Bosulif
(bosutinib)Dosage & Administration
Bosulif Prescribing Information
BOSULIF is indicated for the treatment of:
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- Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies ].
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- Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2)].
Recommended Dosage
The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy.
Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal.
If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.
Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML
The recommended dosage of BOSULIF is 400 mg orally once daily with food.
Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy
The recommended dosage of BOSULIF is 500 mg orally once daily with food.
Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy
The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules.
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BSA * | Newly-Diagnosed Recommended Dose (Once Daily) | Resistant or Intolerant Recommended Dose (Once Daily) |
< 0.55 m2 | 150 mg | 200 mg |
0.55 to < 0.63 m2 | 200 mg | 250 mg |
0.63 to < 0.75 m2 | 200 mg | 300 mg |
0.75 to < 0.9 m2 | 250 mg | 350 mg |
0.9 to < 1.1 m2 | 300 mg | 400 mg |
≥ 1.1 m2 | 400 mg † | 500 mg † |
Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt
For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing.
Dose | Volume of Applesauce or Yogurt |
100 mg | 10 mL (2 teaspoons) |
150 mg | 15 mL (3 teaspoons) |
200 mg | 20 mL (4 teaspoons) |
250 mg | 25 mL (5 teaspoons) |
300 mg | 30 mL (6 teaspoons) |
350 mg | 30 mL (6 teaspoons) |
400 mg | 35 mL (7 teaspoons) |
450 mg | 40 mL (8 teaspoons) |
500 mg | 45 mL (9 teaspoons) |
550 mg | 45 mL (9 teaspoons) |
600 mg | 50 mL (10 teaspoons) |
Dose Escalation
In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage.
In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments.
The maximum dose in pediatric and adult patients is 600 mg once daily.
Dosage Adjustments for Non-Hematologic Adverse Reactions
Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue BOSULIF [see Warnings and Precautions (5.3)].
Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3–4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily [see Warnings and Precautions (5.1)].
For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at a dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to the starting dose taken once daily.
In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or greater, reduce dose similarly to adults.
Dosage Adjustments for Myelosuppression
Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).
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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.
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Dosage Adjustments for Renal Impairment or Hepatic Impairment
The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below.
| Recommended Starting Dosage | |||
|---|---|---|---|
| [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. | |||
| Newly-diagnosed chronic phase Ph+ CML | Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy | |
Normal renal and hepatic function | 400 mg daily | 500 mg daily | |
Renal impairment | |||
| Creatinine clearance 30 to 50 mL/min | 300 mg daily | 400 mg daily |
| Creatinine clearance less than 30 mL/min | 200 mg daily | 300 mg daily |
Hepatic impairment | |||
| Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) | 200 mg daily | 200 mg daily |
| [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. | ||||
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| Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function | |||
Pediatric Patients by Separated BSA * Band | Normal renal and hepatic function | Renal Impairment: Creatinine clearance 30 to 50 mL/min | Renal Impairment: Creatinine clearance less than 30 mL/min | Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) |
Pediatric < 0.55 m2 | 150 mg | 100 mg | 100 mg | 100 mg |
Pediatric 0.55 to < 0.63 m2 | 200 mg | 150 mg | 100 mg | 100 mg |
Pediatric 0.63 to < 0.75 m2 | 200 mg | 150 mg | 100 mg | 100 mg |
Pediatric 0.75 to < 0.9 m2 | 250 mg | 200 mg | 150 mg | 100 mg |
Pediatric 0.9 to < 1.1 m2 | 300 mg | 200 mg | 200 mg | 150 mg |
Pediatric ≥ 1.1 m2 | 400 mg | 300 mg | 200 mg | 200 mg |
| CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function | |||
Pediatric Patients by Separated BSA * Band | Normal renal and hepatic function | Renal Impairment: Creatinine clearance 30 to 50 mL/min | Renal Impairment: Creatinine clearance less than 30 mL/min | Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) |
Pediatric < 0.55 m2 | 200 mg | 150 mg | 100 mg | 100 mg |
Pediatric 0.55 to < 0.63 m2 | 250 mg | 200 mg | 150 mg | 100 mg |
Pediatric 0.63 to < 0.75 m2 | 300 mg | 200 mg | 200 mg | 150 mg |
Pediatric 0.75 to < 0.9 m2 | 350 mg | 250 mg | 200 mg | 150 mg |
Pediatric 0.9 to < 1.1 m2 | 400 mg | 300 mg | 250 mg | 200 mg |
Pediatric ≥ 1.1 m2 | 500 mg | 400 mg | 300 mg | 200 mg |
Tablets:
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- 100 mg: yellow, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "100" on the other.
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- 400 mg: orange, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "400" on the other.
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- 500 mg: red, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "500" on the other.
Capsules:
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- 50 mg: white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink.
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- 100 mg: white body/brownish-red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively.
Data
Animal Data
In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).
In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively.
Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).
Lactation
Risk Summary
No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for 2 weeks after the last dose.
Animal Data
After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.
Females and Males of Reproductive Potential
Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy
Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF.
Contraception
Females
Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for 2 weeks after the last dose.
Infertility
The risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, BOSULIF may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of BOSULIF have been established in pediatric patients 1 year of age and older with newly-diagnosed CP Ph+ CML and CP Ph+ CML that is resistant or intolerant to prior therapy.
Use of BOSULIF for these indications is based on data from BCHILD [NCT04258943]. The study included pediatric patients with newly diagnosed CP Ph+ CML in the following age groups: 2 patients 1 year of age to less than 6 years of age, 3 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. The study also included pediatric patients with CP Ph+ CML that was resistant or intolerant to prior therapy in the following age groups: 4 patients 1 year of age to less than 6 years of age, 10 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.3)]. BSA-normalized apparent clearance in 27 pediatric patients aged 4 to <17 years (141.3 L/h/m2) was 29% higher than BSA-normalized apparent clearance in adult patients with CP Ph+ CML (109.2 L/h/m2) [see Clinical Pharmacology (12.3)]. The recommended dosage of BOSULIF in pediatric patients is based on body surface area (BSA) [see Dosage and Administration (2.1)].
The safety and effectiveness of BOSULIF in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.
Geriatric Use
In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment
Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CLcr less than 30 mL/min, C-G) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis.
Hepatic Impairment
Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)].
BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis [see Adverse Reactions (6.1)].
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 randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 4 days and the median duration per event was 3 days.
Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, 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).
Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days. Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 2 (range 1 – 198).
To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].
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)].
Hepatic Toxicity
Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]).
Two cases 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) have occurred without alternative causes. This represented 2 out 1711 patients in BOSULIF clinical trials.
In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively.
Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days.
Among 49 pediatric patients with newly‑diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59% and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade, 84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively.
Perform hepatic enzyme tests monthly for the first 3 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)].
Cardiovascular Toxicity
BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders.
In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib.
In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with BOSULIF.
Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each).
Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].
Fluid Retention
Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.
In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema.
Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, Grade 1-2 pericardial effusion, peripheral edema, and face edema were reported in 1 patient each.
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)].
Renal Toxicity
An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 6 identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the pooled leukemia studies regardless of line of therapy. The median duration of therapy with BOSULIF was approximately 24 months (range, 0.03 to 155) for patients in these studies.
| Baseline | Follow-Up | ||||||
|---|---|---|---|---|---|---|---|
| Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients. Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD). Notes: Grading is based on Kidney Disease Improving Global Outcomes (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. | |||||||
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Renal Function Status | N | Normal | Mild | Mild to Moderate | Moderate to Severe | Severe | Kidney Failure |
Normal | 527 | 115 (21.8) | 330 (62.6) | 50 (9.5) | 23 (4.4) | 3 (0.6) | 5 (0.9) |
Mild | 672 | 10 (1.5) | 259 (38.5) | 271 (40.3) | 96 (14.3) | 26 (3.9) | 6 (0.9) |
Mild to Moderate | 137 | 0 | 6 (4.4) | 40 (29.2) | 66 (48.2) | 24 (17.5) | 1 (0.7) |
Moderate to Severe | 33 | 0 | 1 (3.0) | 1 (3.0) | 8 (24.2) | 19 (57.6) | 4 (12.1) |
Severe | 1 | 0 | 0 | 0 | 0 | 0 | 1 (100) |
Total | 1370 | 125 (9.1) | 596 (43.5) | 362 (26.4) | 193 (14.1) | 72 (5.2) | 17 (1.2) |
Overall, 45% of the pediatric patients with newly diagnosed CP Ph+ CML or resistant or intolerant CP Ph+ CML who had normal eGFR at baseline shifted to a maximum of mild, and 40% pediatric patients who had mild eGFR at baseline shifted to a maximum of moderate during treatment.
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 (2.5)].
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].