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CLINICAL PHARMACOLOGY 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. 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. Pharmacokinetics Absorption Following administration of a single dose of BOSULIF 500 mg with food in patients with cancer, the median timeto- 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 and Use In Specific Populations]. 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 and Use In Specific Populations]. 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 ADMINISTRATIONand DRUG INTERACTIONS]. 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 and DRUG INTERACTIONS]. 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. 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 by 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, 506 were considered evaluable for cytogenetic or hematologic efficacy assessment. 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 262 patients with CP CML previously treated with one prior TKI (imatinib), 112 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 132 patients with advanced phase CML previously treated with at least one TKI. Median duration of BOSULIF treatment was 26 months in patients with CP CML previously treated with one TKI (imatinib), 9 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 and MCyR at any time results are summarized 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=262 evaluable) n (%) Prior Treatment with Imatinib and Dasatinib or Nilotinib (N=112 evaluable) n (%) By Week 24 MCyR (95% CI) 105 (40.1) (34.1, 46.3) 29 (25.9) (18.1, 35.0) MCyR any time 156 (59.5) (53.3, 65.5) 45 (40.2) (31.0, 49.9) Abbreviations: CI = confidence interval, MCyR = major cytogenetic response The long term follow-up data analysis was based on a minimum of 60 months for patients with CP CML treated with one prior TKI (imatinib) and a minimum of 48 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 59.5% 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, 65.4% and 42.9% had a MCyR lasting at least 18 and 54 months, respectively. For the 40.2% 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, 64.4% and 35.6% had a MCyR lasting at least 9 and 42 months, respectively. Of the 403 treated patients with CP CML, 20 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=72 evaluable) n (%) BP CML (N=60 evaluable) n (%) CHRa by Week 48 (95% CI) 22 (30.6) (20.2, 42.5) 10 (16.7) (8.3, 28.5) OHRa by Week 48 (95% CI) 41 (56.9) (44.7, 68.6) 17 (28.3) (17.5, 41.4) Abbreviations: CI = confidence interval, OHR = overall hematologic response, CHR = complete hematologic response a. 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/mm3 and less than 450,000/mm3, absolute neutrophil count (ANC) greater than or equal to 1.0×109 /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/mm3 and less than 100,000/mm3) and/or neutropenia (ANC greater than or equal to 0.5×109 /L and less than 1.0×109 /L). Return to chronic phase (RCP) =disappearance of features defining accelerated or blast phases but still in chronic phase. The long term follow-up data analysis was based on a minimum of 48 months for patients with AP CML and BP CML. Of the 79 treated patients with AP CML, 3 patients had confirmed disease transformation to BP while on BOSULIF treatment.

Find Lowest Prices on BOSULIF® (bosutinib) Tablets 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).

INDICATIONS BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. DOSAGE AND ADMINISTRATION Recommended Dosing The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. Continue treatment with BOSULIF until disease progression or patient intolerance. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dose Escalation Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily. Dose Adjustments For Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×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]. 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]. 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 reescalating the dose of BOSULIF to 500 mg once daily. 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 ANCa less than 1000 x 106/L or Platelets less than 50,000 x 106/L Withhold BOSULIF until ANC greater than or equal to1000x106/L and platelets greater than or equal to 50,000x106/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. a Absolute Neutrophil Count 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]. 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]. 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 and CLINICAL PHARMACOLOGY]. HOW SUPPLIED 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. Storage And Handling 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, filmcoated 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. 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]. 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. Distributed by: Pfizer Labs, Division of Pfizer NY, NY 10017. Revised: April 2017

PATIENT INFORMATION BOSULIF® (BAH-su-lif) (bosutinib) Tablets What is BOSULIF? BOSULIF is a prescription medicine used to treat adults who have a certain type of leukemia called Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) who no longer benefit from or did not tolerate other treatment. It is not known if BOSULIF is safe and effective in children less than 18 years of age. Do not take BOSULIF if you are allergic to bosutinib or any of the ingredients in BOSULIF. See the end of this leaflet for a complete list of ingredients of BOSULIF. Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you: have liver problems have heart problems have kidney problems are pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. You should not become pregnant while taking BOSULIF. Tell your doctor right away if you become pregnant while taking BOSULIF. are a woman who may become pregnant. Use effective contraception (birth control) during and for at least 30 days after the final dose of BOSULIF. Talk to your doctor about forms of birth control that may be right for you during this time. are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. You and your doctor should decide if you will take BOSULIF or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. When taken together, BOSULIF and certain other medicines can affect each other. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take BOSULIF? Take BOSULIF exactly as prescribed by your doctor. Do not change your dose or stop taking BOSULIF without first talking with your doctor. Take BOSULIF with food. Swallow BOSULIF tablets whole. Do not crush or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets. If you take an antacid or H2 blocker medicine, take it at least 2 hours before or 2 hours after BOSULIF. If you take a Proton Pump Inhibitor (PPI) medicine, talk to your doctor or pharmacist. You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract during treatment with BOSULIF. Grapefruit products increase the amount of BOSULIF in your body. Your doctor may change your dose of BOSULIF or tell you to stop taking BOSULIF depending on how you respond to treatment. If you miss a dose of BOSULIF, take it as soon as you remember. If you miss a dose by more than 12 hours, skip that dose and take your next dose at your regular time. Do not take 2 doses at the same time. If you take too much BOSULIF, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of BOSULIF? BOSULIF may cause serious side effects, including: Stomach problems. BOSULIF may cause stomach (abdomen) pain, nausea, diarrhea, or vomiting. Tell your doctor about any stomach problems. Low blood cell counts. BOSULIF may cause low platelet counts (thrombocytopenia), low red blood cell counts (anemia) and low white blood cell counts (neutropenia). Your doctor should do blood tests to check your blood cell counts regularly during your treatment with BOSULIF. Call your doctor right away if you have unexpected bleeding or bruising, blood in your urine or stools, fever, or any signs of an infection. Liver problems. BOSULIF may cause liver problems. Your doctor should do blood tests to check your liver function regularly during your treatment with BOSULIF. Call your doctor right away if your skin or the white part of your eyes turns yellow (jaundice) or you have dark “tea color” urine. Your body may hold too much fluid (fluid retention). Fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: shortness of breath and cough chest pain swelling in your hands, ankles, or feet swelling all over your body weight gain Kidney problems. BOSULIF may cause kidney problems. Your doctor should do tests to check your kidney function when you start treatment with BOSULIF and during your treatment. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: you urinate more often than normal you urinate less often than normal you make a much larger amount of urine than normal you make a much smaller amount of urine than normal The most common side effects of BOSULIF include: rash fever tiredness or weakness Tell your doctor right away if you get respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, or itching while taking BOSULIF. These may be symptoms of a severe allergic reaction. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of BOSULIF. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store BOSULIF? Store BOSULIF between 68°F to 77°F (20°C to 25°C). Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF. Keep BOSULIF and all medicines out of the reach of children. General information about the safe and effective use of BOSULIF. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BOSULIF for a condition for which it is not prescribed. Do not give BOSULIF to other people even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about BOSULIF that is written for health professionals. What are the ingredients in BOSULIF? Active ingredient: bosutinib. Inactive ingredients: 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).

OVERDOSE 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. 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.

SIDE EFFECTS The following adverse reactions are discussed in greater detail in other sections of the labeling: Gastrointestinal toxicity see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Myelosuppression see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Hepatic toxicity see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Fluid retention [see WARNINGS AND PRECAUTIONS]. Renal toxicity [see WARNINGS AND PRECAUTIONS]. 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], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash. Adverse reactions of any toxicity grade reported for greater than 20% of patients in Phase 1/2 trial (n=546) were diarrhea (82%), nausea (47%), thrombocytopenia (42%), rash (41%), vomiting (39%), abdominal pain (39%), respiratory tract infection (39%), anemia (30%), pyrexia (27%), liver test abnormalities (24%), fatigue (25%), cough (22%), and headache (20%) [see Clinical Studies]. 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]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients: 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. 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. 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. 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 based on long-term follow-up. Table 3:Adverse Reactions (10% or Greater) in Patients with CML in Study 1* Chronic Phase CML N=403 Advanced Phase CML N=143 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Diarrhea 85 9 76 4 Nausea 47 1 48 2 Abdominal Paina 42 2 31 6 Thrombocytopeniab 40 26 45 39 Respiratory tract infectionc 39 5 38 12 Vomiting 37 3 43 3 Rashd 42 8 38 4 Liver test abnormalitiese 26 9 20 10 Fatiguef 26 2 21 5 Anemiag 27 11 38 27 Pyrexia 23 <1 37 2 Headache 21 <1 17 4 Cough 22 0 22 0 Neutropeniah 18 12 22 20 Edemai 20 1 17 2 Arthralgia 17 <1 14 0 Decreased appetite 14 <1 13 0 Renal impairmentj 13 2 13 5 Back pain 13 <1 8 1 Asthenia 13 2 10 <1 Pruritus 12 <1 7 0 Dizziness 11 0 13 <1 Dyspnea 12 2 20 6 Pleural effusion 12 4 9 4 Leukopeniak 10 4 15 12 Chest painl 7 1 12 1 *Based on a Minimum of 48 Months of Follow-up Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain b Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia c Respiratory tract infection includes the following preferred terms: Acute sinusitis, Acute tonsillitis, Atypical pneumonia, Bronchitis, Bronchitis bacterial, Bronchitis pneumococcal, Bronchopneumonia, Chronic tonsillitis, H1N1 influenza, Influenza, Laryngitis, Lobar pneumonia, Lower respiratory tract infection, Lung infection, Nasopharyngitis, Pertussis, Pharyngitis, Pharyngotonsillitis, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia pneumococcal, Pneumonia streptococcal, Pulmonary mycosis, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Sinusitis, Tonsillitis, Tonsillitis bacterial, Tracheitis, Upper respiratory tract infection, Viral upper respiratory tract infection d Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Eczema, Eczema asteatotic, Erythema, Generalised erythema, Intertrigo, Palmar erythema, Prurigo, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculopapular, Skin irritation, Stasis dermatitis e Liver Test Abnormalities 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, Hyperbilirubinaemia, Liver function test abnormal, Transaminases increased f Fatigue includes the following preferred terms: Fatigue, Malaise gAnaemia includes the following preferred terms: Anaemia, Haemoglobin decreased hNeutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased i Edema includes the following preferred terms containing: Acute pulmonary edema, Allergic edema, Angioedema, Bone marrow edema, Circumoral edema, Eyelid edema, Eye edema, Face edema, Gastrointestinal edema, Localised edema, Edema, Edema peripheral, Periorbital edema, Pharyngeal edema, Pulmonary edema, Scrotal edema, Testicular edema, Tongue edema, Weight increased j Renal impairment includes the following preferred terms: Acute kidney injury, Acute prerenal failure, Anuria, Blood creatinine abnormal, Blood creatinine increased, Chronic kidney disease, Oliguria, Prerenal failure, Renal failure, Renal impairment k Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased l Chest pain included the following preferred terms: Chest pain, chest discomfort. 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 based on long-term follow-up. 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=403 n (%) Advanced Phase CML N=143 n (%) All CP and AdvP CML N=546 n (%) 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) *Based on a Minimum of 48 Months of Follow-up 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 881 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; less than 1% - 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, gastrointestinal hemorrhage (Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Hematemesis, Hematochezia, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Melena, Rectal hemorrhage, Upper gastrointestinal hemorrhage); 0.1% and less than 1% - acute pancreatitis General Disorders and Administrative Site Conditions: 1% and less than 10% - pain Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity (includes Allergic hepatitis, Ascites, Cholestasis, Drug-induced liver injury, Hepatic steatosis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury) Immune System Disorders: 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock Investigations: 1% and less than 10% - electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome), blood creatine phosphokinase increased, amylase increased. Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration, hypophosphatemia Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% - myalgia Nervous System Disorders: 1% and less than 10% - dysgeusia Respiratory, Thoracic and Mediastinal Disorders: 0.1% and less than 1% - respiratory failure, pulmonary hypertension Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption 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 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 [see DOSAGE AND ADMINISTRATION]. 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]. 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]. 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]. 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]. 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.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Gastrointestinal Toxicity Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. Among 546 patients in a 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 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-268). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. 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 and ADVERSE REACTIONS]. 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. Among the 546 patients in a single-arm Phase 1/2 clinical trial the incidence of ALT elevation was 18% and AST elevation was 15%. 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 35 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 and ADVERSE REACTIONS]. Fluid Retention Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Among 546 patients in a single-arm Phase 1/2 clinical trial, Grade 3 or 4 fluid retention was reported in 26 patients (5%). Some patients experienced more than one fluid retention event. Specifically, 21 patients experienced Grade 3 or 4 pleural effusions, 7 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema. Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [ssee DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. 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 (%) Normal 274 53 (19) 174 (64) 30 (11) 14 (5) 1 (<1) 1 (<1) Mild 438 10 (2) 170 (39) 177 (40) 63 (14) 14 (3) 2 (1) Mild to Moderate 79 0 4 (5) 28 (35) 37 (47) 10 (13) 0 Moderate to Severe 24 0 1 (4) 1 (4) 6 (25) 15 (63) 1 (4) Severe 1 0 0 0 0 0 1 (100) Total 816 63 (8) 349 (43) 236 (29) 120 (15) 40 (5) 5 (1) Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD). KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2. *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]. Embryofetal Toxicity 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. There are no adequate and well controlled studies of BOSULIF in pregnant women. Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 30 days after the final dose. 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]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). 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 [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Liver Problems Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. Renal Problems Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria or oliguria [see WARNINGS AND PRECAUTIONS] 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 [see CONTRAINDICATIONS and ADVERSE REACTIONS]. 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 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. 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 [see Use In Specific Populations]. 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 [see Use In Specific Populations]. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take BOSULIF treatment while pregnant or breastfeeding [see Use In Specific Populations]. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician [see Use In Specific Populations]. 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 [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. Nonclinical Toxicology 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). Use In Specific Populations Pregnancy Pregnancy Category D [see WARNINGS AND PRECAUTIONS] 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. Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 30 days after the final dose. 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, 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 (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 ,ADVERSE REACTIONS and CLINICAL PHARMACOLOGY]. 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 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. BOSULIF has not been studied in patients undergoing hemodialysis.