Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 25 May 2018

Indication(s)

1 INDICATIONS AND USAGE BOSULIF 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 [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow up trial. Chronic phase, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy. BOSULIF is a kinase inhibitor indicated for the treatment of adult patients with Newly-diagnosed chronic phase Ph+ chronic myelogenous leukemia (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. (1, 14) Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy. (1)

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Advisory information

contraindications
4 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. Hypersensitivity to BOSULIF. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Gastrointestinal toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Myelosuppression [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. Hepatic toxicity [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)]. Fluid retention [see Warnings and Precautions (5.4)]. Renal toxicity [see Dosage and Administration (2.5) and Warnings and Precautions (5.5)]. Most common adverse reactions in patients with newly-diagnosed CML (incidence ≥20%) are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, increased aspartate aminotransferase. (6) Most common adverse reactions in patients with CML who were resistant or intolerant to prior therapy (incidence ≥20%) are diarrhea, nausea, abdominal pain, rash, thrombocytopenia, vomiting, anemia, fatigue, pyrexia, cough, headache, alanine aminotransferase, and edema. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 [see Contraindications (4)], 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) [see Clinical Studies (14.1)]. The safety population (received at least 1 dose of BOSULIF) included: two hundred sixty-eight (268) patients with newly-diagnosed CP CML 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 greater than or equal to 20% of bosutinib 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%) [see Clinical Studies (14.1)]. Table 4 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population. Table 4: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study Adverse Reaction Bosutinib 400 mg Chronic Phase CML N=268 Imatinib 400 mg Chronic Phase CML N=265 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Abbreviation: CML=Chronic myelogenous leukemia, N=number of patients. Diarrhea 70 8 34 <1 Nausea 35 0 38 0 ThrombocytopeniaThrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia. 35 14 20 6 RashRash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis exfoliative, Drug reaction with eosinophilia and systemic symptoms, Photosensitivity reaction, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria. 34 1 21 2 Alanine aminotransferase increased 31 19 6 2 Abdominal painAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain. 25 2 15 <1 Aspartate aminotransferase increased 23 10 6 2 AnemiaAnemia includes the following preferred terms: Anemia, Hemoglobin decreased 19 3 19 5 Headache 19 1 13 1 FatigueFatigue includes the following preferred terms: Fatigue, Malaise. 19 <1 19 0 Vomiting 18 1 16 0 Lipase increasedLipase increased includes the following preferred terms: Hyperlipasemia, Lipase increased. 13 10 8 5 Pyrexia 13 <1 8 0 Respiratory tract infectionRespiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection. 12 <1 12 <1 NeutropeniaNeutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased. 11 7 21 12 Arthralgia 11 <1 13 0 Asthenia 11 0 6 0 Appetite decreased 10 <1 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. Table 4 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population. Table 5: Number (%) of Patients With Clinically Relevant or Grade 3/4 Laboratory Test Abnormalities in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study, Safety Population Bosutinib Chronic Phase CML N=268 n (%) Imatinib Chronic Phase CML N=265 n (%) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Hematology Parameters Platelet Count (Low) less than 50×109/L 38 (14.2) 17 (6.4) Absolute Neutrophil Count less than 1×109/L 24 (9.0) 49 (18.5) Hemoglobin (Low) less than 80 g/L 19 (7.1) 15 (5.7) White Blood Cell Count (Low) less than 2×109/L 15 (5.6) 20 (7.5) Biochemistry Parameters SGPT/ALT greater than 5.0×ULN 62 (23.1) 7 (2.6) SGOT/AST greater than 5.0×ULN 32 (11.9) 8 (3.0) Lipase greater than 2×ULN 35 (13.1) 16 (6.0) Phosphorus (Low) less than 0.6 mmol/L 12 (4.5) 45 (17.0) Total Bilirubin greater than 3.0×ULN 3 (1.1) 2 (0.8) Amylase greater than 2×ULN 6 (2.2) 4 (1.5) Creatinine greater than 3.0×baseline; greater than 3.0×ULN 0 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 [see Clinical Studies (14)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients: two hundred eighty-four (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. one hundred nineteen (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. one hundred forty-three (143) patients with advanced phase 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 (20%), and edema (20%) [see Clinical Studies (14.2)]. Table 6 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up. Table 6: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm TrialBased on a Minimum of 48 Months of Follow-up. Chronic Phase CML N=403 Advanced Phase CML N=143 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Abbreviations: CML=chronic myelogenous leukemia; N=number of patients. Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML. Diarrhea 85 9 76 4 Nausea 47 1 48 2 Abdominal PainAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain 42 2 31 6 RashRash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Drug eruption, Exfoliative rash, Photosensitivity reaction, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria 42 9 38 5 ThrombocytopeniaThrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia 40 26 45 39 Vomiting 37 3 43 3 AnemiaAnemia includes the following preferred terms: Anemia, Hemoglobin decreased. 27 11 38 27 FatigueFatigue includes the following preferred terms: Fatigue, Malaise. 26 2 21 5 Pyrexia 23 <1 37 2 Cough 22 0 22 0 Headache 21 <1 17 4 Alanine aminotransferase increased 20 8 10 5 NeutropeniaNeutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased 18 12 22 20 Arthralgia 17 <1 14 0 Aspartate aminotransferase increased 16 3 11 3 EdemaEdema includes the following preferred terms containing: Edema, Edema peripheral, Face edema, Localized edema. 20 1 17 2 Respiratory tract infectionRespiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection. 15 <1 10 0 Decreased appetite 14 <1 13 0 Back pain 13 <1 8 1 Nasopharyngitis 13 0 6 0 Asthenia 13 2 10 <1 Pleural effusion 12 4 9 4 Dyspnea 12 2 20 6 Pruritus 12 <1 7 0 Dizziness 11 0 13 <1 LeukopeniaLeukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased. 10 4 15 12 Blood creatinine increased 10 <1 6 <1 Influenza 10 <1 3 0 Chest painChest pain included the following preferred terms: Chest discomfort, Chest pain. 7 1 12 1 In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 1 patient (0.2%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 7 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up. Table 7: Number (%) of Patients With Clinically Relevant 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 TherapyBased on a Minimum of 48 Months of Follow-up. Chronic Phase (CP) CML N=403 n (%) Advanced Phase (AdvP) CML N=143 n (%) All CP and AdvP CML N=546 n (%) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. Hematology Parameters Platelet Count (Low) less than 50×109/L 105 (26) 82 (57) 187 (34) Absolute Neutrophil Count less than 1×109/L 65 (16) 55 (39) 120 (22) Hemoglobin (Low) less than 80 g/L 51 (13) 54 (38) 105 (19) Biochemistry Parameters SGPT/ALT greater than 5.0×ULN 43 (11) 8 (6) 51 (9) SGOT/AST greater than 5.0×ULN 19 (5) 5 (4) 24 (4) Lipase greater than 2×ULN 42 (10) 9 (6) 51 (9) Phosphorus (Low) less than 0.6 mmol/L 30 (7) 10 (7) 40 (7) Total Bilirubin greater than 3.0×ULN 3 (1) 4 (3) 7 (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 1272 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: less than 0.01% - Febrile neutropenia, Granulocytopenia 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 Vascular Disorders: 1% and less than 10% - Hypertension Gastrointestinal Disorders: 1% and less than 10% - Gastritis; 0.1% and less than 1% - Pancreatitis (includes Pancreatitis, Pancreatitis acute), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain Hepatobiliary Disorders: 1% and less than 10% - Hepatotoxicity (includes Hepatotoxicity, Hepatitis, Hepatitis toxic, Liver disorder), Hepatic function abnormal (includes Hepatic function abnormal, Liver function test abnormal, Transaminases increased); 0.1% and less than 1% - Liver injury (includes Liver injury, Drug-induced liver injury) Immune System Disorders: 0.1% and less than 1% - Anaphylactic shock, Drug hypersensitivity Infections and Infestations: 1% and less than 10% - pneumonia (includes pneumonia, atypical pneumonia), influenza, bronchitis Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome), Blood bilirubin increased (includes Blood bilirubin increased, Hyperbilirubinaemia), Blood creatine phosphokinase increased, Amylase increased, GGT increased Metabolism and Nutrition Disorders: 1% and less than 10% - Hypophosphatemia (includes Hypophosphatemia, Blood phosphorus decreased), Hyperkalemia (includes Hyperkalemia, Blood potassium increased), 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, Acute renal failure, Renal failure Respiratory, Thoracic and Mediastinal Disorders: 0.1% and less than 1% - Acute pulmonary edema, Respiratory failure, Pulmonary hypertension Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme 6.2 Post-Marketing 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. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food. (2.1) Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food. (2.1) Consider dose escalation by increments of 100 mg once daily to a maximum of 600 mg daily in patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 or greater adverse reactions. (2.2) Adjust dosage for toxicity and organ impairment (2) 2.1 Recommended Dosing The recommended dose is taken orally once daily with food. The tablet is to be swallowed whole and should not be broken or cut. Continue treatment with BOSULIF until disease progression or intolerance to therapy. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Newly-Diagnosed CP Ph+ CML The recommended dose of BOSULIF is 400 mg orally once daily with food. CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. 2.2 Dose Escalation In clinical studies of adult Ph+ CML patients, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. 2.3 Dose Adjustments for Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×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×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue BOSULIF [see Warnings and Precautions (5.3)]. Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (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 [see Warnings and Precautions (5.1)]. For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at a dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to the starting dose taken once daily. Doses less than 300 mg/day have been used in patients; however, efficacy has not been established. 2.4 Dose Adjustments for Myelosuppression Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1). Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia ANCAbsolute Neutrophil Count less than 1000×106/L or Platelets less than 50,000×106/L Withhold BOSULIF until ANC greater than or equal to1000×106/L and platelets greater than or equal to 50,000×106/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 dose by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have been used in patients; however, efficacy has not been established. 2.5 Dose Adjustments for Renal Impairment or Hepatic Impairment The recommended starting doses for patients with renal and hepatic impairment are described in Table 2 below. Table 2: Dose Adjustments for Renal and Hepatic Impairment Recommended Starting Dosage Newly-diagnosed chronic phase Ph+ CML2 Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. Abbreviations: CML=chronic myelogenous leukemia; Ph+=Philadelphia chromosome-positive. Normal renal and hepatic function 400 mg daily 500 mg daily Renal impairment Creatinine clearance 30 to 50 mL/min 300 mg daily 400 mg daily Creatinine clearance less than 30 mL/min 200 mg daily 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) 200 mg dailyThere are no clinical data for efficacy at the dose of 200 mg once daily in patients with CML. 200 mg daily
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 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 adverse developmental outcomes including fetal anomalies and reduced fetal body weights at maternal exposures (AUC) approximately 2.3 and 1.7 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively (see Data ). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively. Data Animal Data In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (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 30 mg/kg/day of bosutinib (1.8 and 1.3 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a separate study, 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 an embryo-fetal development 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 2 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 2.3 and 1.7 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. 8.2 Lactation Risk Summary 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 1 month after the last dose. Animal Data After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours. 8.3 Females and Males of Reproductive Potential Pregnancy Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF. Contraception Females Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. 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 1 month after the last dose. Infertility 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 [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established. 8.5 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, 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. 8.6 Renal Impairment Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CLcr 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 [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis. 8.7 Hepatic Impairment Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with BOSULIF. (7.1) Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. (7.1) Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. (7.1) 7.1 Effect of Other Drugs on BOSULIF Strong or Moderate CYP3A Inhibitors Concomitant use with a strong or moderate CYP3A inhibitor increased bosutinib Cmax and AUC compared to BOSULIF alone [see Clinical Pharmacology (12.3)] 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 Cmax and AUC compared to BOSULIF alone [see Clinical Pharmacology (12.3)] 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 Cmax and AUC compared to BOSULIF alone [see Clinical Pharmacology (12.3)] 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.

More information

Category Value
Authorisation number NDA203341
Agency product number 844ZJE6I55
Orphan designation No
Product NDC 0069-0135,0069-0193,0069-0136
Date Last Revised 22-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1307624
Storage and handling 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder Pfizer Laboratories Div Pfizer Inc