BOSULIF

BOSULIF- bosutinib monohydrate tablet, film coated
Pfizer Laboratories Div Pfizer Inc

1 INDICATIONS AND USAGE

BOSULIF is indicated for the treatment of adult patients with:

Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML).
Chronic phase, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy.

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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.

2.3 Dose Adjustments for Non-Hematologic Adverse Reactions

Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy’s law case definition), discontinue BOSULIF [see Warnings and Precautions (5.3)].

Diarrhea: For 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 [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 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.

2.4 Dose Adjustments for Myelosuppression

Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
*
Absolute Neutrophil Count

ANC * less than 1000×106 /L

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 been used in patients; however, efficacy has not been established.

2.5 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
Recommended Starting Dosage
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
Abbreviations: CML=chronic myelogenous leukemia; Ph+=Philadelphia chromosome-positive.
*
There are no clinical data for efficacy at the dose of 200 mg once daily in patients with CML.

Newly-diagnosed chronic phase Ph+ CML2

Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy

Normal renal and hepatic function

400 mg daily

500 mg daily

Renal impairment

Creatinine clearance 30 to 50 mL/min

300 mg daily

400 mg daily

Creatinine clearance less than 30 mL/min

200 mg daily

300 mg daily

Hepatic impairment

Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C)

200 mg daily *

200 mg daily *

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.

4 CONTRAINDICATIONS

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

5.1 Gastrointestinal Toxicity

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

In the randomized clinical trial in 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 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).

To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].

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