Drug Safety-related Labeling Changes (SrLC)

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BOSULIF (NDA-203341)

(BOSUTINIB MONOHYDRATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/02/2026 (SUPPL-27)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

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 all 1372 patients with 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.

. . .

Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme, Cutaneous vasculitis

12/03/2024 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Cardiovascular Toxicity

Additions and/or revisions underlined:

…

In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with BOSULIF.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Additional Adverse Reactions From Multiple Clinical Trials

…

Cardiac Disorders: 1% and less than 10% - Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% - Pericarditis

…

09/26/2023 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Gastrointestinal Toxicity

Additions and/or revisions underlined:

Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement.

In the randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 4 days and the median duration per event was 3 days.

Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-268).

Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days. Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 2 (range 1 – 198).

…

5.3 Hepatic Toxicity

Additions and/or revisions underlined:

…

In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first

3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively.

Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days.

Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59% and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade, 84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively.

…

5.4 Cardiovascular Toxicity

Additions and/or revisions underlined:

…

In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib.

In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 4.9% of patients treated with BOSULIF.

Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each).

…

5.5 Fluid Retention

Additions and/or revisions underlined:

…

In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion.

Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema.

Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, Grade 1-2 pericardial effusion, peripheral edema, and face edema were reported in 1 patient each.

…

5.6 Renal Toxicity

Additions and/or revisions underlined:

…

Overall, 45% of the pediatric patients with newly diagnosed CP Ph+ CML or resistant or intolerant CP Ph+ CML who had normal eGFR at baseline shifted to a maximum of mild, and 40% pediatric patients who had mild eGFR at baseline shifted to a maximum of moderate during treatment.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

7 Drug Interactions

7.1 Effect of Other Drugs on BOSULIF

Additions and/or revisions underlined:

Strong or Moderate CYP3A Inhibitors

Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF. Bosutinib is a CYP3A substrate.

…

Strong CYP3A Inducers

Avoid the concomitant use of strong CYP3A inducers with BOSULIF. Bosutinib is a CYP3A substrate.

…

Proton Pump Inhibitors (PPI)

As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from BOSULIF dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with a PPI decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BOSULIF efficacy.

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information

The safety and effectiveness of BOSULIF have been established in pediatric patients 1 year of age and older with newly-diagnosed CP Ph+ CML and CP Ph+ CML that is resistant or intolerant to prior therapy.

Use of BOSULIF for these indications is based on data from BCHILD [NCT04258943]. The study included pediatric patients with newly diagnosed CP Ph+ CML in the following age groups: 2 patients 1 year of age to less than 6 years of age, 3 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. The study also included pediatric patients with CP Ph+ CML that was resistant or intolerant to prior therapy in the following age groups: 4 patients 1 year of age to less than 6 years of age, 10 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. [see Adverse Reactions (6.1) and Clinical Studies (14.3]. BSA-normalized apparent clearance in 27 pediatric patients aged 4 to <17 years (141.3 L/h/m2) was 29% higher than BSA-normalized apparent clearance in adult patients with CP Ph+ CML (109.2 L/h/m2) [see Clinical Pharmacology (12.3)]. The recommended dosage of BOSULIF in pediatric patients is based on body-surface area (BSA) [see Dosage and Administration (2.1)].

The safety and effectiveness of BOSULIF in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Dosage 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: “Swallow tablets whole. Do not crush, break, or cut tablet. Do not touch or handle crushed or broken tablets.” Patients should be advised: “Capsules may be swallowed whole. For those that cannot swallow the capsule whole, the capsule can be opened and the contents mixed with applesauce or yogurt.”

…

• 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, pruritus or constipation 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)].

 

PATIENT INFORMATION

Additions and/or revisions underlined:

BOSULIF® (BAH-su-lif) (bosutinib) capsules

What is BOSULIF?

BOSULIF is a prescription medicine used to treat:

• adults and children 1 year of age and older who have a certain type of leukemia called chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment.

• adults with accelerated phase (AP), or blast phase (BP) Ph+ CML who can no longer benefit from or did not tolerate other treatment.

It is not known if BOSULIF is safe and effective in children less than 1 year of age with CP Ph+ CML who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment or in children with AP Ph+ CML or BP Ph+ CML.

…

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.

• If your child takes BOSULIF, your healthcare provider will change the dose as your child grows.

• Take BOSULIF with food.

• Swallow BOSULIF tablets whole. Do not crush, break, chew or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets.

• Swallow BOSULIF capsules whole. If you cannot swallow BOSULIF capsules whole, tell your healthcare provider.

• If you cannot swallow BOSULIF capsules whole, see the “Instructions for Use” for detailed instructions on how to prepare and give a dose of BOSULIF capsules by opening the capsules and mixing the capsule contents with applesauce or yogurt.

…

What are the possible side effects of BOSULIF?

…

The most common side effects of BOSULIF in adults and children with CML include:

• Constipation

…

How should I store BOSULIF?

• Store BOSULIF tablets and capsules at room temperature between 68°F to 77°F (20°C to 25°C).

• The BOSLUIF tablets and capsules bottle has a child-resistant closure.

• The BOSULIF tablets bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant.

• Store the BOSULIF capsules in the original bottle.

…

What are the ingredients in BOSULIF?

Active ingredient: bosutinib.

Inactive ingredients: Tablets: croscarmellose sodium, iron oxide red (for 400 mg, and 500 mg tablet) and iron oxide yellow (for 100 mg, and 400 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide. Capsules: croscarmellose sodium, gelatin, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer, povidone, red iron oxide, titanium dioxide, yellow iron oxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution.

04/20/2023 (SUPPL-24)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% - Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure

…

05/14/2021 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis [see Adverse Reactions (6.1)].

5 Warnings and Precautions

5.3 Hepatic Toxicity

Additions and/or revisions underlined:

Two cases consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) have occurred without alternative causes. This represented 2 out 1711 patients in BOSULIF clinical trials.

In the 268 patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and AST elevation was 56.0%. Of patients who experienced transaminase elevations of any grade, 73% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively.

Among the 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of ALT elevation was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 81% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days …

5.4 Cardiovascular Toxicity

BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders.

In a randomized study with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib.

In a single-arm study in patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 4.9% of patients treated with BOSULIF.

Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3)].

5.5 Fluid Retention

Additions and/or revisions underlined:

… In the randomized clinical trial of 268 patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema …

5.6 Renal Toxicity

Additions and/or revisions underlined:

… The median duration of therapy with BOSULIF was approximately 24 months (range, 0.03 to 155) for patients in these studies.

Table 3: Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (N=1372)*

6 Adverse Reactions

‘Cardiovascular toxicity’ replaces ‘Cardiac failure’ in the bulleted line listing.

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

• Cardiovascular Toxicity

Advise patients that cardiac failure, left ventricular dysfunction, and cardiac ischemic events have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of cardiac failure and cardiac ischemia occur, such as shortness of breath, weight gain, or fluid retention [see Warnings and Precautions (5.4)].

PATIENT INFORMATION

Additions and/or revisions underlined:

Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you:

• have high blood pressure

• have diabetes

What are the possible side effects of BOSULIF? BOSULIF may cause serious side effects, including:

• Heart problems. BOSULIF may cause heart problems, including heart failure and decreased blood flow to the heart which can lead to heart attack. Get medical help right away if you get shortness of breath, weight gain, chest pain, or swelling in your hands, ankles or feet.

The most common side effects of BOSULIF in people with CML include:

• vomiting

• tiredness

• liver problems

• respiratory tract infections (infections in nose, throat or lungs)

• fever

• headache

• changes in certain blood tests. Your doctor may do blood tests during treatment with BOSULIF to check for changes

Tell your doctor or get medical help right away if you get respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, rash or itching while taking BOSULIF. These may be symptoms of a severe allergic reaction.

06/17/2020 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

(Newly added information)

Endocrine Disorders: 1% and less than 10% - Hypothyroidism; 0.1% and less than 1% - Hyperthyroidism

10/09/2019 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.4 Cardiac Failure

Cardiac failure and left ventricular dysfunction have been reported in patients taking BOSULIF. These events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure.

In a randomized study with newly diagnosed CML, cardiac failure occurred in 1.5% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib.

In a single-arm study in patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients treated with BOSULIF.

Monitor patients for signs and symptoms consistent with cardiac failure and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary.

6 Adverse Reactions

Newly added to bulleted line listing:

Cardiac Failure

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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, vomiting, or blood in your stools. Get medical help right away for any stomach problems.

• Heart problems. BOSULIF may cause heart problems, including heart failure. Get medical help right away if you get shortness of breath, weight gain or swelling in your hands, ankles or feet.

• 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. Get medical help right away …

Tell your doctor or get medical help right away if you get respiratory tract infections …

08/14/2019 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose.

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

 •       Gastrointestinal toxicity

•       Myelosuppression

•       Hepatic toxicity

•       Fluid retention

•       Renal toxicity

8 Use in Specific Populations

Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Pregnancy

Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF.

Contraception  

Females

Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for at least 2 weeks after the last dose.

Lactation

Additions and/or revisions underlined:

Risk Summary

No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for at least 2 weeks after the last dose.

Pregnancy

Additions and/or revisions underlined:

Risk Summary

Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Data

Animal Data

In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an  approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively.

Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise females of reproductive potential, to use effective contraception during treatment and for at least 2 weeks after receiving the last dose of BOSULIF.

Advise lactating women not to breastfeed during treatment with BOSULIF and for at least 2 weeks after the last dose.

PATIENT INFORMATION

Additions and/or revisions underlined:

Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you:

- are pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting treatment with BOSULIF. Tell your doctor right away if you become pregnant during treatment with BOSULIF.

     - Females who are able to become pregnant should use effective birth control (contraception) during treatment with BOSULIF and for at least 2 weeks after the last dose. Talk to your doctor about birth control methods that may be right for you.

- are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. Do not breastfeed during treatment with BOSULIF and for at least 2 weeks after the last dose.

10/18/2018 (SUPPL-15)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

(Additions and/or revisions are underlined)

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.

 Blood and Lymphatic System Disorders: Thrombotic microangiopathy

04/13/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Gastrointestinal Toxicity

(Additions and/or revisions are underlined)

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)…

5.3 Hepatic Toxicity

(Additions and/or revisions are underlined)

Among the 546 patients in a single-arm Phase 1/2 clinical trial the incidence of ALT elevation was 18% and AST levation 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.

5.4 Fluid Retention

(Additions and/or revisions are underlined)

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…

5.6 Embryofetal Toxicity

(Additions and/or revisions are underlined)

… 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…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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%).

•         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 ½ CML safety population based on long-term follow-up.

Table 3: Adverse Reactions (10% or Greater) in Patients with CML in Study 1*

*Based on a Minimum of 48 Months of Follow-up

Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML

a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain

b Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia

c Respiratory tract infection includes the following preferred terms: Acute sinusitis, Acute

tonsillitis, Atypical pneumonia, Bronchitis, Bronchitis bacterial, Bronchitis pneumococcal, Bronchopneumonia, Chronic tonsillitis, H1N1 influenza, Influenza, Laryngitis, Lobar pneumonia, Lower respiratory tract infection, Lung infection, Nasopharyngitis, Pertussis, Pharyngitis, Pharyngotonsillitis, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia pneumococcal, Pneumonia streptococcal, Pulmonary mycosis, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Sinusitis, Tonsillitis, Tonsillitis bacterial, Tracheitis, Upper respiratory tract infection, Viral upper respiratory tract infection

d Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic, Eczema, Eczema asteatotic, Erythema, Generalised erythema, Intertrigo, Palmar erythema, Prurigo, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Skin irritation, Stasis dermatitis

e Liver Test Abnormalities includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hyperbilirubinaemia, Liver function test abnormal, Transaminases increased

f Fatigue includes the following preferred terms: Fatigue, Malaise

g Anaemia includes the following preferred terms: Anaemia, Haemoglobin decreased

h Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased

i Edema includes the following preferred terms containing: Acute pulmonary edema, Allergic edema, Angioedema, Bone marrow edema, Circumoral edema, Eyelid edema, Eye edema, Face edema, Gastrointestinal edema, Localised edema, Edema, Edema peripheral, Periorbital edema, Pharyngeal edema, Pulmonary edema, Scrotal edema, Testicular edema, Tongue edema, Weight increased

j Renal impairment includes the following preferred terms: Acute kidney injury, Acute prerenal failure, Anuria, Blood creatinine abnormal, Blood creatinine increased, Chronic kidney disease,

Oliguria, Prerenal failure, Renal failure, Renal impairment

k Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased

l Chest pain included the following preferred terms: Chest pain, chest discomfort.

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.

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...

Blood and Lymphatic System Disorders: 1% and less than 10% - febrile neutropenia; less than 1% - granulocytopenia

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

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)

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Pregnancy Category D

…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…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you:

•         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.

04/13/2017 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

(Newly Added Subsection)

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

11/17/2016 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience (Addition underlined)

Vascular Disorders: 1% and less than 10% - hypertension