BOSULIF® Dosage and Administration

(bosutinib)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy.

Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal.

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

Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML

The recommended dosage of BOSULIF is 400 mg orally once daily with food.

Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy

The recommended dosage of BOSULIF is 500 mg orally once daily with food.

Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy

The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules.

Table 1: Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy
*
BSA=Body Surface Area
maximum starting dose (corresponding to maximum starting dose in adult indication)

BSA*

Newly-Diagnosed Recommended Dose

(Once Daily)

Resistant or Intolerant Recommended Dose

(Once Daily)

< 0.55 m2

150 mg

200 mg

0.55 to < 0.63 m2

200 mg

250 mg

0.63 to < 0.75 m2

200 mg

300 mg

0.75 to < 0.9 m2

250 mg

350 mg

0.9 to < 1.1 m2

300 mg

400 mg

≥ 1.1 m2

400 mg

500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing.

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes

Dose

Volume of Applesauce or Yogurt

100 mg

10 mL (2 teaspoons)

150 mg

15 mL (3 teaspoons)

200 mg

20 mL (4 teaspoons)

250 mg

25 mL (5 teaspoons)

300 mg

30 mL (6 teaspoons)

350 mg

30 mL (6 teaspoons)

400 mg

35 mL (7 teaspoons)

450 mg

40 mL (8 teaspoons)

500 mg

45 mL (9 teaspoons)

550 mg

45 mL (9 teaspoons)

600 mg

50 mL (10 teaspoons)

2.2 Dose Escalation

In clinical studies of adult patients with Ph+ CML, 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.

In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments.

The maximum dose in pediatric and adult patients is 600 mg once daily.

2.3 Dosage 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.

In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or greater, reduce dose similarly to adults.

2.4 Dosage Adjustments for Myelosuppression

Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients
*
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, or by 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment.



If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment, or by an additional 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment.

2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment

The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below.

Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients
 Recommended Starting Dosage
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

 

Newly-diagnosed chronic phase Ph+ CML

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

Table 5: Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
*
BSA=Body Surface Area

 

Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function

Pediatric Patients by Separated BSA* Band

Normal renal and hepatic function

Renal Impairment: Creatinine clearance 30 to 50 mL/min

Renal Impairment: Creatinine clearance less than 30 mL/min

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

Pediatric < 0.55 m2

150 mg

100 mg

100 mg

100 mg

Pediatric 0.55 to < 0.63 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.63 to < 0.75 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.75 to < 0.9 m2

250 mg

200 mg

150 mg

100 mg

Pediatric 0.9 to < 1.1 m2

300 mg

200 mg

200 mg

150 mg

Pediatric ≥ 1.1 m2

400 mg

300 mg

200 mg

200 mg

 

CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function

Pediatric Patients by Separated BSA* Band

Normal renal and hepatic function

Renal Impairment: Creatinine clearance 30 to 50 mL/min

Renal Impairment: Creatinine clearance less than 30 mL/min

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

Pediatric < 0.55 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.55 to < 0.63 m2

250 mg

200 mg

150 mg

100 mg

Pediatric 0.63 to < 0.75 m2

300 mg

200 mg

200 mg

150 mg

Pediatric 0.75 to < 0.9 m2

350 mg

250 mg

200 mg

150 mg

Pediatric 0.9 to < 1.1 m2

400 mg

300 mg

250 mg

200 mg

Pediatric ≥ 1.1 m2

500 mg

400 mg

300 mg

200 mg

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Dosage and Administration

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy.

Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal.

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

Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML

The recommended dosage of BOSULIF is 400 mg orally once daily with food.

Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy

The recommended dosage of BOSULIF is 500 mg orally once daily with food.

Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy

The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules.

Table 1: Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy
*
BSA=Body Surface Area
maximum starting dose (corresponding to maximum starting dose in adult indication)

BSA*

Newly-Diagnosed Recommended Dose

(Once Daily)

Resistant or Intolerant Recommended Dose

(Once Daily)

< 0.55 m2

150 mg

200 mg

0.55 to < 0.63 m2

200 mg

250 mg

0.63 to < 0.75 m2

200 mg

300 mg

0.75 to < 0.9 m2

250 mg

350 mg

0.9 to < 1.1 m2

300 mg

400 mg

≥ 1.1 m2

400 mg

500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing.

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes

Dose

Volume of Applesauce or Yogurt

100 mg

10 mL (2 teaspoons)

150 mg

15 mL (3 teaspoons)

200 mg

20 mL (4 teaspoons)

250 mg

25 mL (5 teaspoons)

300 mg

30 mL (6 teaspoons)

350 mg

30 mL (6 teaspoons)

400 mg

35 mL (7 teaspoons)

450 mg

40 mL (8 teaspoons)

500 mg

45 mL (9 teaspoons)

550 mg

45 mL (9 teaspoons)

600 mg

50 mL (10 teaspoons)

2.2 Dose Escalation

In clinical studies of adult patients with Ph+ CML, 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.

In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments.

The maximum dose in pediatric and adult patients is 600 mg once daily.

2.3 Dosage 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.

In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or greater, reduce dose similarly to adults.

2.4 Dosage Adjustments for Myelosuppression

Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients
*
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, or by 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment.



If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment, or by an additional 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment.

2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment

The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below.

Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients
 Recommended Starting Dosage
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

 

Newly-diagnosed chronic phase Ph+ CML

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

Table 5: Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
*
BSA=Body Surface Area

 

Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function

Pediatric Patients by Separated BSA* Band

Normal renal and hepatic function

Renal Impairment: Creatinine clearance 30 to 50 mL/min

Renal Impairment: Creatinine clearance less than 30 mL/min

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

Pediatric < 0.55 m2

150 mg

100 mg

100 mg

100 mg

Pediatric 0.55 to < 0.63 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.63 to < 0.75 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.75 to < 0.9 m2

250 mg

200 mg

150 mg

100 mg

Pediatric 0.9 to < 1.1 m2

300 mg

200 mg

200 mg

150 mg

Pediatric ≥ 1.1 m2

400 mg

300 mg

200 mg

200 mg

 

CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function

Pediatric Patients by Separated BSA* Band

Normal renal and hepatic function

Renal Impairment: Creatinine clearance 30 to 50 mL/min

Renal Impairment: Creatinine clearance less than 30 mL/min

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

Pediatric < 0.55 m2

200 mg

150 mg

100 mg

100 mg

Pediatric 0.55 to < 0.63 m2

250 mg

200 mg

150 mg

100 mg

Pediatric 0.63 to < 0.75 m2

300 mg

200 mg

200 mg

150 mg

Pediatric 0.75 to < 0.9 m2

350 mg

250 mg

200 mg

150 mg

Pediatric 0.9 to < 1.1 m2

400 mg

300 mg

250 mg

200 mg

Pediatric ≥ 1.1 m2

500 mg

400 mg

300 mg

200 mg

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