BOSULIF (bosutinib) tablet Dosage And Administration

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Recommended Dose and Dosage Adjustment

Bosutinib should be taken orally once daily, swallowed whole, with a meal. Patients should take their dose of bosutinib at approximately the same time each day. Do not take with grapefruit products and star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4 (see DRUG INTERACTIONS, Serious Drug and Drug-Food Interactions). Tablets should not be crushed or cut, and should not be dissolved in a liquid.

In clinical trials, treatment with bosutinib continued until disease progression or until intolerance to therapy.

If a patient misses a dose (delayed by more than 12 hours), the patient should not take a dose that day, but take the usual prescribed dose on the following day.

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 a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. Dose escalations are expected to result in greater toxicity.

Newly-diagnosed chronic phase Ph+ CML

The recommended dose of BOSULIF is 400 mg orally once daily swallowed whole with a meal.

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

The recommended dose and schedule of BOSULIF is 500 mg orally once daily swallowed whole, with a meal.

Dose Adjustments for Non-Hematologic Adverse Reactions

Elevated liver transaminases: If elevations in liver transaminases >5 x institutional upper limit of normal (ULN) occur, BOSULIF should be interrupted until recovery to ≤2.5 x ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of BOSULIF should be considered. If transaminase elevations ≥3 x ULN occur concurrently with bilirubin elevations >2 x ULN and alkaline phosphatase <2 x ULN, BOSULIF should be discontinued.

Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of ≥7 stools/day over baseline/pretreatment), BOSULIF should be interrupted temporarily. Patients with these events should be managed using standard of care treatment, including antidiarrheal medication, and/or fluid replacement. BOSULIF may be resumed at a dose reduced by 100 mg taken once daily upon recovery to grade ≤1.

If other clinically significant moderate or severe non-hematological toxicity develops, BOSULIF should be interrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity has resolved. If clinically appropriate, re-escalation of the dose to the starting dose taken once daily may be considered. Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.

Dose Adjustments for Hematologic Adverse Reactions

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described below. Dose interruptions and/or reductions may be needed for hematologic toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 10).

Table 10: Dose Adjustments for Neutropenia and Thrombocytopenia

Absolute Neutrophil Count
ANCa <1.0x109/L

or


Platelets <50x109/L

Hold BOSULIF until ANC ≥1.0x109/L and platelets ≥50x109/L.

Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment.

If either of these cytopenias 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.

Dosing Considerations

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 possible (see DRUG INTERACTIONS, Serious Drug and Drug-Food Interactions).

Concomitant Use With CYP3A Inducers

Avoid the concomitant use of strong or moderate CYP3A with BOSULIF. Based on the large reduction in bosutinib exposure that occurred when BOSULIF was co-administered with rifampin, increasing the dose of BOSULIF when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure (see DRUG INTERACTIONS, Drug-Drug Interactions).

Hepatic Impairment

BOSULIF is contraindicated in patients with hepatic impairment at baseline. (see CONTRAINDICATIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Hepatic Impairment).

Renal Impairment

Newly-diagnosed chronic phase Ph+ CML

In patients with moderate renal impairment (creatinine clearance [CLCr] 30 to <50  mL/min, estimated by the Cockcroft‑Gault formula ), the recommended dose of bosutinib is 300 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

In patients with severe renal impairment (CLCr <30 mL/min, estimated by the Cockcroft‑Gault formula), the recommended dose of bosutinib is 200 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

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

In patients with moderate renal impairment [creatinine clearance (CrCL) 30 to 50 mL/min, estimated by the Cockcroft-Gault formula, the recommended dose of bosutinib is 400 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment ).

In patients with severe renal impairment (CrCL <30 mL/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

The starting dose recommendation in patients with moderate or severe renal impairment was based on pharmacological modeling; the efficacy and safety of BOSULIF have not been investigated in these patients. Initiate BOSULIF therapy in these patients only when perceived benefits outweigh the potential risks. Patients should be closely monitored for renal function at baseline and during therapy (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment).

Missed Dose

If a dose is missed (delayed by more than 12 hours), the patient should not take a dose that day, but take the usual prescribed dose on the following day.

Administration

For oral use.