain upper , Abdominal tenderness , Dyspepsia , Epigastric discomfort , Gastrointestinal pain , Hepatic pain . b
Rash includes the following preferred terms : Acarodermatitis , Acne , Angular cheilitis , Blister , Dermatitis , Dermatitis acneiform , Dermatitis psoriasiform , Drug eruption , Eczema , Eczema asteatotic , Erythema , Erythema annulare , Exfoliative rash , Lichenoid keratosis , Palmar erythema , Photosensitivity reaction , Pigmentation disorder , Psoriasis , Pyoderma gangrenosum , Pyogenic granuloma , Rash , Rash erythematous , Rash generalized , Rash macular , Rash maculopapular , Rash pruritic , Rash pustular , Seborrheic dermatitis , Seborrheic keratosis , Skin depigmentation , Skin discoloration , Skin disorder , Skin exfoliation , Skin hyperpigmentation , Skin hypopigmentation , Skin irritation , Skin lesion , Skin plaque , Skin toxicity , Stasis dermatitis . c
Hepatic dysfunction includes the following preferred terms : Alanine aminotransferase increased , Aspartate aminotransferase increased , Bilirubin conjugated increased , Blood alkaline phosphatase increased , Blood bilirubin increased , Blood bilirubin unconjugated increased , Gamma-glutamyltransferase increased , Hepatic enzyme increased , Hepatic function abnormal , Hepatic steatosis , Hepatitis toxic , Hepatomegaly , Hepatotoxicity , Hyperbilirubinemia , Liver disorder , Liver function test abnormal , Liver function test increased , Transaminases increased .
d
Respiratory tract infection includes the following preferred terms : Nasopharyngitis , Respiratory tract congestion , Respiratory tract infection , Respiratory tract infection viral , Upper respiratory tract infection , Viral upper respiratory tract infection . e
Edema includes the following preferred terms : Eye edema , Eyelid edema , Face edema , Generalized edema , Localized edema , Edema , Edema peripheral , Penile edema , Periorbital edema , Periorbital swelling , Peripheral swelling , Scrotal edema , Scrotal swelling , Swelling , Swelling face , Swelling of eyelid , Testicular edema , Tongue edema . f
Influenza includes the following preferred terms : H1N1 influenza , Influenza . g
Hypertension * includes the following preferred terms : Blood pressure increased , Blood pressure systolic increased , Essential hypertension , Hypertension , Hypertensive crisis , Retinopathy hypertensive . h
Pneumonia includes the following preferred terms : Atypical pneumonia , Lower respiratory tract congestion , Lower respiratory tract infection , Pneumonia , Pneumonia aspiration , Pneumonia bacterial , Pneumonia fungal , Pneumonia necrotizing , Pneumonia streptococcal . i
Chest pain includes the following preferred terms : Chest discomfort , Chest pain . * ADR identified postmarketing .
In the single-arm study in patients with CML who were resistant or intolerant to prior therapy , 2 patients ( 0.4 %) experienced QTcF interval of greater than 500 msec . Patients with uncontrolled or significant cardiovascular disease , including QT interval prolongation , were excluded by protocol .
Number (%) of Patients with Clinically Relevant All Grade or Grade 3 / 4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy ( CP [ all grades / grade 3 / 4 ]; AdvP [ all grades / grade 3 / 4 ]): Hematology parameters were platelet count decreased ( 66 / 26 ; 80 / 57 ), absolute neutrophil count decreased ( 50 / 16 ; 66 / 39 ), hemoglobin decreased ( 89 / 13 ; 97 / 38 ), lymphocyte decreased ( 79 / 14 ; 82 / 21 ), white blood cell count decreased ( 51 / 7 ; 57 / 27 ). Biochemistry parameters were SGPT / ALT increased ( 58 / 11 ; 39 / 6 ), SGOT / AST increased ( 50 / 5 ; 37 / 3.5 ), lipase increased ( 32 / 12 ; 19 / 6 ), phosphorus decreased ( 41 / 8 ; 33 / 7 ), total bilirubin increased ( 16 / 0.7 ; 22 / 2.8 ), creatinine increased ( 95 / 3 ; 87 / 1.4 ), alkaline phosphatase increased ( 39 / 0 ; 39 / 1.4 ), glucose increased ( 42 / 2.7 ; 39 / 6 ), sodium increased ( 23 / 0.5 ; 11 / 0 ), sodium decreased ( 18 / 2.2 ; 27 / 6 ), calcium decreased ( 55 / 4.7 ; 45 / 3.5 ), urate increased ( 49 / 6 ; 43 / 6 ), magnesium increased ( 27 / 7 ; 18 / 4.9 ), potassium decreased ( 22 / 1.7 ; 29 / 4.9 ), potassium increased ( 25 / 2.7 ; 19 / 2.1 ).
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 all 1372 patients with 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 : 0.1 % and less than 1 % - 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 Endocrine Disorders : 1 % and less than 10 % - Hypothyroidism ; 0.1 % and less than 1 % - Hyperthyroidism
Gastrointestinal Disorders : 1 % and less than 10 % - Gastritis , Pancreatitis ( includes Edematous pancreatitis , Pancreatic enzymes increased , Pancreatitis , Pancreatitis acute , Pancreatitis chronic ), Gastrointestinal hemorrhage ( includes Anal hemorrhage , Gastric hemorrhage , Gastrointestinal hemorrhage , Intestinal hemorrhage , Lower gastrointestinal hemorrhage , Rectal hemorrhage , Upper gastrointestinal hemorrhage )
General Disorders and Administrative Site Conditions : 1 % and less than 10 % - Pain
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 % - Bronchitis
Investigations : 1 % and less than 10 % - Electrocardiogram QT prolonged ( includes Electrocardiogram QT prolonged , Long QT syndrome )
Metabolism and Nutrition Disorders : 1 % and less than 10 % - Dehydration Musculoskeletal and Connective Tissue Disorders : 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 kidney injury , Renal impairment , Renal failure
Respiratory , Thoracic , and Mediastinal Disorders : 1 % and less than 10 % - Pulmonary hypertension ( includes Pulmonary hypertension , Pulmonary arterial hypertension , Pulmonary arterial pressure increased ); 0.1 % and less than 1 % - Acute pulmonary edema ( includes Acute pulmonary edema , Pulmonary edema ), Respiratory failure
Skin and Subcutaneous Disorders : 0.1 % and less than 1 % - Erythema multiforme Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of BOSULIF . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
Blood and Lymphatic System Disorders : Thrombotic microangiopathy Skin and Subcutaneous Tissue Disorders : Stevens-Johnson syndrome
DRUG INTERACTIONS Effect of Other Drugs on Bosulif
Strong or Moderate CYP3A Inhibitors : Concomitant use with a strong or moderate CYP3A inhibitor increased bosutinib C max and AUC compared to BOSULIF alone , which may increase the risk of toxicities . Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF .
Strong CYP3A Inducers : Concomitant use with a strong CYP3A inducer decreased bosutinib C max and AUC compared to BOSULIF alone , which may reduce BOSULIF efficacy . Avoid the concomitant use of strong CYP3A inducers with BOSULIF .
Proton Pump Inhibitors ( PPI ): Concomitant use with a PPI decreased bosutinib C max and AUC compared to BOSULIF alone , which may reduce BOSULIF efficacy . As an alternative to PPIs , use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from BOSULIF dosing .
USE IN SPECIFIC POPULATIONS
Pregnancy : 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 drugassociated risk . In animal reproduction studies conducted in rats and rabbits , oral administration of bosutinib during organogenesis caused adverse developmental outcomes , including structural abnormalities , embryofetal 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 . Lactation : No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production . However , bosutinib is present in the milk of lactating rats . Because of the potential for serious adverse reactions in a nursing child , breastfeeding is not recommended during treatment with BOSULIF and for at least 2 weeks after the last dose .
Females and Males of Reproductive Potential : Based on findings from animal studies , BOSULIF can cause fetal harm when administered to a pregnant woman . Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF . Advise females of reproductive potential to use effective contraception ( methods that result in less than 1 % pregnancy rates ) during treatment with BOSULIF and for at least 2 weeks after the last dose . The risk of infertility in females or males of reproductive potential has not been studied in humans . Based on findings from animal studies , BOSULIF may cause reduced fertility in females and males of reproductive potential .
Pediatric Use : The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established .
Geriatric Use : In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph + CML , 20 % were age 65 and over and 4 % were 75 and over . Of the 268 patients who received bosutinib in the study for newly diagnosed CML , 20 % were age 65 and over , 5 % 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 .
Renal Impairment : Reduce the BOSULIF starting dose in patients with moderate ( creatinine clearance [ CL cr ] 30 to 50 mL / min , estimated by Cockcroft-Gault [ C-G ]) and severe ( CL cr less than 30 mL / min , C-G ) renal impairment at baseline . For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose , follow dose adjustment recommendations for toxicity . BOSULIF has not been studied in patients undergoing hemodialysis .
Hepatic Impairment : Reduce the BOSULIF dosage in patients with hepatic impairment ( Child-Pugh A , B , or C ). 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 , break , 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 . Cardiovascular Problems : Advise patients that cardiac failure , left ventricular dysfunction , and cardiac ischemic events have been reported . Advise patients to seek immediate medical attention if any symptoms suggestive of cardiac failure and cardiac ischemia occur , such as shortness of breath , weight gain , or fluid retention . 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 . Embryo-Fetal Toxicity : Advise females to inform their healthcare provider if they are pregnant or become pregnant . Inform female patients of the risk to a fetus and potential loss of the pregnancy . Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after receiving the last dose of BOSULIF . Advise lactating women not to breastfeed during treatment with BOSULIF and for at least 2 weeks after the last dose . 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 0443-14.7 , revised May 2021 .
PP-BOS-USA-0748-02 © 2021 Pfizer Inc . All rights reserved . June 2021