Indications and
Usage for Bosulif
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.
Bosulif 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 (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.
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
or
Platelets less than 50,000×106/L
|
Withhold Bosulif until ANC greater than or equal
to1000×106/L and platelets
greater than or equal to 50,000×106/L.
Resume treatment with Bosulif at the same dose if recovery occurs within 2
weeks. If blood counts remain low for greater than 2 weeks, upon recovery,
reduce dose by 100 mg and resume treatment.
If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and
resume treatment.
Doses less than 300 mg/day have not been evaluated.
|
Concomitant Use
With CYP3A Inhibitors
Avoid the
concomitant use of strong or moderate CYP3A inhibitors with Bosulif as an
increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors
include boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and
voriconazole. Moderate CYP3A inhibitors include amprenavir, aprepitant,
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem,
erythromycin, fluconazole, fosamprenavir, grapefruit products, imatinib and
verapamil) [see Drug Interactions (7.1)].
Concomitant Use
With CYP3A Inducers
Avoid the
concomitant use of strong or moderate CYP3A inducers with Bosulif as a large
reduction in exposure is expected (strong CYP3A inducers include carbamazepine,
phenytoin, rifampin and St. John's Wort. Moderate CYP3A inducers include
bosentan, efavirenz, etravirine, modafinil and nafcillin) [see Drug
Interactions (7.2)].
Recommended
Starting Dosage with Hepatic Impairment or Renal Impairment
|
Organ Function Status
|
Recommended Starting Dosage
|
|
Normal hepatic and renal function
|
500 mg once daily
|
|
Hepatic impairment
|
|
Mild (Child-Pugh A), Moderate (Child-Pugh
B) or severe (Child-Pugh C)
|
200 mg daily
|
|
Renal impairment
|
|
Creatinine clearance 30 to 50 mL/min
|
400 mg daily
|
|
Creatinine clearance less than 30 mL/min
|
300 mg daily
|
|
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
|
Dosage Forms and
Strengths
100 mg tablets:
yellow, oval, biconvex, film-coated tablets debossed with "Pfizer" on
one side and "100" on the other.
400 mg tablets:
orange, oval, biconvex, film-coated tablets debossed with "Pfizer" on
one side and "400" on the other.
500 mg tablets:
red, oval, biconvex, film-coated tablets debossed with "Pfizer" on
one side and "500" on the other.
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.
Warnings and
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 (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
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 (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.
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 [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 2 identifies the shift from baseline to lowest
observed estimated glomerular filtration rate (eGFR) during Bosulif therapy for
patients in the global Ph+ Leukemia studies. The median duration of therapy
with Bosulif was approximately 17 months (range, 0.03 to 95) for patients in
these studies.
Table 2: Shift from Baseline to Lowest Observed eGFR
Group During Treatment Safety Population in Clinical Studies (n=818)*
|
|
Baseline
|
Follow-Up
|
|
Renal Function Status
|
n
|
Normal
n (%)
|
Mild
n (%)
|
Mild to Moderate
n (%)
|
Moderate to Severe
n (%)
|
Severe
n (%)
|
Kidney Failure
n (%)
|
|
Notes: Grading is based on Modification in Diet in
Renal Disease method (MDRD).
KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60
to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30
to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15
ml/min/1.73 m2.
|
|
*
Among the 818
patients, eGFR was missing in 5 patients at baseline or on-therapy. There
were no patients with kidney failure at baseline.
|
|
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)
|
Monitor renal
function at baseline and during therapy with Bosulif, with particular attention
to those patients who have preexisting renal impairment or risk factors for
renal dysfunction. Consider dose adjustment in patients with baseline and
treatment emergent renal impairment [see Dosage and
Administration (2.7)].
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 (8.1)].
Adverse
Reactions
The following
adverse reactions are discussed in greater detail in other sections of the
labeling:
Gastrointestinal
toxicity [see Dosage and
Administration (2.3) and Warnings
and Precautions (5.1)].Myelosuppression [see Dosage and
Administration (2.4) and Warnings
and Precautions (5.2)].Hepatic
toxicity [see Dosage and
Administration (2.5) and Warnings
and Precautions (5.3)].Fluid
retention [see Warnings
and Precautions (5.4)].Renal
toxicity [see Warnings
and Precautions (5.5)].
Clinical Trials
Experience
Because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed
in practice.
Serious adverse
reactions reported include anaphylactic shock [see Contraindications
(4)], myelosuppression, gastrointestinal
toxicity (diarrhea), fluid retention, hepatotoxicity and rash.
Adverse
reactions of any toxicity grade reported for greater than 20% of patients in
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
(14)].
Adverse
Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase
(CP), Accelerated Phase (AP), and Blast Phase (BP) CML
The single-arm
Phase 1/2 clinical trial (Study 1) enrolled patients with Ph+ chronic,
accelerated, or blast phase chronic myelogenous leukemia (CML) and with
resistance or intolerance to prior therapy [see Clinical Studies
(14)]. The safety population (received at
least 1 dose of Bosulif) included 546 CML patients:
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
(%)
|
|
|
Advanced Phase CML includes patients with Accelerated
Phase and Blast Phase CML
|
|
|
*
Based on a Minimum of 48 Months of Follow-up
†
Abdominal pain includes the following preferred terms:
Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain
upper, Abdominal tenderness, Gastrointestinal pain
‡
Thrombocytopenia includes the following preferred
terms: Platelet count decreased, Thrombocytopenia
§
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
¶
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
maculo-papular, Skin irritation, Stasis dermatitis
#
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
Þ
Fatigue includes the following preferred terms:
Fatigue, Malaise
ß
Anaemia includes the following preferred terms:
Anaemia, Haemoglobin decreased
à
Neutropenia includes the following preferred terms:
Neutropenia, Neutrophil count decreased
è
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
ð
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
ø
Leukopenia includes the following preferred terms:
Leukopenia, White blood cell count decreased
ý
Chest pain
included the following preferred terms: Chest pain, chest discomfort.
|
|
|
Diarrhea
|
85
|
9
|
76
|
4
|
|
|
Nausea
|
47
|
1
|
48
|
2
|
|
|
Abdominal Pain†
|
42
|
2
|
31
|
6
|
|
|
Thrombocytopenia‡
|
40
|
26
|
45
|
39
|
|
|
Respiratory tract infection§
|
39
|
5
|
38
|
12
|
|
|
Vomiting
|
37
|
3
|
43
|
3
|
|
|
Rash¶
|
42
|
8
|
38
|
4
|
|
|
Liver test abnormalities#
|
26
|
9
|
20
|
10
|
|
|
FatigueÞ
|
26
|
2
|
21
|
5
|
|
|
Anemiaß
|
27
|
11
|
38
|
27
|
|
|
Pyrexia
|
23
|
<1
|
37
|
2
|
|
|
Headache
|
21
|
<1
|
17
|
4
|
|
|
Cough
|
22
|
0
|
22
|
0
|
|
|
Neutropeniaà
|
18
|
12
|
22
|
20
|
|
|
Edemaè
|
20
|
1
|
17
|
2
|
|
|
Arthralgia
|
17
|
<1
|
14
|
0
|
|
|
Decreased appetite
|
14
|
<1
|
13
|
0
|
|
|
Renal impairmentð
|
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
|
|
|
Leukopeniaø
|
10
|
4
|
15
|
12
|
|
|
Chest painý
|
7
|
1
|
12
|
1
|
|
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 (%)
|
|
*
Based on a
Minimum of 48 Months of Follow-up
|
|
Hematology Parameters
|
|
|
|
|
Platelet Count (Low) less than 50×109/L
|
105 (26)
|
82 (57)
|
187 (34)
|
|
Absolute Neutrophil Count less than 1×109/L
|
65 (16)
|
55 (39)
|
120 (22)
|
|
Hemoglobin (Low) less than 80 g/L
|
51 (13)
|
54 (38)
|
105 (19)
|
|
|
|
Biochemistry Parameters
|
|
|
|
|
SGPT/ALT greater than 5.0×ULN
|
43 (11)
|
8 (6)
|
51 (9)
|
|
SGOT/AST greater than 5.0×ULN
|
19 (5)
|
5 (4)
|
24 (4)
|
|
Lipase greater than 2×ULN
|
42 (10)
|
9 (6)
|
51 (9)
|
|
Phosphorus (Low) less than 0.6 mmol/L
|
30 (7)
|
10 (7)
|
40 (7)
|
|
Total Bilirubin greater than 3.0×ULN
|
3 (1)
|
4 (3)
|
7 (1)
|
Additional
Adverse Reactions from Multiple Clinical Trials
The following
adverse reactions were reported in patients in clinical trials with Bosulif
(less than 10% of Bosulif-treated patients). They represent an evaluation of
the adverse reaction data from 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 (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)].
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.
USE IN SPECIFIC
POPULATIONS
Pregnancy
Pregnancy
Category D [see Warnings and
Precautions (5.6)]
Based on its
mechanism of action and findings in animals, Bosulif can cause fetal harm when
administered to a pregnant woman. Studies in animals showed reproductive
toxicities. 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 (2.7), Adverse
Reactions (6), and Clinical Pharmacology (12.3)].
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 (2.7) and Clinical
Pharmacology (12.3)].
Bosulif has not
been studied in patients undergoing hemodialysis.
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.
Bosulif 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 3 strengths: a 100 mg yellow,
oval, biconvex, film-coated tablet debossed with "Pfizer" on one side
and "100" on the other; a 400 mg orange, oval, biconvex, film-coated
tablet debossed with "Pfizer" on one side and "400" 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 400 mg Bosulif tablet contains 413.60 mg of bosutinib
monohydrate, equivalent to 400 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, and 400 mg tablet) and iron oxide red
(for 400 mg, and 500 mg tablet).
Bosulif -
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 time-to-peak concentration (tmax) was 4–6 hours.
Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose
range of 200 to 800 mg. After 15 daily doses of Bosulif (500 mg) with food in
patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and the
mean (SD) AUC was 3650 (425) ng∙h/mL. When given with a high fat meal, the Cmax and AUC of
bosutinib increased 1.8- and 1.7-fold, respectively.
Following
administration of a single dose of Bosulif (500 mg) with food to healthy
subjects, the absolute bioavailability was 34%.
Distribution
After
administration of a single dose of Bosulif 500 mg with food in patients with
CML, bosutinib had a mean apparent volume of distribution ± standard deviation
of 6080 ± 1230 L.
Bosutinib was
highly bound to human plasma proteins in vitro (94%)
and ex vivo in healthy subjects (96%), and binding was not
concentration-dependent.
Metabolism
Bosutinib is
primarily metabolized by CYP3A4. The major circulating metabolites identified
in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure)
and N-desmethylated (M5) bosutinib (25% of parent exposure),
with bosutinib N-oxide (M6) as a minor circulating
metabolite. All the metabolites were deemed inactive.
Elimination
In patients with
CML given single oral doses of Bosulif 500 mg with food, the mean terminal
phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean
(SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given a
single oral dose of [14C] radiolabeled bosutinib, 91.3% of the
dose was recovered in feces and 3% of the dose recovered in urine.
Hepatic
Impairment
In a dedicated
hepatic impairment trial, a single dose of Bosulif 200 mg was administered with
food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C)
and 9 matched healthy volunteers. Cmax of bosutinib increased 2.4-fold,
2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and
bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively [see Dosage and
Administration (2.7), and Use in Specific Populations (8.6)].
Renal Impairment
In a dedicated
renal impairment trial, a single dose of Bosulif 200 mg was administered with
food to 26 subjects with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50
mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to 8 subjects
with normal renal function. Creatinine Clearance for category classification
was calculated by the Cockcroft-Gault formula. Subjects with moderate and
severe renal impairment had a 35% and 60% increase in AUC compared to subjects
with normal renal function, respectively. Bosutinib exposure was not changed in
subjects with mild renal impairment. The Bosulif dose should be reduced in
patients with severe (CLcr less than 30 mL/min) or moderate (CLcr between 30 to
50 mL/min) renal impairment [see Dosage and Administration (2.1) and Use in Specific
Populations (8.7)].
Drug
Interactions
CYP3A Inhibitors
In a cross-over
drug-drug interaction trial in healthy subjects (n=24), a single dose of 100 mg
Bosulif was administered alone or in combination with five daily doses of 400
mg ketoconazole (a strong CYP3A inhibitor) under fasting conditions.
Ketoconazole increased bosutinib Cmax and AUC by 5.2-fold and 8.6-fold,
respectively.
In a cross-over
drug-drug interaction trial in healthy subjects (n=18), a single dose of 500 mg
Bosulif was administered alone or in combination with 125 mg aprepitant (a
moderate CYP3A inhibitor) under fed conditions. Aprepitant increased bosutinib
Cmax and AUC by 1.5-fold and 2.0-fold,
respectively [see Dosage and Administration (2.5) and Drug
Interactions (7.1)].
CYP3A Inducers
In a cross-over
drug-drug interaction trial in healthy subjects (n=22), a single dose of 500 mg
Bosulif was administered alone or in combination with six daily doses of 600 mg
rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by
86% and 94%, respectively [see Dosage and Administration (2.5) and Drug Interactions
(7.2)].
P-gp Substrates
In a cross-over
drug-drug interaction trial in healthy subjects (n=25), a single dose of 500 mg
Bosulif was administered in combination with a single dose of 150 mg dabigatran
etexilate mesylate (a P-glycoprotein (P-gp) substrate). Bosutinib did not
increase Cmax or AUC of dabigatran in plasma, as compared with
administration of dabigatran etexilate mesylate alone under fed conditions. The
study results indicate that bosutinib is not a P-gp inhibitor clinically.
pH Altering
Medications
Bosulif displays
pH-dependent aqueous solubility, in vitro. In a
cross-over trial in 23 healthy volunteers, a single oral dose of 400 mg of
Bosulif was either administered alone or in combination with multiple-oral
doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased
bosutinib Cmaxand AUC by 46% and 26%, respectively.
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).
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 (%)
|
|
Abbreviations: CI = confidence interval, MCyR = major
cytogenetic response
|
|
By Week 24
|
|
|
|
MCyR
|
105 (40.1)
|
29 (25.9)
|
|
(95% CI)
|
(34.1, 46.3)
|
(18.1, 35.0)
|
|
MCyR any time
|
156 (59.5)
|
45 (40.2)
|
|
|
(53.3, 65.5)
|
(31.0, 49.9)
|
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 (%)
|
|
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
|
22 (30.6)
|
10 (16.7)
|
|
(95% CI)
|
(20.2, 42.5)
|
(8.3, 28.5)
|
|
OHR* by Week 48
|
41 (56.9)
|
17 (28.3)
|
|
(95% CI)
|
(44.7, 68.6)
|
(17.5, 41.4)
|
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.
How
Supplied/Storage and Handling
How Supplied
Bosulif
(bosutinib) tablets are supplied for oral administration in 3 strengths: a 100
mg yellow, oval, biconvex, film-coated tablet debossed with "Pfizer"
on one side and "100" on the other; a 400 mg orange, oval, biconvex,
film-coated tablet debossed with "Pfizer" on one side and
"400" on the other; and a 500 mg red, oval, biconvex, film-coated
tablet debossed with "Pfizer" on one side and "500" on the
other. Bosulif (bosutinib) tablets are available in the following packaging
configurations (Table 7):
Table 7: Tablet Presentations
|
|
Bosulif Tablets
|
|
Package Configuration
|
Tablet Strength (mg)
|
NDC
|
Tablet Description
|
|
120 tablets per bottle
|
100 mg
|
0069-0135-01
|
Yellow, oval, biconvex, film-coated tablets, debossed
"Pfizer" on one side and "100" on the other.
|
|
30 tablets per bottle
|
400 mg
|
0069-0193-01
|
Orange, oval, biconvex, film-coated tablet debossed
with "Pfizer" on one side and "400" 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.
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 (5.1)].
• 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 (5.2)].
• Liver Problems
Advise patients
of the possibility of developing liver function abnormalities and to
immediately report jaundice [see Warnings and Precautions (5.3)].
• 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 (5.4)].
• Renal Problems
Advise patients
of the possibility of developing renal problems and to immediately report
frequent urination, polyuria or oliguria [see Warnings and
Precautions (5.5)]
• 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
(4) and Adverse
Reactions (6)].
• 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 (5.6) and Use in Specific
Populations (8.1)]. 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 (8.2)].
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 (8.3)]. 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 (8.1 and 8.2)]. If a patient
wishes to restart breastfeeding after treatment, advise her to discuss the
appropriate timing with her physician [see Use in
Specific Populations (8.2)].
• 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-0443-9.0
|
PATIENT INFORMATION
Bosulif® (BAH-su-lif)
(bosutinib)
tablets
|
|
This Patient Information has been approved by the U.S.
Food and Drug Administration.
|
Revised: 10/2017
|
|
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 problemshave heart problemshave kidney problemsare 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:
|
|
|
o shortness of breath and cough
o chest pain
o swelling in your hands, ankles, or feet
|
o swelling all over your body
o 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 normalyou urinate less often than normalyou make a much larger amount of urine than
normalyou 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 and 400
mg tablets) and iron oxide red (for 400 mg and 500 mg tablets).
|
|
|
|
LAB-0639-7.0
|
|
For more information, go to www.Bosulif.com or
www.pfizermedicalinformation.com or call 1-800-438-1985.
|
|
|
|
|
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
PRINCIPAL
DISPLAY PANEL - 400 mg Tablet Bottle Label
Pfizer
NDC 0069-0193-01
Bosulif®
(bosutinib) tablets
400 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 LABEL
|
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 MONOHYDRATE
|
100 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
POVIDONE K25
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL,
UNSPECIFIED
|
|
|
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
|
|
|
1
|
NDC:0069-0135-01
|
120 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
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 LABEL
|
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 MONOHYDRATE
|
500 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
POVIDONE K25
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL,
UNSPECIFIED
|
|
|
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
|
|
|
1
|
NDC:0069-0136-01
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
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 LABEL
|
Item Code (Source)
|
NDC:0069-0193
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
BOSUTINIB MONOHYDRATE (BOSUTINIB)
|
BOSUTINIB MONOHYDRATE
|
400 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
POVIDONE K25
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL,
UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
POLYETHYLENE GLYCOL 3350
|
|
|
TALC
|
|
|
FERRIC OXIDE RED
|
|
|
POLOXAMER 188
|
|
|
|
Product Characteristics
|
|
Color
|
ORANGE
|
Score
|
no score
|
|
Shape
|
OVAL (biconvex)
|
Size
|
18mm
|
|
Flavor
|
|
Imprint Code
|
Pfizer;400
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0069-0193-01
|
30 TABLET, FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA203341
|
10/01/2017
|
|
|
|
Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pfizer Manufacturing Deutschland GmbH (Betriebsstätte
Freiburg)
|
|
341970073
|
MANUFACTURE(0069-0135, 0069-0136, 0069-0193)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Esteve Quimica, SA
|
|
633485529
|
API MANUFACTURE(0069-0135, 0069-0136, 0069-0193)
|
Revised: 11/2017
Pfizer
Laboratories Div Pfizer Inc
