BOSUTINIB MONOHYDRATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BOSUTINIB MONOHYDRATE (BOSUTINIB MONOHYDRATE).
Bosutinib is a dual Src/Abl tyrosine kinase inhibitor. It inhibits the BCR-ABL kinase, which is constitutively active in chronic myeloid leukemia (CML), and also inhibits Src family kinases. It has minimal inhibitory activity against c-KIT and PDGFR.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of P-glycoprotein (P-gp). Minor contributions from other CYP isoforms. |
| Excretion | Primarily fecal (91%, as unchanged drug and metabolites) with renal excretion accounting for <3%. |
| Half-life | 22.5 hours; supports once-daily dosing, with steady-state achieved by day 8. |
| Protein binding | 96% bound to plasma proteins, primarily albumin and α1-acid glycoprotein. |
| Volume of Distribution | Approximately 2.5 L/kg (based on 70 kg); indicates extensive tissue distribution. |
| Bioavailability | 34% (oral); absorption is increased by 1.7- to 2-fold when administered with food (high-fat meal). |
| Onset of Action | Not applicable; continuous oral dosing required for cytogenetic response; maximal plasma concentration occurs 4-6 hours post-dose. |
| Duration of Action | Sustained BCR-ABL1 inhibition over the 24-hour dosing interval; continuous exposure necessary for therapeutic effect. |
400 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | CrCl 30 to 50 mL/min: 400 mg once daily; CrCl <30 mL/min: 200 mg once daily. |
| Liver impairment | Child-Pugh A: 400 mg once daily; Child-Pugh B: 200 mg once daily; Child-Pugh C: 100 mg once daily. |
| Pediatric use | Not approved in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment required; monitor renal function and adjust accordingly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BOSUTINIB MONOHYDRATE (BOSUTINIB MONOHYDRATE).
| Breastfeeding | No data are available on the presence of bosutinib in human milk, its effects on the breastfed infant, or its effects on milk production. Due to the potential for serious adverse reactions in nursing infants, women should not breastfeed during treatment with bosutinib and for at least 2 weeks after the last dose. Bosutinib is highly protein bound and has a molecular weight of approximately 530 Da, suggesting limited excretion into breast milk; however, the M/P ratio is unknown. |
| Teratogenic Risk | Bosutinib is embryotoxic and fetotoxic in animal studies at exposures below human clinical exposure. In pregnant rats, increased post-implantation loss, reduced fetal body weights, and skeletal variations were observed. In rabbits, embryofetal mortality and malformations (including cardiovascular and skeletal defects) occurred. Based on its mechanism of action (BCR-ABL kinase inhibition) and animal data, bosutinib is expected to cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. First trimester exposure carries the highest risk of major malformations; second and third trimester exposure may affect fetal growth and development due to ongoing organogenesis and maturation. |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to bosutinib or any component of the formulation"]
| Precautions | ["Gastrointestinal toxicity: Diarrhea, nausea, vomiting, and abdominal pain. Manage with antiemetics and antidiarrheals.","Hepatotoxicity: Elevations in ALT, AST, and bilirubin; monitor liver function monthly.","Myelosuppression: Neutropenia, thrombocytopenia, anemia; monitor blood counts regularly.","Cardiovascular effects: May cause QT prolongation; avoid in patients with hypokalemia or hypomagnesemia.","Fluid retention: Edema, pleural effusion, pericardial effusion; evaluate promptly if symptoms occur.","Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential to use effective contraception."] |
| Food/Dietary | Avoid grapefruit and grapefruit juice. May increase bosutinib plasma concentration. Take with food to reduce diarrhea risk. No other specific food restrictions are recommended. |
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| Fetal Monitoring | Monitor complete blood counts (CBC) with differential at baseline and periodically during treatment due to risk of myelosuppression. Assess liver function tests (ALT, AST, bilirubin) at baseline and monthly; monitor for hepatotoxicity. Monitor serum lipase and amylase for pancreatitis. Monitor renal function and electrolytes. Perform pregnancy testing before initiation of therapy in females of reproductive potential and confirm negative status. During pregnancy, monitor fetal growth and development via ultrasound. Consider non-stress tests and biophysical profiles in third trimester if significant maternal toxicity occurs. Monitor for maternal fluid retention (edema, pleural effusion, pericardial effusion). |
| Fertility Effects | Based on animal studies, bosutinib may impair fertility in females. In rats, ovarian atrophy and decreased corpora lutea were observed at clinically relevant exposures. Effects on male fertility have not been adequately studied, but testicular degeneration was noted in animal studies. It is recommended that males with female partners of reproductive potential use effective contraception during treatment and for at least 3 months after the last dose. Females of reproductive potential should use effective contraception during treatment and for at least 1 month after the last dose. |
| Clinical Pearls | Bosutinib is a BCR-ABL tyrosine kinase inhibitor indicated for chronic, accelerated, or blast phase Ph+ CML with resistance/intolerance to prior therapy. Monitor for myelosuppression, hepatic transaminase elevation, and diarrhea. QT prolongation possible; obtain ECG before start and as needed. Avoid grapefruit products. Assess for hypertension and fluid retention. Dose adjustment required for severe hepatic impairment (Child-Pugh C). |
| Patient Advice | Take bosutinib with food to reduce gastrointestinal irritation. · Do not take grapefruit or grapefruit juice while on this medication. · Report immediately if you experience yellowing of skin/eyes, dark urine, or severe diarrhea. · Use effective contraception during treatment and for at least 2 weeks after last dose. · Avoid activities requiring mental alertness if you experience dizziness or fatigue. |