inib exposure. Separate antacid or H2 blocker dosing and Bosulif dosing by more than 2 hours.
Drugs That May Have Their Plasma Concentrations Altered By Bosutinib
Substrates of P-glycoprotein: An in vitro study suggests that Bosulif may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.5)]
Based on its mechanism of action and findings in animals, Bosulif can cause fetal harm when administered to a pregnant woman. Studies in animals showed reproductive toxicities. If Bosulif is used during pregnancy, or if the patient becomes pregnant while taking Bosulif, the patient should be apprised of the potential hazard to the fetus.
Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3 and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully eva luate adverse outcomes.
In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib.
Nursing Mothers
It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bosulif, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of Bosulif in patients less than 18 years of age have not been established.
Geriatric Use
In the Phase 1/2 clinical trial of Bosulif in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial, the exposure to bosutinib increased (Cmax increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold) in patients with hepatic impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9) [see Dosage and Administration (2.7), Adverse Reactions (6), and Clinical Pharmacology (12.3)].
Renal Impairment
Based on population PK analysis, creatinine clearance had no meaningful influence on the exposure to Bosulif. The population PK analysis included CrCL range of 25 to 120 mL/min [see Clinical Pharmacology (12.3)].
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