BOSULIF
BOSULIF (bosutinib monohydrate) tablet, film coated
[Pfizer Laboratories Div Pfizer Inc]
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
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 hematologic and non-hematologic toxicity. (2.3, 2.4)
Hepatic impairment (at baseline): reduce BOSULIF dose to 200 mg daily. (2.7)
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)
Embryofetal toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF. (5.5)
ADVERSE REACTIONS
Most common adverse reactions (incidence greater than 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)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 09/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
2.2 Dose Escalation
2.3 Dose Adjustments for Non-Hematologic Adverse Reactions
2.4 Dose Adjustments for Myelosuppression
2.5 Concomitant Use With CYP3A Inhibitors
2.6 Concomitant Use With CYP3A Inducers
2.7 Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Gastrointestinal Toxicity
5.2 Myelosuppression
5.3 Hepatic Toxicity
5.4 Fluid Retention
5.5 Embryofetal Toxicity
6 ADVERSE REACTIONS
6.1 Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
6.2 Additional Data from Multiple Clinical Trials
7 DRUG INTERACTIONS
7.1 Drugs That May Increase Bosutinib Plasma Concentrations
7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
7.3 Drugs That May Have Their Plasma Concentrations Altered By Bosutinib
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 QT/QTc Prolongation
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Handling and Disposal
17 PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION
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
*
Absolute Neutrophil Count
ANC* less than 1000×106/L Withhold BOSULIF until ANC greater than or equal to1000×106/L and platelets greater than or equal to 50,000×106/L.
or
Platelets less than 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 eva luated.
2.5 Concomitant Use With CYP3A Inhibitors
Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [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 rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine) [see Drug Interactions (7.2)].
2.7 Hepatic Impairment
In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of BOSULIF is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML [see Use in Special Populations (8.6)].
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
Hypersensitivity to BOSULIF. 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/or 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. Patients with CML who are receiving BOSULIF should have a complete blood count performed weekly for the first month 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 per cent 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 monthly hepatic enzyme tests for the first three months of treatment with BOSULIF 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 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)].
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, hepatoxicity 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%).
6.1 Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients. Within the safety population there were 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. There were 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. There were 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 2 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 2: Adverse Reactions (10% or greater) in patients with CML
System Organ Class
Preferred Term CP CML
N=406
n (%) AdvP CML
N=140
n (%) All CP and AdvP CML
N=546
n (%)
All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
CP CML = Chronic Phase CML; AdvP CML = Advanced Phase CML (includes patients with Accelerated Phase and Blast Phase CML)
*
Abdominal pain includes the following preferred terms: Abdominal pain, Abdominal pain upper, Abdominal pain lower, Abdominal tenderness, Gastrointestinal pain, Abdominal discomfort
†
Fatigue includes the following preferred terms: Fatigue, Malaise
‡
Edema includes the following preferred terms: Edema, Edema peripheral, Localized edema, Face edema
§
Respiratory tract infection includes the following preferred terms: Respiratory tract infection, Upper respiratory tract infection, Lower respiratory tract infection, Viral upper respiratory tract infection, Respiratory tract infection viral
¶
Rash includes the following preferred terms: Rash, Rash macular, Rash pruritic, Rash generalized, Rash papular, Rash maculo-papular
Gastrointestinal Disorders
Diarrhea 342 (84) 38 (9) 107 (76) 7 (5) 449 (82) 45 (8)
Nausea 186 (46) 5 (1) 66 (47) 3 (2) 252 (46) 8 (1)
Abdominal Pain* 162 (40) 6 (1) 41 (29) 7 (5) 203 (37) 13 (2)
Vomiting 152 (37) 12 (3) 59 (42) 5 (4) 211 (39) 17 (3)
Blood and Lymphatic System Disorders
Thrombocytopenia 163 (40) 105 (26) 59 (42) 52 (37) 222 (41) 157 (29)
Anemia 94 (23) 35 (9) 52 (37) 37 (26) 146 (27) 72 (13)
Neutropenia 65 (16) 43 (11) 26 (19) 25 (18) 91 (17) 68 (12)
General Disorders and Administrative Site Conditions
Fatigue† 104 (26) 6 (1) 28 (20) 6 (4) 132 (24) 12 (2)
Pyrexia 90 (22) 2 (<1) 51 (36) 4 (3) 141 (26) 6 (1)
Edema‡ 56 (14) 1 (<1) 19 (14) 1 (1) 75 (14) 2 (<1)
Asthenia 45 (11) 5 (1) 14 (10) 1 (1) 59 (11) 6 (1)
Infections and Infestations
Respiratory tract infection§ 49 (12) 2 (<1) 14 (10) 0 63 (12) 2 (<1)
Nasopharyngitis 47 (12) 0 7 (5) 0 54 (10) 0
Investigations
Alanine aminotransferase increased 81 (20) 30 (7) 14(10) 7(5) 95(17) 37(7)
Aspartate aminotransferase increased 64 (16) 15 (4) 15(11) 4 (3) 79(14) 19(3)
Metabolism and nutrition disorder
Decreased appetite 53 (13) 3 (1) 19 (14) 0 72 (13) 3 (1)
Musculoskeletal and Connective Tissue Disorder
Arthalgia 58 (14) 2 (<1) 18 (13) 0 76 (14) 2 (<1)
Back pain 49 (12) 3 (1) 10 (7) 2 (1) 59 (11) 5 (1)
Nervous System Disorders
Headache 82 (20) 3 (1) 25 (18) 6 (4) 107 (20) 9 (2)
Dizziness 39 (10) 0 18 (13) 1 (1) 57 (10) 1 (<1)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea 41 (10) 4 (1) 26 (19) 8 (6) 67 (12) 12 (2)
Cough 80(20) 0 30(21) 0 110(20) 0
Skin and Subcutaneous Disorders
Rash¶ 140 (34) 32 (8) 49 (35) 6 (4) 189 (35) 38 (7)
Pruritus 43 (11) 3 (1) 11 (8) 0 54 (10) 3 (1)
In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population.
Table 3: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities In the Phase 1/2 Clinical Study, Safety Population
CP CML
N=406
n (%) AdvP 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)
6.2 Additional Data 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 eva luation 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 hemorrhage1
General Disorders and Administrative Site Conditions: 1% and less than 10% - chest pain2, pain
Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity3, abnormal hepatic function4; 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% - pneumonia5, 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
1
Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage
2
Chest pain includes the following preferred terms: chest pain, chest discomfort
3
Hepatotoxicity includes the following preferred terms: hepatoxicity, toxic hepatitis, cytolytic hepatitis
4
Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder
5
Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia
7 DRUG INTERACTIONS
7.1 Drugs That May Increase Bosutinib Plasma Concentrations
CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp 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.
7.3 Drugs That May Have Their Plasma Concentrations Altered By Bosutinib
Substrates of P-glycoprotein: An in vitro study suggests that BOSULIF may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.5)]
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 eva luate 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
Based on population PK analysis, creatinine clearance had no meaningful influence on the exposure to BOSULIF. The population PK analysis included CrCL range of 25 to 120 mL/min [see Clinical Pharmacology (12.3)].
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.
12.3 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.
Distribution
After administration of a single dose of BOSULIF (500mg) 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. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters.
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 (500mg) 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 hepatically impaired volunteers (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.
Drug Interactions
CYP3A Inhibitors
In a cross-over trial of 24 healthy volunteers, a single dose of 100 mg of BOSULIF was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively.
CYP3A Inducers
In a cross-over trial of 24 healthy volunteers, a single dose of 500 mg of BOSULIF was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively.
P-gp Substrates
An in vitro study suggests that BOSULIF has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of BOSULIF.
pH Altering Medications
BOSULIF displays pH-dependent aqueous solubility, in vitro. In a cross-over trial in 24 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.
12.4 QT/QTc Prolongation
The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was eva luated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 70 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed.
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 was conducted to eva luate 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 eva luable for efficacy. Patients were eva luable for efficacy if they had received at least one dose of BOSULIF and had a valid baseline efficacy assessment. Among eva luable 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 6.
Table 6: Efficacy Results in Patients with Ph+ CP CML with Resistance to or Intolerance to Imatinib
Prior Treatment
with Imatinib Only
(N=266 eva luable)
n (%)
at 24 Weeks Prior Treatment with Imatinib and Dasatinib or Nilotinib
(N=108 eva luable)
n (%)
by 24 Weeks
Abbreviations: CI = confidence interval, MCyR = major cytogenetic response
Week 24
MCyR
(95% CI)
90 (33.8)
(28.2, 39.9)
29 (26.9)
(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 eva luable 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 7.
Table 7: Efficacy Results in Patients with Accelerated Phase and Blast Phase CML Previously Treated with at Least Imatinib
AP CML
(N=69 eva luable)
n (%) BP CML
(N=60 eva luable)
n (%)
Abbreviations: CI = confidence interval, OHR = overall hematologic response, CHR = complete hematologic response
*
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.
CHR* by Week 48
(95% CI)
21 (30.4)
(19.9, 42.7) 9 (15)
(7.1, 26.6)
OHR* by Week 48 38 (55.1) 17 (28.3)
(95% CI) (42.6, 67.1) (17.5, 41.4)
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 eva luable 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 8):
Table 8 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.
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
• Dosing and Administration
Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF with a meal. 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.
• Low Blood Cell Counts
Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising.
• Liver Problems
Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice.
• 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.
• 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.
• 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. 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.
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. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take BOSULIF treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician.
• 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 (2.5) and Drug Interactions (7)].
LAB-0443-1.0
September 2012
PATIENT INFORMATION
BOSULIF® (BAH-su-lif)
(bosutinib)
tablets
Read the Patient Information that comes with BOSULIF before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.
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.
Who should not take BOSULIF?
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.
What should I tell my doctor before taking BOSULIF?
Before you take BOSULIF, tell your doctor if you:
have liver problems
have heart problems
have any other medical conditions
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 completing treatment with BOSULIF. Talk to your doctor about forms of birth control.
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 the medicines you take, including prescription medicines, non-prescription medicines, vitamins, and herbal supplements. BOSULIF and certain other medicines can affect each other.
Especially tell your doctor if you take:
medicines that increase the amount of BOSULIF in your blood stream, such as:
amprenavir (Agenerase®)
aprepitant (Emend®)
atazanavir (Reyataz®)
boceprevir (Victrelis®)
ciprofloxacin (Cipro®, Proquin XR®)
clarithromycin (Biaxin®, Prevpac®)
conivaptan (Vaprisol®)
crizotinib (Xalkori®)
darunavir (Prezista®)
digoxin (Lanoxin®)
diltiazem (Cardizem®, Dilacor XR®, Tiazac®)
erythromycin (Ery-tab®)
fluconazole (Diflucan®)
fosamprenavir (Lexiva®)
imatinib (Gleevec®)
indinavir (Crixivan®)
itraconazole (Onmel®, Sporanox®)
ketoconazole (Nizoral®)
nefazodone (Serzone®)
nelfinavir (Viracept®)
posaconazole (Noxafil®)
ritonavir (Kaletra®, Norvir®)
saquinavir (Invirase®, Fortovase®)
telaprevir (Incivek®)
telithromycin (Ketek®)
verapamil (Calan®, Covera-HS®, Tarka®, Verelan PM®)
voriconazole (Vfend®)
medicines that decrease the amount of BOSULIF in your blood stream, such as:
bosentan (Tracleer®)
carbamazepine (Carbatrol®, Equetro®, Tegretol®)
efavirenz (Sustiva®)
etravirine (Intelence®)
modafinil (Provigil®)
nafcillin (Unipen®, Nallpen®)
phenobarbital (Solfoton®)
phenytoin (Dilantin®)
rifabutin (Mycobutin®)
rifampin (Rifamate®, Rifater®, Rifadin®)
St. John's wort
BOSULIF is best absorbed from your stomach into your blood stream in the presence of stomach acid. You should avoid taking BOSULIF with medicines that reduce stomach acid, such as:
esomeprazole (Nexium®)
dexlansoprazole (Dexilant®)
lansoprazole (Prevacid®)
omeprazole (Prilosec®, Vimovo®, Zegerid®)
pantoprazole sodium (Protonix®)
rabeprazole (AcipHex®)
Medicines that neutralize stomach acid, such as: cimetidine (Tagamet®), famotidine (Pepcid®), ranitidine (Zantac®), aluminum hydroxide/magnesium hydroxide (Maalox®), calcium carbonate (Tums®), or calcium carbonate and magnesia (Rolaids®) may be taken up to 2 hours before or 2 hours after BOSULIF.
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.
You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract while taking 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 it has been more than 12 hours since your last dose, take your next dose at your regular time. Do not take two 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
The other 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 do 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 BOSULIF:
Medicines are sometimes prescribed for purposes other than those listed in the 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.
This Patient Information leaflet summarizes the most important information about BOSULIF. If you would like more information, talk with your doctor. You may ask your doctor or pharmacist for information about BOSULIF that is written for healthcare professionals.
For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1-800-438-1985.
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).
This Patient Information has been approved by the U.S. Food and Drug Administration.
LAB-0639-1.0
September 2012
PRINCIPAL DISPLAY PANEL - 100 mg Bottle Label
Pfizer
NDC 0069-0135-01
Bosulif®
(bosutinib) tablets
100 mg*
Do not crush or cut tablet
For Oncology Use Only
120 Tablets
Rx only
PRINCIPAL DISPLAY PANEL - 500 mg Bottle Label
Pfizer
NDC 0069-0136-01
Bosulif®
(bosutinib) tablets
500 mg*
Do not crush or cut tablet
For Oncology Use Only
30 Tablets
Rx only
BOSULIF
bosutinib monohydrate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0135
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Bosutinib monohydrate (Bosutinib) Bosutinib 100 mg
Inactive Ingredients
Ingredient Name Strength
cellulose, microcrystalline
croscarmellose sodium
POVIDONE K25
magnesium stearate
polyvinyl alcohol
titanium dioxide
POLYETHYLENE GLYCOL 3350
talc
ferric oxide yellow
POLOXAMER 188
Product Characteristics
Color YELLOW Score no score
Shape OVAL (biconvex) Size 11mm
Flavor Imprint Code Pfizer;100
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0069-0135-01 120 TABLET, FILM COATED in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA203341 09/04/2012
BOSULIF
bosutinib monohydrate tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0136
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Bosutinib monohydrate (Bosutinib) Bosutinib 500 mg
Inactive Ingredients
Ingredient Name Strength
cellulose, microcrystalline
croscarmellose sodium
POVIDONE K25
magnesium stearate
polyvinyl alcohol
titanium dioxide
POLYETHYLENE GLYCOL 3350
talc
ferric oxide red
POLOXAMER 188
Product Characteristics
Color RED Score no score
Shape OVAL (biconvex) Size 18mm
Flavor Imprint Code Pfizer;500
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0069-0136-01 30 TABLET, FILM COATED in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA203341 09/04/2012
Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)
Establishment
Name Address ID/FEI Operations
Esteve Quimica, SA 633485529 API MANUFACTURE
Establishment
Name Address ID/FEI Operations
Pfizer Manufacturing Deutschland GmbH (Betriebsstätte Freiburg) 341970073 PACK, LABEL, ANALYSIS, MANUFACTURE
Establishment
Name Address ID/FEI Operations
Excella GmbH 329809800
