Bosulif

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to bosutinib.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• 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• Ask your doctor or pharmacist about the right way to throw away outdated or unused Bosulif.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.

Bosutinib interferes with the growth of some cancer cells.

Bosutinib is used in adults to treat a type of blood cancer called Philadelphia chromosome positive chronic myelogenous leukemia (CML).

Bosutinib is usually given after other similar medications have been tried without success.

Bosutinib may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use bosutinib if you are allergic to it.

To make sure bosutinib is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• heart disease; or

• asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder.

Do not use bosutinib if you are pregnant. It could harm the unborn baby. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication and for at least 30 days after your treatment ends.

It is not known whether bosutinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. After you stop taking bosutinib, ask your doctor how long to wait before breast-feeding again.

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Storage

Oral

20–25°C (may be exposed to 15–30°C).1

Bosutinib is used to treat chronic myeloid leukemia (CML) that is Philadelphia chromosome-positive (Ph+). Leukemia is a type of cancer where the body makes abnormal white blood cells.

Bosutinib is an antineoplastic (cancer) medicine. It interferes with the growth of cancer cells, which are eventually destroyed by the body. Since the growth of normal cells may also be affected by bosutinib, other side effects can occur. Before you begin treatment, talk to your doctor about the benefits of this medicine as well as the possible risks of using it.

This medicine is available only with your doctor's prescription.

• It is used to treat a type of leukemia.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Dizziness.
• Feeling tired or weak.
• Belly pain.
• Not hungry.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Joint pain.
• Back pain.
• Nose and throat irritation.
• Change in taste.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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 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.

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.

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.

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.

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.

Bosulif is usually taken once per day. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take with food.

Do not break or crush a Bosulif tablet. The medicine from a crushed or broken pill can be dangerous if it gets on your skin. If this occurs, wash your skin with soap and water. Ask your doctor or pharmacist how to safely handle and dispose of a broken tablet.

Bosulif can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

You should not stop using Bosulif without your doctor's advice.

Store at room temperature away from moisture and heat.

Usual Adult Dose for Chronic Myelogenous Leukemia:

500 mg orally once a day with food
Duration of therapy: Until disease progression or patient intolerance

Comments: If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.

Use: 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.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Grapefruit and grapefruit juice may interact with bosutinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking Bosulif.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Get emergency medical help if you have signs of an allergic reaction to Bosulif: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Bosulif and call your doctor at once if you have:

• severe or ongoing nausea, vomiting, stomach pain, or diarrhea;

• swelling in your hands or feet, rapid weight gain;

• sudden weakness or ill feeling, fever, chills, flu-like symptoms, mouth sores, red or swollen gums, trouble swallowing;

• skin sores, pale skin, easy bruising, unusual bleeding;

• rapid heart rate, feeling light-headed;

• liver problems - nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• swelling or fluid build-up in the lungs - anxiety, sweating, pale skin, severe shortness of breath, pain when you breathe, feeling short of breath while lying down, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate.

Your cancer treatments may be delayed if you have certain side effects.

Common Bosulif side effects may include:

• feeling tired;

• nausea, vomiting, diarrhea, stomach pain;

• fever;

• rash; or

• pale skin, bruising or bleeding.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.