Bosulif (bosutinib)

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.
• 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.
• 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 if you get any of the following symptoms during your treatment with Bosulif:
  • shortness of breath and cough
  • swelling all over your body
  • chest pain
  • weight gain
  • swelling in your hands, ankles, or feet
• 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 normal
  • you urinate less often than normal
  • you make a much larger amount of urine than normal
  • you make a much smaller amount of urine than normal

The most common side effects of Bosulif in people with newly-diagnosed CML include:

• diarrhea
• rash
• nausea
• changes in liver function test
• low platelet counts
• stomach (abdomen) pain

The most common side effects of Bosulif in people with CML who no longer benefit from or did not tolerateother treatment include:

• diarrhea
• tiredness
• nausea
• fever
• stomach (abdomen) pain
• cough
• rash
• headache
• low platelet counts
• change in liver function test
• vomiting
• swelling
• low red blood cell counts

Tell your doctor or get medical help 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.

Your doctor may change your dose, temporarily stop, or permanently stop treatment with Bosulif if you have certain side effects.

Bosulif may cause fertility problems in females and males. This may affect your ability to have a child. Talk toyour doctor if this is a concern for you.

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.

Recommended Dosing

The recommended dose is taken orally once daily with food. The tablet is to be swallowed whole and should not be broken or cut. Continue treatment with Bosulif until disease progression or intolerance to therapy.

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

Newly-Diagnosed CP Ph+ CML

• The recommended dose of Bosulif is 400 mg orally once daily with food.

CP, AP, Or BP Ph+ CML With Resistance Or Intolerance To Prior Therapy

• The recommended dose and schedule of Bosulif is 500 mg orally once daily with food.

Dose Escalation

• In clinical studies of adult Ph+ CML patients, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage.

Dose Adjustments For Non-Hematologic Adverse Reactions

• Elevated liver transaminases: If elevations in liver transaminases greater than 5xinstitutional upper limit of normal (ULN) occur, withhold Bosulif until recovery to less than or equal to 2.5xULN 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 3xULN occur concurrently with bilirubin elevations greater than 2xULN and alkaline phosphatase less than 2xULN (Hy's law case definition), discontinue Bosulif.

Diarrhea

• For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold Bosulif until recovery to Grade less than or equal to 1. Bosulif may be resumed at 400 mg once daily.
• For other clinically significant, moderate or severe non-hematological toxicity, withhold Bosulif until the toxicity has resolved, then consider resuming Bosulif at a dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of Bosulif to the starting dose taken once daily. Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.

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

Dose Adjustments For Renal Impairment Or Hepatic Impairment

The recommended starting doses for patients with renal and hepatic impairment are described in Table 2 below.

Table 2: Dose Adjustments for Renal and Hepatic Impairment

Effect Of Other Drugs On Bosulif

Strong Or Moderate CYP3A Inhibitors

• Concomitant use with a strong or moderate CYP3A inhibitor increased bosutinib Cmax and AUC compared to Bosulif alone which may increase the risk of toxicities. Avoid the concomitant use of strong or moderate CYP3A inhibitors with Bosulif.

Strong CYP3A Inducers

• Concomitant use with a strong CYP3A inducer decreased bosutinib Cmax and AUC compared to Bosulif alone which may reduce Bosulif efficacy. Avoid the concomitant use of strong CYP3A inducers with Bosulif.

Proton Pump Inhibitors (PPI)

• Concomitant use with a PPI decreased bosutinib Cmax and AUC compared to Bosulif alone which may reduce Bosulif efficacy. As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from Bosulif dosing.

• 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.
• 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.
• 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.