BOSULIF

Small Molecule Antineoplastic B-Cell Lymphoma-2 (BCL-2) Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

thrombocytopenia / Delayed / 14.0-57.0
neutropenia / Delayed / 9.0-39.0
leukopenia / Delayed / 6.0-27.0
hepatotoxicity / Delayed / 10.0-27.0
elevated hepatic enzymes / Delayed / 3.5-26.0
lymphopenia / Delayed / 12.0-21.0
infection / Delayed / 0-12.0
GI bleeding / Delayed / 1.0-10.0
diarrhea / Early / 4.0-10.0
pericardial effusion / Delayed / 0.4-10.0
pulmonary hypertension / Delayed / 1.0-10.0
renal failure (unspecified) / Delayed / 1.0-10.0
rash / Early / 2.0-9.0
hypophosphatemia / Delayed / 7.0-9.0
abdominal pain / Early / 2.0-7.0
hypermagnesemia / Delayed / 0-7.0
fluid retention / Delayed / 1.1-6.0
fatigue / Early / 1.0-6.0
dyspnea / Early / 1.0-6.0
hyponatremia / Delayed / 0-6.0
hyperuricemia / Delayed / 6.0-6.0
heart failure / Delayed / 1.9-5.3
hypertension / Early / 3.0-5.0
hypokalemia / Delayed / 0-4.9
hypocalcemia / Delayed / 1.5-4.7
pleural effusion / Delayed / 0.7-4.0
headache / Early / 1.0-4.0
hyperamylasemia / Delayed / 0-3.4
vomiting / Early / 1.0-3.0
fever / Early / 1.0-3.0
hyperbilirubinemia / Delayed / 0-2.8
hyperkalemia / Delayed / 0-2.7
nausea / Early / 0-2.0
anorexia / Delayed / 0-1.0
constipation / Delayed / 0-1.0
pulmonary edema / Early / 0.1-1.0
edema / Delayed / 0-1.0
influenza / Delayed / 0-1.0
anaphylactic shock / Rapid / 0.1-1.0
arthralgia / Delayed / 0-1.0
back pain / Delayed / 0-1.0
dizziness / Early / 0-1.0
chest pain (unspecified) / Early / 0-1.0
pericarditis / Delayed / 0.1-1.0
respiratory failure / Delayed / 0.1-1.0
erythema multiforme / Delayed / 0.1-1.0
pruritus / Rapid / 0-1.0
pancreatitis / Delayed / 0.1-1.0
QT prolongation / Rapid / 0.2-0.4
hypertensive crisis / Early / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
erythema nodosum / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
thrombotic microangiopathy / Delayed / Incidence not known

anemia / Delayed / 59.0-80.0
hyperglycemia / Delayed / 33.0-54.0
hypernatremia / Delayed / 0-22.5
gastritis / Delayed / 1.0-10.0
dehydration / Delayed / 1.0-10.0
hypothyroidism / Delayed / 1.0-10.0
interstitial lung disease / Delayed / 0.1-1.0
hyperthyroidism / Delayed / 0.1-1.0
hepatitis / Delayed / Incidence not known
steatosis / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
bullous rash / Early / Incidence not known
psoriasis / Delayed / Incidence not known
psoriaform rash / Delayed / Incidence not known
erythema / Early / Incidence not known

cough / Delayed / 11.0-24.0
myalgia / Early / 1.0-10.0
dysgeusia / Early / 1.0-10.0
tinnitus / Delayed / 1.0-10.0
dyspepsia / Early / Incidence not known
asthenia / Delayed / Incidence not known
skin hypopigmentation / Delayed / Incidence not known
vesicular rash / Delayed / Incidence not known
lichen planus-like eruption / Delayed / Incidence not known
skin irritation / Early / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
cheilitis / Delayed / Incidence not known
skin discoloration / Delayed / Incidence not known

BOSULIF

Rx

Multi-tyrosine kinase inhibitor
Used for the treatment of adult patients with certain types of Philadelphia chromosome-positive chronic myelogenous leukemia
Anaphylactic shock has been reported

Any baseline hepatic impairment (Child-Pugh A, B, or C): Initiate bosutinib at 200 mg PO once daily.
Liver transaminase level elevations of greater than 5-times the upper limit of normal (ULN) during therapy: Hold bosutinib therapy until levels 2.5-times the ULN or less, then resume therapy at 400 mg/day. Discontinue therapy if recovery is longer than 4 weeks.
Liver transaminase level elevations of 3-times or higher than the ULN concurrently with bilirubin level elevations greater than 2-times the ULN and alkaline phosphatase levels less than 2-times the ULN during therapy: Discontinue therapy.

Baseline creatinine clearance (CrCl) of greater than 50 mL/min: No initial dosage adjustment necessary.
Baseline CrCl 30 to 50 mL/min: Initiate at a reduced dose of 300 mg/day PO for newly diagnosed chronic phase CML patients and 400 mg/day PO for patients with CML that is resistant (or intolerant) to prior therapy.
Baseline CrCl less than 30 mL/min: Initiate at a reduced dose of 200 mg/day PO for newly diagnosed chronic phase CML patients and 300 mg/day PO for patients with CML that is resistant (or intolerant) to prior therapy.

Adagrasib: (Major) Avoid concomitant use of bosutinib and adagrasib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A inhibitor.
Aluminum Hydroxide: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Antacids: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Apalutamide: (Major) Avoid coadministration of bosutinib with apalutamide due to decreased plasma concentrations of bosutinib. Bosutinib is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bosutinib exposure by 94%.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of bosutinib and aprepitant, fosaprepitant; bosutinib plasma exposure was significantly increased in a drug-interaction study. Bosutinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor; CYP3A4 inhibition is weak when administered as a single 40 or 125 mg oral dose, or as fosaprepitant 150 mg IV. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when a single oral dose of bosutinib 500 mg was administered with aprepitant 125 mg.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Aspirin, ASA; Omeprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Atazanavir: (Major) Avoid concomitant use of bosutinib and atazanavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and atazanavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of bosutinib and atazanavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and atazanavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor. (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Berotralstat: (Major) Avoid concomitant use of bosutinib and berotralstat as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Calcium Carbonate: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours. (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Calcium Carbonate; Magnesium Hydroxide: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Calcium Carbonate; Simethicone: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Calcium; Vitamin D: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Carbamazepine: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as carbamazepine, as a large decrease in bosutinib plasma exposure may occur. Carbamazepine may interact with chemotherapeutic agents by different mechanisms. Although documentation of drug-drug interactions may not always be available, myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine. Clinicians should be alert to changes in the clinical effects of these agents. If coadministration is necessary, dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Ceritinib: (Major) Avoid concomitant use of bosutinib and ceritinib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Ciprofloxacin: (Major) Avoid concomitant use of bosutinib and ciprofloxacin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Clarithromycin: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cobicistat: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Conivaptan: (Major) Avoid concomitant use of bosutinib and conivaptan as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. The bosutinib peak and overall exposure were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of bosutinib and crizotinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Darunavir: (Major) Avoid concomitant use of bosutinib and darunavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Darunavir; Cobicistat: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (Major) Avoid concomitant use of bosutinib and darunavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (Major) Avoid concomitant use of bosutinib and darunavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Dexlansoprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as dexlansoprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Diltiazem: (Major) Avoid concomitant use of bosutinib and diltiazem as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Duvelisib: (Major) Avoid concomitant use of bosutinib and duvelisib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Elbasvir; Grazoprevir: (Major) Administering bosutinib with grazoprevir may result in elevated bosutinib plasma concentrations. Bosutinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Encorafenib: (Moderate) Coadministration of encorafenib with bosutinib may result in increased toxicity or decreased efficacy of bosutinib. Bosutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Enzalutamide: (Major) Avoid coadministration of bosutinib with enzalutamide due to decreased plasma concentrations of bosutinib. Bosutinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bosutinib exposure by 94%.
Erythromycin: (Major) Avoid concomitant use of bosutinib and erythromycin as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Esomeprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as esomeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Famotidine: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Fedratinib: (Major) Avoid concomitant use of bosutinib and fedratinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Fluconazole: (Major) Avoid concomitant use of bosutinib and fluconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Fosamprenavir: (Major) Avoid concomitant use of bosutinib and fosamprenavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
Fosphenytoin: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin or fosphenytoin, as a large decrease in bosutinib plasma exposure may occur.
Grapefruit juice: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, and grapefruit juice, a CYP3A4 inhibitor, as bosutinib plasma exposure may increase.
H2-blockers: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Ibuprofen; Famotidine: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with bosutinib, a CYP3A substrate, as bosutinib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Imatinib: (Major) Avoid concomitant use of bosutinib and imatinib, STI-571; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Indinavir: (Major) Avoid concomitant use of bosutinib and indinavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Isavuconazonium: (Major) Avoid concomitant use of bosutinib and isavuconazonium; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of bosutinib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as a large decrease in bosutinib plasma exposure may occur. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 86% and 94%, respectively, following a single oral dose of bosutinib 500 mg administered after 6 days of oral rifampin 600 mg/day.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of bosutinib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as a large decrease in bosutinib plasma exposure may occur. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 86% and 94%, respectively, following a single oral dose of bosutinib 500 mg administered after 6 days of oral rifampin 600 mg/day.
Itraconazole: (Major) Avoid bosutinib use during and for 2 weeks after discontinuation of itraconazole treatment due to the potential for increased bosutinib plasma exposure resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Ivosidenib: (Moderate) Monitor for loss of efficacy of bosutinib during coadministration of ivosidenib; a bosutinib dose adjustment may be necessary. Bosutinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased bosutinib concentrations.
Ketoconazole: (Major) Avoid concomitant use of bosutinib and ketoconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of bosutinib by 8.6-fold.
Lansoprazole: (Major) Concomitant use of bosutinib and lansoprazole resulted in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours. Bosutinib displays pH-dependent aqueous solubility. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 46% and 26%, respectively, following a single oral dose of bosutinib 400 mg administered after multiple oral doses of lansoprazole 60 mg.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (Major) Concomitant use of bosutinib and lansoprazole resulted in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours. Bosutinib displays pH-dependent aqueous solubility. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 46% and 26%, respectively, following a single oral dose of bosutinib 400 mg administered after multiple oral doses of lansoprazole 60 mg.
Lefamulin: (Major) Avoid concomitant use of bosutinib and oral lefamulin as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Lenacapavir: (Major) Avoid concomitant use of bosutinib and lenacapavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
Letermovir: (Major) Avoid concurrent use of letermovir and bosutinib, as taking these drugs together may increase bosutinib concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Bosutinib is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A inhibitor increased bosutinib maximum plasma concentration by 5.2-fold and exposure by 8.6-fold. The maximum plasma concentrations and exposure increased by 1.5- and 2-fold, respectively, when administered with a moderate CYP3A inhibitor.
Levoketoconazole: (Major) Avoid concomitant use of bosutinib and ketoconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of bosutinib by 8.6-fold.
Lonafarnib: (Major) Avoid concomitant use of bosutinib and lonafarnib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of bosutinib and ritonavir or lopinavir; ritonavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of bosutinib by significantly decreasing its systemic exposure; avoid concomitant use. Bosutinib is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 86% and 94%, respectively, after a single oral dose of bosutinib 500 mg administered after 6 days of another CYP3A inducer (oral rifampin 600 mg/day).
Magnesium Hydroxide: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Mitotane: (Major) Avoid the concomitant use of mitotane with bosutinib; if coadministration cannot be avoided, monitor for decreased efficacy of bosutinib. Mitotane is a strong CYP3A4 inducer and bosutinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of bosutinib. After 6 days of administration of rifampin (600 mg/day), another strong CYP3A4 inducer, to healthy volunteers in a cross-over trial (n = 24), the Cmax and AUC values of bosutinib (single dose) were decreased by 86% and 94%, respectively.
Naproxen; Esomeprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as esomeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Nefazodone: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, as bosutinib plasma exposure may increase.
Nelfinavir: (Major) Avoid concomitant use of bosutinib and nelfinavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid concomitant use of bosutinib and netupitant; palonosetron; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of bosutinib and ritonavir or lopinavir; ritonavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Nizatidine: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Omeprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Omeprazole; Amoxicillin; Rifabutin: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Omeprazole; Sodium Bicarbonate: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours. (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
Pantoprazole: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as pantoprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Phenobarbital: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenobarbital, as a large decrease in bosutinib plasma exposure may occur.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenobarbital, as a large decrease in bosutinib plasma exposure may occur.
Phenytoin: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin, as a large decrease in bosutinib plasma exposure may occur.
Posaconazole: (Major) Avoid concomitant use of bosutinib and posaconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Rabeprazole: (Major) Concomitant use of bosutinib and proton-pump inhibitors, such as rabeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
Ranitidine: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
Ribociclib: (Major) Avoid concomitant use of bosutinib and ribociclib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Major) Avoid concomitant use of bosutinib and ribociclib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Rifampin: (Major) Avoid the concomitant use of bosutinib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as a large decrease in bosutinib plasma exposure may occur. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 86% and 94%, respectively, following a single oral dose of bosutinib 500 mg administered after 6 days of oral rifampin 600 mg/day.
Rifapentine: (Major) Avoid coadministration of bosutinib with rifapentine as concurrent use may decrease bosutinib exposure which may lead to decreased efficacy. Bosutinib is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased bosutinib exposure by 94%.
Ritlecitinib: (Major) Avoid concomitant use of bosutinib and ritlecitinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
Ritonavir: (Major) Avoid concomitant use of bosutinib and ritonavir or lopinavir; ritonavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Saquinavir: (Major) Avoid concomitant use of bosutinib and saquinavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sodium Bicarbonate: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as St. John's Wort, as a large decrease in bosutinib plasma exposure may occur.
Trandolapril; Verapamil: (Major) Avoid concomitant use of bosutinib and verapamil or as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Tucatinib: (Major) Avoid concomitant use of bosutinib and tucatinib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Verapamil: (Major) Avoid concomitant use of bosutinib and verapamil or as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Voriconazole: (Major) Avoid concomitant use of bosutinib and voriconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Voxelotor: (Major) Avoid concomitant use of bosutinib and voxelotor as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.

BOSULIF/Bosutinib Oral Tab: 100mg, 400mg, 500mg

600 mg/day PO.

600 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Bosutinib is an oral tyrosine kinase inhibitor (TKI) that works by dual inhibition of the Bcr-Abl kinase that promotes chronic myelogenous leukemia (CML) and the Src-family of kinases (SFK) Src, Lyn, and Hck. In murine myeloid cell lines, bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl; T315I and V299L mutant cells were not inhibited. Bosutinib caused CML tumor cell reduction and myeloid tumor growth inhibition in several imatinib-resistant forms of Bcr-Abl in mice models. Bosutinib is 200-times more potent for the Bcr-Abl kinase than imatinib. SFK coordinate signaling from various transmembrane receptor-associated tyrosine kinases including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), platelet derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). Dysregulation and increased activity of Src occur in many malignancies and Src inhibitors have demonstrated activity in vitro in breast, colon, lung, pancreatic, and prostate tumors. Multidrug resistance (MDR) transporters promote the efflux of TKIs and upregulation of these transporters is one mechanism of resistance to TKIs. Bosutinib is not an efficient substrate for MDR transporters and may inhibit transport proteins at concentrations greater than 1 micromolar.

Bosutinib is administered orally. It exhibits dose proportional pharmacokinetics over a dosage range of 200 to 800 mg. Bosutinib was highly bound to plasma proteins in healthy subjects (96%); binding was not concentration dependent. Following a single oral dose of 500 mg (with food), the mean apparent volume of distribution was 6,080 +/- 1,230 L; the mean clearance was 189 +/- 48 L/hour; and the mean terminal elimination half-life was 22.5 +/- 1.7 hours. Bosutinib is metabolized in the liver, primarily by CYP3A4. Following a single oral dose of 14C-bosutinib given to 6 healthy male volunteers, 91.3% of the dose was recovered in the feces and 3.3% of the dose was recovered in the urine.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Bosutinib is a substrate of CYP3A4. Avoid concurrent use of bosutinib with strong or moderate CYP3A inhibitors and strong CYP3A inducers. Bosutinib does not inhibit P-glycoprotein (P-gp) based on a cross-over drug-drug interaction trial in 25 healthy subjects who received a single dose of bosutinib 500 mg in combination with a single dose of dabigatran etexilate mesylate 150 mg (a P-gp substrate). Bosutinib may inhibit the breast cancer resistance protein (BCRP) transporter in the gastrointestinal tract in vitro; however, it has a low potential to inhibit BCRP, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2 systemically at clinically relevant concentrations.

Bosutinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant during bosutinib therapy. Pregnant women receiving bosutinib should be apprised of the potential hazard to the fetus. Placental transfer of bosutinib resulting in fetal exposure has been demonstrated in pregnant rats. Embryo-fetal toxicity including fused sternebrae, various visceral abnormalities in 2 fetuses, and a decrease in fetal weight was observed in pregnant rabbits who received bosutinib doses (30 mg/kg per day) that resulted in AUC values approximately 5.1- and 3.8-times the recommended human dose of 400 mg/day and 500 mg/day, respectively.[51739]

It is not known if bosutinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during bosutinib therapy and for at least 2 weeks after the last dose.