Bosulif（bosutinib中文译名  伯舒替尼）为白血病治疗增加新选择 美国食品和药物管理局（FDA）9月5日批准Bosulif（博舒替尼）用于治疗慢性粒细胞性白血病（CML），本病是常见于老年人的血液和骨髓疾病。 据估计，在2012年将有5430例男性和女性被诊断出患有CML。大多数CML患者的费城染色体基因（PH）产生突变，从而导致骨髓产生称为酪氨酸激酶的酶。此酶会导致产生大量称为粒细胞的异常白细胞。粒细胞的作用是抵抗感染。 Bosulif适用于慢性、加速或急变期PH阳性、耐药或不耐受其他治疗方法包括伊马替尼的CML患者。Bosulif是通过阻断促进产生异常粒细胞的酪氨酸激酶的信号传导发挥作用。 “随着酪氨酸激酶抑制剂的批准，我们看到CML治疗的改进是基于在分子水平上对CML的更好理解。”FDA药物评价和研究中心血液学和肿瘤学产品办公室主任、医学博士Richard Pazdur说，“在CML慢性期与加速期已经观察到了这些改进。” FDA近年批准的治疗各种形式的CML的其他药物包括伊马替尼（2001）、达沙替尼（2006年）和尼洛替尼（2007年）。 在入选了546例慢性、加速或急变期CML患者的单一临床试验中，对Bosulif的安全性和有效性进行了评估。所有患者均为经伊马替尼治疗或伊马替尼之后用达沙替尼和/或尼洛替尼治疗后疾病继续发展或不能耐受治疗不良反应的患者。所有患者在试验中均接受Bosulif治疗。 在CML慢性期患者中，确定疗效的主要指标是在治疗第24周的主要细胞遗传学缓解（MCyR）患者数。结果显示，先前经伊马替尼治疗的患者，有34%在24周后达到MCyR。有52.8%在任何时间达到MCyR的患者，他们的应答至少持续了18个月。在伊马替尼之后经达沙替尼和/或尼洛替尼治疗的患者中，约有27%的患者在第24周达到了MCyR。在任何时间达到McyR患者中，有51.4%患者的MCyR至少持续了9个月。 在以前至少经伊马替尼治疗的CML加速期的患者中，有33%的患者在治疗在第48周全血计数恢复到正常范围（完全血液学反应），有55%达到无白血病症状的正常全血计数（整体血液学反应）。同时，CML急变期患者的15%达到完全血液学反应，28%达到整体血液学反应。 在接受Bosulif治疗患者中观察到的最常见的不良反应为：腹泻、恶心、血小板低（血小板减少症）、呕吐、腹痛、皮疹、红细胞计数低（贫血）、发热和疲劳。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BOSULIF safely and effectively. See full prescribing information for BOSULIF. BOSULIF ® (bosutinib) tablets, for oral use Initial U.S. Approval: 2012 RECENT MAJOR CHANGES Dosage and Administration (2) 09/2015 INDICATIONS AND USAGE BOSULIF is a kinase inhibitor indicated for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. (1) DOSAGE AND ADMINISTRATION Recommended Dose: 500 mg orally once daily with food. (2.1) Consider dose escalation to 600 mg daily in patients who do not reach complete hematologic response by week 8 or complete cytogenetic response by week 12 and do not have Grade 3 or greater adverse reactions. (2.2) Adjust dosage for toxicity and organ impairment (2) DOSAGE FORMS AND STRENGTHS Tablets: 100 mg and 500 mg. (3) CONTRAINDICATIONS Hypersensitivity to BOSULIF. (4) WARNINGS AND PRECAUTIONS Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. (2.3, 5.1) Myelosuppression: Monitor blood counts and manage as necessary. (2.4, 5.2) Hepatic Toxicity: Monitor liver enzymes at least monthly for the first three months and as needed. Withhold, dose reduce, or discontinue BOSULIF. (2.3, 5.3) Fluid Retention: Monitor patients and manage using standard of care treatment. Withhold, dose reduce, or discontinue BOSULIF. (2.3, 5.4) Renal Toxicity Monitor patients for renal function at baseline and during therapy with BOSULIF (5.5) Embryofetal Toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF. (5.6) ADVERSE REACTIONS Most common adverse reactions (incidence ≥20%) are diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. (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. DRUG INTERACTIONS CYP3A Inhibitors and Inducers: Avoid concurrent use of BOSULIF with strong or moderate CYP3A inhibitors and inducers. (2.5, 2.6, 7.1, 7.2) Proton Pump Inhibitors: May decrease bosutinib drug levels. Consider short-acting antacids in place of proton pump inhibitors. (7.2) USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue nursing if drug is important to mother. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 4/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 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. 2 DOSAGE AND ADMINISTRATION 2.1 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. 2.2 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. 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 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 400 mg once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to 500 mg once daily. 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 ANC* 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 not been evaluated. Absolute Neutrophil Count 2.5 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) [see Drug Interactions (7.1)]. 2.6 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) [see Drug Interactions (7.2)]. 2.7 Recommended Starting Dosage with Hepatic Impairment or Renal Impairment Organ Function Status Recommended Starting Dosage Normal hepatic and renal function 500 mg once daily Hepatic impairment   Mild (Child-Pugh A), Moderate (Child-Pugh B) or severe (Child-Pugh C) 200 mg daily Renal impairment   Creatinine clearance 30 to 50 mL/min 400 mg daily   Creatinine clearance less than 30 mL/min 300 mg daily [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS 100 mg tablets: yellow, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "100" on the other. 500 mg tablets: red, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "500" on the other.  4 CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients. 5 WARNINGS AND PRECAUTIONS 5.1 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 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.2 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 [see Dosage and Administration (2.4) and Adverse Reactions (6)]. 5.3 Hepatic Toxicity One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×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 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.4 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 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.5 Renal Toxicity An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 2 identifies the shift from baseline to lowest observed estimated glomerular filtration rate (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. Table 2: 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 n (%) Mild n (%) Mild to Moderate n (%) Moderate to Severe n (%) Severe n (%) Kidney Failure n (%) 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 m2. 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) 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 [see Dosage and Administration (2.7)]. 5.6 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 [see Use in Specific Populations (8.1)]. 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 Warnings and Precautions (5.5)]. 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 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%) [see Clinical Studies (14)]. 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 (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (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: 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. 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. Table 3 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. Table 3: Adverse Reactions (10% or Greater) in Patients with CML in Study 1 Chronic Phase CML N=406 Advanced Phase CML N=140 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML Diarrhea 84 9 76 5 Nausea 46 1 47 2 Abdominal Pain* 40 1 29 5 Thrombocytopenia 40 26 42 37 Vomiting 37 3 42 4 Rash 34 8 35 4 Fatigue 26 1 20 4 Anemia 23 9 37 26 Pyrexia 22 <1 36 3 Increased alanine aminotransferase 20 7 10 5 Headache 20 1 18 4 Cough 20 0 21 0 Increased aspartate aminotransferase 16 4 11 3 Neutropenia 16 11 19 18 Edema 14 <1 14 1 Arthralgia 14 <1 13 0 Decreased appetite 13 1 14 0 Respiratory tract infection 12 <1 10 0 Nasopharyngitis 12 0 5 0 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 Abdominal pain includes the following terms: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, gastrointestinal pain, abdominal discomfort Rash includes the following terms: rash, macular rash, pruritic rash, generalized rash, popular rash, maculo-papular rash Fatigue includes the following terms: fatigue, malaise Edema includes the following terms: edema, peripheral edema, localized edema, face edema Respiratory tract infection includes the following 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 milliseconds. 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 1/2 CML safety population Table 4: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML in Study 1, Safety Population Chronic Phase CML N=406 n (%) Advanced Phase CML N=140 n (%) All CP and AdvP CML N=546 n (%) Hematology Parameters   Platelet Count (Low) less than 50×109/L 102 (25) 80 (57) 182 (33)   Absolute Neutrophil Count less than 1×109/L 74 (18) 52 (37) 126 (23)   Hemoglobin (Low) less than 80 g/L 53 (13) 49 (35) 102 (19)   Biochemistry Parameters   SGPT/ALT greater than 5.0×ULN 39 (10) 8 (6) 47 (9)   SGOT/AST greater than 5.0×ULN 17 (4) 4 (3) 21 (4)   Lipase greater than 2×ULN 33 (8) 4 (3) 37 (7)   Phosphorus (Low) less than 0.6 mmol/L 30 (7) 10 (7) 40 (7)  Total Bilirubin greater than 3.0×ULN 3 (1) 2 (1) 5 (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 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 (includes gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% - chest pain (includes chest pain and chest discomfort), pain Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity (includes hepatotoxicity, toxic hepatitis, and cytolytic hepatitis), abnormal hepatic function (includes abnormal hepatic function, liver disorder); 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 (includes pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia), 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 7 DRUG INTERACTIONS 7.1 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 [see Dosage and Administration (2.5)]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to BOSULIF alone [see Clinical Pharmacology (12.3)]. 7.2 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 [see Dosage and Administration (2.6)]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to BOSULIF alone [see Clinical Pharmacology (12.3)]. Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to BOSULIF alone [see Clinical Pharmacology (12.3)]. 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)] 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. 8.3 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. 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 Phase 1/2 clinical trial 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 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 (Cmax 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) [see Dosage and Administration (2.7), Adverse Reactions (6), and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Reduce the BOSULIF starting dose in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr 30 to 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 CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively, compared to subjects with normal renal function [see Dosing and Administration (2.7) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis. 10 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. 11 DESCRIPTION Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3∙H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. BOSULIF® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. Each 100 mg BOSULIF tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg BOSULIF tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl. 12.2 Pharmacodynamics The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed. 12.3 Pharmacokinetics Absorption Following administration of a single dose of BOSULIF 500 mg with food in patients with cancer, the median time-to-peak concentration (tmax) was 4–6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800 mg. After 15 daily doses of BOSULIF (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUC was 3650 (425) ng∙h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively. Following administration of a single dose of BOSULIF (500 mg) with food to healthy subjects, the absolute bioavailability was 34%. Distribution After administration of a single dose of BOSULIF 500 mg with food in patients with CML, bosutinib had a mean apparent volume of distribution ± standard deviation of 6080 ± 1230 L. Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent. Metabolism Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive. Elimination In patients with CML given single oral doses of BOSULIF 500 mg with food, the mean terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given a single oral dose of [14C] radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine. Hepatic Impairment In a dedicated hepatic impairment trial, a single dose of BOSULIF 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively [see Dosage and Administration (2.7), and Use in Specific Populations (8.6)]. Renal Impairment In a dedicated renal impairment trial, a single dose of BOSULIF 200 mg was administered with food to 26 subjects with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 subjects with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had a 35% and 60% increase in AUC compared to subjects with normal renal function, respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. The BOSULIF dose should be reduced in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr between 30 to 50 mL/min) renal impairment [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. Drug Interactions CYP3A Inhibitors In a cross-over drug-drug interaction trial in healthy subjects (n=24), a single dose of 100 mg BOSULIF was administered alone or in combination with five daily doses of 400 mg ketoconazole (a strong CYP3A inhibitor) under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC by 5.2-fold and 8.6-fold, respectively. In a cross-over drug-drug interaction trial in healthy subjects (n=18), a single dose of 500 mg BOSULIF was administered alone or in combination with 125 mg aprepitant (a moderate CYP3A inhibitor) under fed conditions. Aprepitant increased bosutinib Cmax and AUC by 1.5-fold and 2.0-fold, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.1)]. CYP3A Inducers In a cross-over drug-drug interaction trial in healthy subjects (n=22), a single dose of 500 mg BOSULIF was administered alone or in combination with six daily doses of 600 mg rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.2)]. P-gp Substrates In a cross-over drug-drug interaction trial in healthy subjects (n=25), a single dose of 500 mg BOSULIF was administered in combination with a single dose of 150 mg dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate). Bosutinib did not increase Cmax or AUC of dabigatran in plasma, as compared with administration of dabigatran etexilate mesylate alone under fed conditions. The study results indicate that bosutinib is not a P-gp inhibitor clinically. pH Altering Medications BOSULIF displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 23 healthy volunteers, a single oral dose of 400 mg of BOSULIF was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5- to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure). 14 CLINICAL STUDIES Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CML A single-arm, Phase 1/2 open-label, multicenter trial (Study 1) was conducted to evaluate the efficacy and safety of BOSULIF 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within four weeks; (2) failure to achieve a complete hematologic response (CHR) by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-Abl gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial. The efficacy endpoints for patients with CP CML previously treated with one prior TKI (imatinib) were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed complete hematologic response (CHR) and overall hematologic response (OHR). The trial enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 503 were considered evaluable for efficacy. Patients were evaluable for efficacy if they had received at least one dose of BOSULIF and had a valid baseline efficacy assessment. Among evaluable patients, there were 266 patients with CP CML previously treated with one prior TKI (imatinib), 108 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 129 patients with advanced phase CML previously treated with at least one TKI. Median duration of BOSULIF treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), 8 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. The 24 week efficacy results are present in Table 5. Table 5: Efficacy Results in Patients with Ph+ CP CML with Resistance to or Intolerance to Imatinib Prior Treatment with Imatinib Only (N=266 evaluable) n (%) at 24 Weeks Prior Treatment with Imatinib and Dasatinib or Nilotinib (N=108 evaluable) n (%) by 24 Weeks Abbreviations: CI = confidence interval, MCyR = major cytogenetic response Week 24   MCyR 90 (33.8) 29 (26.9)   (95% CI) (28.2, 39.9) (18.8, 36.2) The minimum follow-up was 23 months for patients with CP CML treated with one prior TKI (imatinib) and 13 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 53.4% of patients with CP CML treated with one prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 52.8% had a MCyR lasting at least 18 months. For the 32.4% of patients with CP CML treated with imatinib and at least one additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 51.4% had a MCyR lasting at least 9 months. Of the 374 evaluable patients with CP CML, 16 patients had confirmed disease transformation to AP or BP while on treatment with BOSULIF. The 48 week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 6. Table 6: Efficacy Results in Patients with Accelerated Phase and Blast Phase CML Previously Treated with at Least Imatinib AP CML (N=69 evaluable) n (%) BP CML (N=60 evaluable) n (%) Abbreviations: CI = confidence interval, OHR = overall hematologic response, CHR = complete hematologic response CHR* by Week 48 21 (30.4) 9 (15)   (95% CI) 19.9, 42.7) (7.1, 26.6) OHR* by Week 48 38 (55.1) 17 (28.3)   (95% CI) (42.6, 67.1) (17.5, 41.4) Overall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm 3 and less than 450,000/mm 3, absolute neutrophil count (ANC) greater than or equal to 1.0×10 9 /L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm 3 and less than 100,000/mm 3) and/or neutropenia (ANC greater than or equal to 0.5×10 9 /L and less than 1.0×10 9 /L). Return to chronic phase (RCP) =disappearance of features defining accelerated or blast phases but still in chronic phase.  The CHR and OHR rates were based on a minimum follow-up of 12 months for patients with AP CML and 18 months for patients with BP CML. Of the 69 evaluable patients with AP CML, 4 patients had confirmed disease transformation to BP while on BOSULIF treatment. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied BOSULIF (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "100" on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with "Pfizer" on one side and "500" on the other. BOSULIF (bosutinib) tablets are available in the following packaging configurations (Table 7): Table 7: Tablet Presentations  BOSULIF Tablets Package Configuration Tablet Strength (mg) NDC Tablet Description 120 tablets per bottle 100 mg 0069-0135-01 Yellow, oval, biconvex, film-coated tablets, debossed "Pfizer" on one side and "100" on the other. 30 tablets per bottle 500 mg 0069-0136-01 Red, oval, biconvex, film-coated tablets, debossed "Pfizer" on one side and "500" on the other. 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]. 16.3 Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adc84ad5-a04d-4fee-9ba8-91f7abd928e3 辉瑞旗下博舒替尼在欧洲获有条件批准用于CML治疗 辉瑞旗下酪氨酸激酶抑制剂博舒替尼 (Bosulif)在欧洲被有条件批准用于慢性期、加速期或急变期费城染色体呈阳性的慢性粒细胞性白血病(CML)成年患者的治疗。但博舒替尼仅限使用于先前接受过一种或多种酪氨酸激酶抑制剂治疗的患者，以及对诺华一线治疗药物格列卫、百时美施贵宝和日本大冢制药的达沙替尼和诺华二线治疗药物尼罗替尼不适用的患者。有条件批准是考虑到紧急公共卫生的需要，对研发中表现出明显健康益处，但完整安全性和有效性试验还没完成的药物进行的一种批准方式。 慢性粒细胞白血病的治疗方案随着2001年格列卫的上市发生了改变， 虽然这种治疗方案使患者生存状况得到了改善，但随着治疗抵抗的发展以及疾病的进展，需要辅以其它治疗药物。“其它治疗选择对慢性粒细胞白血病患者来说是非常关键的，因为每一位患者对治疗的响应是不一样的，并且有独特的需求，”意大利米兰S. Gerardo医院的Carlo Gambacorti-Passerini评论说，他也是博舒替尼注册临床研究的主要研究者。“基于对博舒替尼的经验，我认为这种日服一次的治疗药物以其明显的安全特征，可以为患者提供一种重要的新选择，”他补充说。 博舒替尼于去年9月份基于一项由546名患者参与的单一试验研究在美国获得上市批准，该试验研究（作为格列卫之后的二线治疗药物）显示博舒替尼在34%的患者身上获得了主要细胞遗传学缓解，而达沙替尼或尼洛替尼为27%。 其它慢性粒细胞白血病候选治疗药物有阿瑞雅德(Ariad)制药公司的ponatinib，该药物的上市申请已于去年被提交到美国和欧洲，ponatinib的作用机制与目前的该类治疗药物相比有稍微的差别，另外还有瑟法隆公司与赫士睿公司的Omapro (omacetaxine)，Pharma公司的GVAX以及Deciphera公司的ABL抑制剂rebastinib (DCC-2036)。