Bosutinib is an oral multi-tyrosine kinase inhibitor that works by inhibiting Bcr-Abl and Src family kinases. It is indicated for the treatment of adult and pediatric patients aged 1 year and older with chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) that is newly diagnosed or resistance or intolerance to prior therapy. Bosutinib is also indicated for the treatment of adults with accelerated phase or blast phase Ph+ CML with resistance or intolerance to prior therapy. Serious adverse reactions reported with bosutinib use include myelosuppression, gastrointestinal toxicity, fluid retention, and hepatotoxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.
Route-Specific Administration
Oral Administration
-Take bosutinib with food.
-Do not take bosutinib with grapefruit, grapefruit juice, or supplements containing grapefruit extract.
-Take antacids or H2-blockers at least 2 hours before or 2 hours after bosutinib.
-If a dose is missed, take it as soon as possible. If the dose is more than 12 hours late, skip the dose and take the next dose at your regular scheduled time.
-Store bosutinib in the original container.
Oral Solid Formulations
Tablets
-Swallow bosutinib tablets whole; do not cut, crush, chew, or break tablets.
Capsules
-Bosutinib capsules may be swallowed whole or opened and mixed with room temperature applesauce or yogurt in patients who cannot swallow capsules whole.
Preparation:
-To prepare a dose mixed in applesauce or yogurt, follow instructions for use provided by manufacturer.
-Using gloves, open the capsule(s) required for the dose and mix with applesauce or yogurt in a small, clean container as follows:
Add 100 mg to 10 mL (2 teaspoonfuls) of applesauce or yogurt.
Add 150 mg to 15 mL (3 teaspoonfuls) of applesauce or yogurt.
Add 200 mg to 20 mL (4 teaspoonfuls) of applesauce or yogurt.
Add 250 mg to 25 mL (5 teaspoonfuls) of applesauce or yogurt.
Add 300 mg to 30 mL (6 teaspoonfuls) of applesauce or yogurt.
Add 350 mg to 30 mL (6 teaspoonfuls) of applesauce or yogurt.
Add 400 mg to 35 mL (7 teaspoonfuls) of applesauce or yogurt.
Add 450 mg to 40 mL (8 teaspoonfuls) of applesauce or yogurt.
Add 500 mg to 45 mL (9 teaspoonfuls) of applesauce or yogurt.
Add 550 mg to 45 mL (9 teaspoonfuls) of applesauce or yogurt.
Add 600 mg to 50 mL (10 teaspoonfuls) of applesauce or yogurt.
Administration:
-Swallow the entire mixture immediately; do not chew.
-If the entire mixture is not swallowed, do not mix another dose; wait until the next day to give the next scheduled dose.
Gastrointestinal (GI) adverse events have been reported with bosutinib therapy in patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) in clinical trials. Monitor for the development of GI toxicity. Treat symptoms with antidiarrheal and/or antiemetic agents and fluid replacement if required. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop moderate or severe GI toxicity. Diarrhea (75%; grade 3 or 4, 9%), nausea (37%), abdominal pain including dyspepsia (39%; grade 3 or 4, 2%), vomiting (21%; grade 3 or 4, 1%), constipation (13%), and decreased appetite/anorexia (11%; grade 3 or 4, 1%) were reported in adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. The median time to diarrhea onset was 4 days and the median duration of diarrhea per event was 3 days. Diarrhea (CP: 85%, grade 3 or 4, 10%; AP: 76%, grade 3 or 4, 4%), nausea (CP: 47%; grade 3 or 4, 1%; AP: 48%, grade 3 or 4, 2%), abdominal pain including dyspepsia (CP: 49%; grade 3 or 4, 2%; AP: 36%, grade 3 or 4, 7%), vomiting (CP: 38%; grade 3 or 4, 3%; AP: 43%, grade 3 or 4, 3%), constipation (CP: 15%; grade 3 or 4, less than 1%; AP: 17%, grade 3 or 4, 1%), and anorexia (CP: 14%; grade 3 or 4, 1%; AP: 14%) occurred in adult CP-CML (n = 403) and AP-CML (n = 143) patients who received bosutinib in a phase 1/2 study; fatal GI bleeding was reported in 0.2% of patients. The median number of diarrhea episodes per patient was 3 (range, 1 to 268 episodes); the median time to diarrhea onset was 2 days and the median duration of diarrhea was 2 days. Diarrhea (82%; grade 3 or 4, 12%), abdominal pain (73%; grade 3 or 4, 4%), vomiting (55%; grade 3 or 4, 6%), nausea (49%; grade 3 or 4, 2%), anorexia (27%; grade 3 or 4, 2%), and constipation (20%) were reported in pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. The median number of diarrhea episodes per patient was 2 (range, 1 to 198 episodes); the median time to diarrhea onset was 2 days and the median duration of diarrhea was 2 days. Gastritis and GI bleeding (e.g., anal and rectal bleeding) occurred in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Hematologic adverse events have been reported with bosutinib therapy in patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) in clinical trials. Obtain a complete blood count (CBC) panel weekly for the first month of bosutinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop hematologic toxicity. Platelet count decreased/thrombocytopenia (68%; grade 3 or 4, 14%), hemoglobin level decreased/anemia (89%; grade 3 or 4, 9%), white blood cell count decreased/leukopenia (50%; grade 3 or 4, 6%), lymphocyte count decreased/lymphopenia (84%; grade 3 or 4, 12%), and neutrophil count decreased/neutropenia (42%; grade 3 or 4, 9%) that worsened from baseline were reported in adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. Thrombocytopenia (CP: 66%, grade 3 or 4, 26%; AP: 80%, grade 3 or 4, 57%), anemia (CP: 89%; grade 3 or 4, 13%; AP: 97%, grade 3 or 4, 38%), neutropenia (CP: 50%; grade 3 or 4, 16%; AP: 66%, grade 3 or 4, 39%), lymphopenia (CP: 79%; grade 3 or 4, 14%; AP: 82%, grade 3 or 4, 21%), and leukopenia (CP: 51%; grade 3 or 4, 7%; AP: 57%, grade 3 or 4, 27%) that worsened from baseline occurred in adult CP-CML (n = 403) and AP-CML (n = 143) patients who received bosutinib in a phase 1/2 study. Leukopenia (53%; grade 3 or 4, 4%), thrombocytopenia (49%; grade 3 or 4, 18%), anemia (31%; grade 3 or 4, 8%), neutropenia (31%; grade 3 or 4, 12%), and lymphopenia (29%; grade 3 or 4, 2%) that worsened from baseline were reported in pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Febrile neutropenia was reported in 0.1% to less than 1% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Drug-induced hepatotoxicity was reported in 2 of 1,711 patients treated with bosutinib in clinical trials. Additionally, elevated hepatic enzymes have been reported in 37% to 68% of patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) who received bosutinib in clinical trials. Obtain liver function tests (LFTs) monthly for the first 3 months of bosutinib therapy, then monitor LFTs as clinically indicated; increase the frequency of monitoring if transaminase level elevations occur. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop hepatotoxicity. Hepatotoxicity/hepatic dysfunction (45%, grade 3 or 4, 27%) and increased ALT (68%, grade 3 or 4, 26%), AST (56%, grade 3 or 4, 13%), and alkaline phosphatase (41%) levels that worsened from baseline were reported in adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. The median times to increased ALT and AST levels onset were 29 and 56 days, respectively; the median durations of increased transaminase levels were 19 and 15 days, respectively. Hepatic dysfunction (CP: 29%, grade 3 or 4, 11%; AP: 21%, grade 3 or 4, 10%) and increased ALT (CP: 58%, grade 3 or 4, 11%; AP: 39%, grade 3 or 4, 9%), AST (CP: 50%, grade 3 or 4, 5%; AP: 37%, grade 3 or 4, 3.5%), and alkaline phosphatase (CP: 39%; AP: 39%, grade 3 or 4, 1.4%) levels and hyperbilirubinemia (CP: 16%; grade 3 or 4, 0.7%; AP: 22%; grade 3 or 4, 2.8%) that worsened from baseline occurred in adult patients with CP-CML (n = 403) and AP-CML (n = 143) who received bosutinib in a phase 1/2 study. The median times to increased ALT and AST levels onset were 22 and 29 days; the median duration of increased transaminase levels was 21 days. Hepatic dysfunction (37%, grade 3 or 4, 14%) and increased ALT (59%; grade 3 or 4, 14%) and AST (49%; grade 3 or 4, 18%) levels that worsened from baseline were reported in pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. The median times to increased ALT and AST levels onset were 22 and 215 days. The term hepatic dysfunction included increased ALT, AST, alkaline phosphatase, and gamma-glutamyltransferase levels; hyperbilirubinemia; hepatic steatosis; toxic hepatitis; and hepatomegaly.
Fluid retention has been reported with bosutinib therapy in patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) in clinical trials. Monitor patients for the development of fluid retention; use current standards of care to manage symptoms. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop moderate or severe fluid retention. Edema (15%), fluid retention (grade 3, 1.1%), pericardial effusion (grade 3, 0.4%), and pleural effusion (grade 3, 0.7%) were reported in adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. Edema (CP: 19%, grade 3 or 4, less than 1%; AP: 17%, grade 3 or 4, 1%) and pleural effusion (CP: 14%, grade 3 or 4, 4%; AP: 9%, grade 3 or 4, 4%) occurred in adult CP-CML (n = 403) and AP-CML (n = 143) patients who received bosutinib in a phase 1/2 study; fatal acute pulmonary edema was reported in 0.2% of patients. The term edema included face edema, tongue edema, eye edema, localized edema, scrotal and penile edema, testicular swelling/edema, and peripheral edema/swelling. In this study, 6% of patients had grade 3 or 4 fluid retention; some patients experienced more than one occurrence of severe fluid retention. In a clinical study in pediatric patients aged 1 year and older with CP-CML (n = 49), pericardial effusion, peripheral edema, and face edema were reported in 1 bosutinib-treated patient each. Pericardial effusion was reported in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372); acute pulmonary edema occurred in 0.1% to less than 1% of patients.
Fatigue including asthenia and malaise occurred in 33% (grade 3 or 4, 1%) of adult patients with newly diagnosed chronic phase (CP)-chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Additionally, fatigue was reported in 35% (grade 3 or 4, 3%) of adult CP-CML patients (n = 403) and 27% (grade 3 or 4, 6%) of adult advanced phase-CML patients (n = 143) who received bosutinib in a phase 1/2 study. Fatigue was reported in 37% (grade 3 or 4, 4%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study.
Fever was reported in 17% (grade 3 or 4, 1%) of adult patients with newly diagnosed chronic phase (CP)-chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Fever occurred in 25% (grade 3 or 4, 1%) of adult CP-CML patients (n = 403) and 37% (grade 3 or 4, 3%) of adult advanced phase-CML patients (n = 143) who received bosutinib in a phase 1/2 study. Fever was reported in 31% (grade 3 or 4, 4%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study.
Hyperglycemia was reported in 57% (grade 3 or 4, 3%) of adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Additionally, hyperglycemia occurred in 42% (grade 3 or 4, 2.7%) of adult CP-CML patients (n = 403) and 39% (grade 3 or 4, 6%) of adult advanced phase-CML patients (n = 143) who received bosutinib in a phase 1/2 study. Hyperglycemia that worsened from baseline was reported in 41% of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study.
Infection has been reported in 10% to 27% of patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) who received bosutinib in clinical trials. Respiratory tract infection including nasopharyngitis occurred in 27% (grade 3 or 4, 1%) of adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. Respiratory tract infection including nasopharyngitis (CP: 27%, grade 3 or 4, less than 1%; AP: 17%), influenza (CP: 11%, grade 3 or 4, 1%; AP: 3%), and pneumonia (CP: 10%, grade 3 or 4, 4%; AP: 18%; grade 3 or 4, 12%) were reported in adult patients with CP-CML (n = 403) and AP-CML (n = 143) who received bosutinib in a phase 1/2 study; fatal pneumonia occurred in 0.4% of patients. Respiratory tract infection was reported in 12% (grade 3 or 4, 2%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Bronchitis occurred in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Drug hypersensitivity (1% to less than 10%) and anaphylactic shock (0.1% to less than 1%) were reported in leukemia patients who received bosutinib in clinical trials (n = 1,372).
Arthralgia (18%; grade 3 or 4, 1%), back pain (12%; grade 3 or 4, less than 1%), and increased creatine phosphokinase (CPK) level (36%; grade 3 or 4, 3%) were reported in adult patients with newly diagnosed chronic phase (CP)-chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Arthralgia (CP: 19%, grade 3 or 4, 1%; AP: 15%) and back pain (CP: 14%, grade 3 or 4, 1%; AP: 8%, grade 3 or 4, 1%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a phase 1/2 study. CPK level that worsened from baseline was reported in 25% of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Myalgia and pain each were reported in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Headache was reported in 22% (grade 3 or 4, 1%) of adult patients with newly diagnosed chronic phase (CP)-chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Headache (CP: 21%, grade 3 or 4, 1%; AP: 18%, grade 3 or 4, 4%) and dizziness (CP: 11%; AP: 14%, grade 3 or 4, 1%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a phase 1/2 study. Headache was reported in 35% (grade 3 or 4, 2%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Dysgeusia was reported in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Hypertension (10%; grade 3 or 4, 5%) and QT prolongation (grade 3, 0.4%) were reported in adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Chest pain (unspecified) (CP: 8%, grade 3 or 4, 1%; AP: 12%, grade 3 or 4, 1%), hypertension (CP: 11%, grade 3 or 4, 3%; AP: 8%, grade 3 or 4, 3%), QT prolongation (grade 3, 0.2%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a phase 1/2 study. The term hypertension included hypertensive crisis and hypertensive retinopathy. QT prolongation on electrocardiogram were reported in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372); pericarditis occurred in 0.1% to less than 1% of patients.
Cough (11%) and dyspnea (11%; grade 3 or 4, 1%) were reported in adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Cough (CP: 24%; AP: 22%) and dyspnea (CP: 12%; grade 3 or 4, 2%; AP: 20%; grade 3 or 4, 6%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a 1/2 study; fatal respiratory failure was reported in 0.4% of patients. Pulmonary hypertension (1% to less than 10%), interstitial lung disease (0.1% to less than 1%), and respiratory failure (0.1% to less than 1%) occurred in leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Rash (40%; grade 3 or 4, 2%) and pruritus (11%; grade 3 or 4, less than 1%) were reported in adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Rash (CP: 48%; grade 3 or 4, 9%; AP: 42%; grade 3 or 4, 5%) and pruritus (CP: 12%; grade 3 or 4, 1%; AP: 7%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a 1/2 study. Rash was reported in 49% (grade 3 or 4, 8%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. The term rash included angular cheilitis, acne vulgaris, bullous rash/dermatitis, dyshidrotic eczema, pyoderma gangrenosum, acneiform rash/dermatitis, erythema nodosum, exfoliative dermatitis/rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), erythema/erythematous rash, generalized rash, lichen planus-like eruption, pruritic rash, maculopapular rash, skin discoloration, psoriasis, vesicular rash, skin hypopigmentation, skin hyperpigmentation, skin irritation, psoriaform rash, palmar-plantar erythrodysesthesia (hand and foot syndrome)/palmar erythema, and photosensitivity reaction. Erythema multiforme was reported in 0.1% to less than 1% of leukemia patients treated with bosutinib in clinical trials (n = 1,372). Stevens-Johnson syndrome was reported in postmarketing surveillance of bosutinib.
Tinnitus occurred in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Increased lipase (36%) and amylase (24%) level have been reported in adult patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) who received bosutinib in clinical trials (n = 814). Increased lipase level (53%; grade 3 or 4, 19%) and hyperamylasemia (32%; grade 3 or 4, 3.4%) were reported in adult patients with newly diagnosed CP-CML who received bosutinib (n = 268) in a randomized trial. Additionally, increased lipase level occurred in 32% (grade 3 or 4, 12%) of adult CP-CML patients (n = 403) and 19% (grade 3 or 4, 6%) of adult AP-CML patients (n = 143) who received bosutinib in a phase 1/2 study. Increased amylase level that worsened from baseline was reported in 27% (grade 3 or 4, 4%) of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Pancreatitis and increased pancreatic enzymes each occurred in 0.1% to less than 1% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Hypophosphatemia (54%; grade 3 or 4, 9%) and hypocalcemia (55%; grade 3 or 4, 1.5%) were reported in adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial. Additionally, hypophosphatemia (CP: 41%; grade 3 or 4, 8%; AP: 33%; grade 3 or 4, 7%), hypokalemia (CP: 22%; grade 3 or 4, 1.7%; AP: 29%; grade 3 or 4, 4.9%), hypocalcemia (CP: 55%; grade 3 or 4, 4.7%; AP: 45%; grade 3 or 4, 3.5%), hyponatremia (CP: 18%; grade 3 or 4, 2.2%; AP: 27%; grade 3 or 4, 6%), hypernatremia (CP: 23%; grade 3 or 4, 0.5%; AP: 11%), hypermagnesemia (CP: 27%; grade 3 or 4, 7%; AP: 18%; grade 3 or 4, 4.9%), and hyperkalemia (CP: 25%; grade 3 or 4, 2.7%; AP: 19%; grade 3 or 4, 2.1%) occurred in adult CP-CML (n = 403) and advanced phase-CML (n = 143) patients who received bosutinib in a phase 1/2 study. Hypocalcemia that worsened from baseline was reported in 31% of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study. Dehydration was reported in 1% to less than 10% of leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Treatment-related acute kidney injury, renal impairment, and renal failure (unspecified) were reported in 1% to less than 10% of patients who received bosutinib in clinical trials (safety population, n = 1,372). Nephrotoxicity was evaluated based on estimated glomerular filtration rates using the Modification in Diet in Renal Disease method (MDRD). Monitor renal function at baseline and during bosutinib therapy. Therapy interruption or a dose adjustment may be necessary in patients who develop moderate or severe renal toxicity during therapy. In a safety population analysis, mild (62.8%) mild to moderate (9.5%), moderate to severe (4.4%), severe (0.6%), and renal failure (0.9%) occurred in bosutinib-treated patients who had normal renal function at baseline (n = 527). The incidence of treatment-related moderate to severe and severe renal impairment and renal failure was increased in patients who had baseline renal impairment. Increased creatinine level that worsened from baseline was reported in 94% (grade 3 or 4, 1.1%) of adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial; renal failure resulting in death occurred in 0.4% of patients. Additionally, increased creatinine level occurred in 95% (grade 3 or 4, 3%) of adult CP-CML patients (n = 403) and 87% (grade 3 or 4, 1.4%) of adult advanced phase-CML patients (n = 143) who received bosutinib in a phase 1/2 study; acute kidney injury resulting in death was reported in 0.2% of patients. Increased serum creatinine level that worsened from baseline were reported in 92% of pediatric patients aged 1 year and older with CP-CML who received bosutinib (n = 49) in a clinical study.
Thrombotic microangiopathy was reported in postmarketing surveillance of bosutinib.
Cardiovascular toxicity was reported in patients who received bosutinib in clinical trials. Monitor patients for signs and symptoms of heart failure and cardiac ischemia as clinically indicated. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop cardiotoxicity. Heart failure (1.9%), cardiac ischemic events (4.9%), and coronary artery disease (3.4%) were reported in adult patients with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML) who received bosutinib (n = 268) in a randomized trial; fatal heart failure and fatal coronary artery disease were each reported in 0.4% of patients. Additionally, heart failure (5.3%), cardiac ischemic events (4.9%), and coronary artery disease (3.5%) occurred in adult patients with CP-CML or advanced phase-CML who received bosutinib in a phase 1/2 study (n = 546); fatal coronary artery disease was reported in 0.9% of patients. In a clinical study in 49 pediatric patients aged 1 year and older with CP-CML, tachycardia occurred in 2 patients and angina pectoris, right bundle-branch block, and sinus tachycardia were reported in 1 bosutinib-treated patient each.
Hypothyroidism (1% to less than 10%) and hyperthyroidism (0.1% to less than 1%) were reported in leukemia patients treated with bosutinib in clinical trials (n = 1,372).
Increased urate level/hyperuricemia that worsened from baseline was reported in 41% of adult patients with chronic phase (CP) or advanced phase (AP) chronic myelogenous leukemia (CML) who received bosutinib in clinical trials (n = 814). Hyperuricemia occurred in 49% (grade 3 or 4, 6%) of adult CP-CML patients (n = 403) and 43% (grade 3 or 4, 6%) of adult AP-CML patients (n = 143) who received bosutinib in a phase 1/2 study.
Bosutinib is contraindicated in patients who have a hypersensitivity to bosutinib. Anaphylactic shock has been rarely reported with bosutinib use.
Gastrointestinal (GI) toxicity (e.g., diarrhea, nausea/vomiting, abdominal pain) has been reported commonly with bosutinib use. Monitor for the development of GI toxicity. Treat symptoms with antidiarrheal and/or antiemetic agents and fluid replacement if required. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop moderate or severe GI toxicity.
Myelosuppression (e.g., anemia, thrombocytopenia, neutropenia) has been reported commonly with bosutinib use. Obtain a complete blood count (CBC) panel weekly for the first month of bosutinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop hematologic toxicity.
Hepatotoxicity has been reported with bosutinib use. Obtain liver function tests (LFTs) monthly for the first 3 months of bosutinib therapy, then monitor LFTs as clinically indicated; increase the frequency of monitoring if transaminase level elevations occur. A lower initial bosutinib starting dose is recommended in patients with pre-existing hepatic disease. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop hepatotoxicity.
Fluid retention (e.g., pericardial effusion, pleural effusion, pulmonary edema, peripheral edema) has been reported with bosutinib use. Monitor for the development of fluid retention; use current standards of care to manage symptoms. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop moderate or severe fluid retention.
Renal impairment including renal failure has been reported with bosutinib therapy. Monitor renal function at baseline and during bosutinib therapy. Use caution in patients who have pre-existing renal impairment or renal disease or risk factors for renal dysfunction. A lower initial bosutinib starting dose is recommended in patients with baseline moderate or severe renal impairment. Therapy interruption or a dose adjustment may be necessary in patients who develop moderate or severe nephrotoxicity during therapy.
Cardiovascular toxicity (e.g., heart failure, left ventricular dysfunction, and cardiac ischemic events) has been reported with bosutinib therapy. Monitor patients for signs and symptoms of heart failure (e.g., dyspnea, fluid retention, or weight gain) and cardiac ischemia (e.g., chest pain); treat as clinically indicated. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop cardiotoxicity. Patients with previously treated chronic myelogenous leukemia, advanced age (geriatric patients), or other cardiac risk factors (e.g., history of heart failure) may be at increased risk for developing cardiac adverse events. Additionally, patients with coronary artery disease risk factors (e.g., diabetes mellitus, obesity/body mass index greater than 30, hypertension, and vascular disorders) may be at increased risk for developing cardiac ischemic events.
Bosutinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Apprise pregnant patients 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.
Counsel patients about the reproductive risk and contraception requirements during bosutinib treatment. Perform pregnancy testing prior to starting therapy in patients of reproductive potential. These patients should use effective contraception (i.e., methods that result in less than 1% pregnancy rates) during and for 2 weeks after treatment with bosutinib. Apprise patients who become pregnant while receiving bosutinib of the potential hazard to the fetus. Bosutinib may result in infertility in females or males based on findings from animal studies.
It is not known if bosutinib or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions in nursing infants, patients should discontinue breast-feeding during bosutinib therapy and for 2 weeks after the last dose.
For the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML):
NOTE: The FDA has designated bosutinib as an orphan drug for the treatment of CML.
-for the treatment of newly diagnosed chronic phase Ph+ CML:
Oral dosage:
Adults: 400 mg orally once daily until disease progression. The bosutinib dosage may be increased in increments of 100 mg once daily to a maximum dosage of 600 mg once daily in patients who have not experienced grade 3 or higher toxicity and who have not achieved a complete hematologic, cytogenetic, or molecular response with initial therapy. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The 12-month major molecular response (MMR; 47.2% vs. 36.9%; odds ratio (OR) = 1.55; 95% CI, 1.07 to 2.23; p = 0.02) and complete cytogenetic response (77.2% vs. 66.4%; OR = 1.74; 95% CI, 1.16 to 2.61; p = 0.0075) rates were significantly improved with bosutinib (n = 246) compared with imatinib (n = 241) in patients with newly diagnosed chronic phase Ph+ CML in a multinational, randomized, phase 3 (BFORE) trial. The 60-month MMR rates were 73.9% and 64.6% (OR = 1.57; 95% CI, 1.08 to 2.28) in the bosutinib and imatinib arms, respectively; the estimated 60-month overall survival rates were 94.5% and 94.6% (hazard ratio = 0.95; 95% CI, 0.45 to 1.99), respectively. The median bosutinib dose was 393.6 (range, 39 to 583) mg/day; the median duration of therapy was 55 months.
Children and Adolescents: 300 mg/m2 orally once daily until disease progression. The specific dose is based on body surface area (BSA) as follows: BSA of less than 0.55 m2, give 150 mg PO once daily; BSA of 0.55 to less than 0.75 m2, give 200 mg PO once daily; BSA of 0.75 to less than 0.9 m2, give 250 mg PO once daily; BSA of 0.9 to less than 1.1 m2, give 300 mg PO once daily; and BSA of 1.1 m2 or more, 400 mg PO once daily. As appropriate, the dose may be achieved by combining different strength tablets or capsules. If there is an insufficient response after 3 months, the bosutinib dosage may be increased in 50-mg increments up to a maximum dosage of 100 mg above the starting dose in patients with a BSA less than 1.1 m2; increase the dosage per adult recommendations (i.e., in increments of 100 mg once daily to a maximum dosage of 600 mg once daily) in patients with a BSA of 1.1 m2 or more. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. At a median follow-up time of 14.2 (range, 1.1 to 26.3) months, the major cytogenetic response rate was 72.6%, the complete cytogenetic response rate was 71.4%, and the major molecular response rate was 28.6% in 21 pediatric patients (median age, 14 years; range, 5 to 17 years) with newly diagnosed chronic phase CML in a multicenter, single-arm, phase 1/2 (BCHILD) trial.
-for the treatment of chronic phase Ph+ CML with resistance or intolerance to prior therapy:
Oral dosage:
Adults: 500 mg orally once daily until disease progression. The bosutinib dosage may be increased to 600 mg orally once daily in patients who have not experienced grade 3 or higher toxicity and who have not achieved a complete hematologic, cytogenetic, or molecular response with initial therapy. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Bosutinib was evaluated as second-line treatment (n = 288) and as third- (n = 115) or fourth- (n = 3) line treatment in patients with chronic phase chronic myelogenous leukemia (CP-CML) in a multicenter, single-arm, 2-part, phase 1/2 study. The 24-week major cytogenic response (mCyR; primary endpoint) was 33.8% in CP-CML patients who were resistant (n = 186) or intolerant (n = 80) to 1 prior therapy consisting of imatinib and 32% in CP-CML patients who received prior therapy with imatinib plus dasatinib and/or nilotinib (n = 108). At a median follow-up of 54.8 (range, 0.6 to 96.3) months, second-line treatment with bosutinib (median duration of therapy, 25.6 months; range, 0.2 to 96.3 months) resulted in a cumulative mCyR of 61% in 195 imatinib-resistant patients and 61% in 89 imatinib-intolerant patients. The estimated 5-year overall survival rate was 83.5% in all patients who received bosutinib as second-line therapy.
Children and Adolescents: 400 mg/m2 orally once daily until disease progression. The specific dose is based on body surface area (BSA) as follows: BSA of less than 0.55 m2, give 200 mg PO once daily; BSA of 0.55 to less than 0.63 m2, give 250 mg PO once daily; BSA of 0.63 to less than 0.75 m2, give 300 mg PO once daily; BSA of 0.75 to less than 0.9 m2, give 350 mg PO once daily; BSA of 0.9 to less than 1.1 m2, give 400 mg PO once daily; and BSA of 1.1 m2 or more, 500 mg PO once daily. As appropriate, the dose may be achieved by combining different strength tablets or capsules. If there is an insufficient response after 3 months, the bosutinib dosage may be increased in 50-mg increments up to a maximum dosage of 100 mg above the starting dose in patients with a BSA less than 1.1 m2; increase the dosage per adult recommendations (i.e., in increments of 100 mg once daily to a maximum dosage of 600 mg once daily) in patients with a BSA of 1.1 m2 or more. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. At a median follow-up time of 23.2 (range, 1 to 61.5) months, the major cytogenetic response rate was 82.1%, the complete cytogenetic response rate was 78.6%, and the major molecular response rate was 50% in 28 pediatric patients (median age, 11.5 years; range, 1 to 17 years) with chronic phase CML that was resistant or intolerant to prior therapy in a multicenter, single-arm, phase 1/2 (BCHILD) trial.
-for the treatment of accelerated phase or blast phase Ph+ CML with resistance or intolerance to prior therapy:
Oral dosage:
Adults: 500 mg orally once daily until disease progression. The bosutinib dosage may be increased to 600 mg orally daily in patients who have not experienced grade 3 or higher toxicity and who have not achieved a complete hematologic, cytogenetic, or molecular response with initial therapy. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The 48-week confirmed overall hematologic response (primary endpoint) was 57% (complete hematologic response (CHR), 31%) in patients with previously treated accelerated phase-CML (n = 72) and 28% (CHR, 17%) in patients with previously treated blast phase-CML (n = 60) in a multicenter, single-arm, 2-part, phase 1/2 study. All patients in this study had received prior imatinib therapy.
Therapeutic Drug Monitoring:
Dosage Adjustments due to Treatment-Related Toxicity
Hematologic Toxicity
Absolute neutrophil count (ANC) less than 1,000 X 106 cells/L or platelet count less than 50,000 X 106 cells/L: Hold bosutinib therapy until the ANC is 1,000 X 106 cells/L or more and the platelet count is 50,000 X 106 cells/L or more. Resume bosutinib therapy at the same dose if counts recover within 2 weeks.
Adults
If blood counts remain low for more than 2 weeks, resume therapy at 100 mg less than the previous dose after counts recover. If cytopenia recurs, dose reduce by an additional 100 mg after counts recover.
Pediatric Patients
Body surface area (BSA) of less than 1.1 m2: If blood counts remain low for more than 2 weeks, resume therapy at 50 mg less than the previous dose after counts recover. If cytopenia recurs, dose reduce by an additional 50 mg after counts recover.
BSA of 1.1 m2 or more: If blood counts remain low for more than 2 weeks, use adult dose adjustment recommendations.
Non-Hematologic Toxicity
Adults
Grade 3 or 4 diarrhea (7 stools/day or more compared with baseline): Hold bosutinib therapy until recovery to grade 1 toxicity or less; resume therapy at 400 mg once daily.
Other clinically significant or moderate or severe toxicity: Hold bosutinib therapy until toxicity resolves. Consider resuming therapy at 100 mg/day less than the previous dose. Dosage re-escalation to the starting dose may be considered if clinically appropriate.
Pediatric Patients
BSA of less than 1.1 m2: Follow guidance for adults; however, the dose reduction increments may differ. Reduce the dose of bosutinib by 50 mg less than the previous dose. If the toxicity persists, dose reduce by an additional 50 mg.
BSA of 1.1 m2 or more: Follow guidance and dosage adjustments for adults.
Maximum Dosage Limits:
-Adults
600 mg/day PO.
-Geriatric
600 mg/day PO.
-Adolescents
600 mg/day PO.
-Children
BSA less than 1.1 m2: 100 mg over the starting dose.
BSA of 1.1 m2 or more: 600 mg/day PO.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Adults
Baseline Hepatic Impairment
Child-Pugh A, B, or C: Initiate bosutinib at 200 mg PO once daily.
Treatment-Related Toxicity
Transaminase level elevations of more than 5 times the ULN during therapy: Hold bosutinib therapy until levels fall to 2.5 times the ULN or less, then resume therapy at 400 mg PO once daily. Discontinue therapy if recovery is longer than 4 weeks.
Transaminase level elevations of 3 times the ULN or more concurrently with bilirubin level elevations more than 2 times the ULN and alkaline phosphatase levels less than 2 times the ULN during therapy: Discontinue therapy.
Pediatric Patients
Baseline Hepatic Impairment
Child-Pugh A, B, or C: Initial dose is based on body surface area (BSA).
BSA less than 0.63 m2: 100 mg PO once daily.
BSA of 0.63 to less than 0.9 m2: 100 mg PO once daily for newly diagnosed chronic phase (CP)-CML; 150 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.9 to less than 1.1 m2: 150 mg PO once daily for newly diagnosed CP-CML; 200 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 1.1 m2 or more: 200 mg PO once daily.
Treatment-Related Toxicity:
BSA of less than 1.1 m2: Follow guidance for adults; however, the dose reduction increments may differ. Reduce the dose of bosutinib by 50 mg less than the previous dose. If the toxicity persists, dose reduce by an additional 50 mg.
BSA of 1.1 m2 or more: Follow guidance and dosage adjustments for adults.
Patients with Renal Impairment Dosing
Adults
Baseline Renal Impairment
Creatinine clearance (CrCl) of greater than 50 mL/min: No initial dosage adjustment necessary.
CrCl 30 to 50 mL/min: Initiate at a reduced dose of 300 mg PO once daily for newly diagnosed chronic phase CML patients and 400 mg PO once daily for patients with CML that is resistant or intolerant to prior therapy.
CrCl less than 30 mL/min: Initiate at a reduced dose of 200 mg PO once daily for newly diagnosed chronic phase CML patients and 300 mg PO once daily for patients with CML that is resistant or intolerant to prior therapy.
Pediatric Patients
Baseline Renal Impairment
CrCl greater than 50 mL/min: No initial dosage adjustment necessary.
CrCl 30 to 50 mL/min: Initial dose is based on body surface area (BSA).
BSA less than 0.55 m2: 100 mg PO once daily for newly diagnosed chronic phase (CP)-CML; 150 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.55 to less than 0.75 m2: 150 mg PO once daily for newly diagnosed CP-CML; 200 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.75 to less than 0.9 m2: 200 mg PO once daily for newly diagnosed CP-CML; 250 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.9 to less than 1.1 m2: 200 mg PO once daily for newly diagnosed CP-CML; 300 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 1.1 m2 or more: 300 mg PO once daily for newly diagnosed CP-CML; 400 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
CrCl less than 30 mL/min: Initial dose is based on BSA.
BSA less than 0.55 m2: 100 mg PO once daily.
BSA of 0.55 to less than 0.63 m2: 100 mg PO once daily for newly diagnosed CP-CML; 150 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.63 to less than 0.75 m2: 100 mg PO once daily for newly diagnosed CP-CML; 200 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.75 to less than 0.9 m2: 150 mg PO once daily for newly diagnosed CP-CML; 200 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 0.9 to less than 1.1 m2: 200 mg PO once daily for newly diagnosed CP-CML; 250 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
BSA of 1.1 m2 or more: 200 mg PO once daily for newly diagnosed CP-CML; 300 mg PO once daily for CP-CML resistant or intolerant to prior therapy.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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: (Major) Avoid coadministration of bosutinib with encorafenib as concurrent use may decrease bosutinib exposure which may lead to decreased efficacy. Bosutinib is a sensitive CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased bosutinib exposure by 94%.
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).
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.
Magnesium Salts: (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.
Nirogacestat: (Major) Avoid concomitant use of bosutinib and nirogacestat 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 nirogacestat 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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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 is highly bound to plasma proteins in healthy subjects (96%); binding is 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. In vitro, bosutinib inhibits the breast cancer resistance protein (BCRP) transporter.
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability was 34% following a single 500-mg dose of bosutinib (with food) administered in healthy subjects. In patients with chronic myelogenous leukemia (CML), the steady-state Cmax and AUC values were 127 (coefficient of variation (CV), 31%) nanogram (ng)/mL and 2,270 (CV, 34%) ng X hour/mL, respectively, following multiple doses of oral bosutinib 400 mg and 171 (CV, 38%) ng/mL and 3,150 (CV, 38%) ng X hour/mL, respectively, following multiple doses of oral bosutinib 500 mg. Following a single bosutinib 500-mg oral dose (with food), the median Tmax was 6 hours in patients with CML.
Effects of food: When bosutinib was administered with a high-fat meal in healthy subjects, the Cmax and AUC values were increased by 1.8-fold and 1.7-fold, respectively, with bosutinib tablets and 1.6-fold and 1.5-fold, respectively, with bosutinib capsules compared with the fasted state. There were no clinically significant differences in the pharmacokinetic parameters of bosutinib following administration of either the tablet or capsule dosage forms at the same dose, under fed conditions or of the capsule dosage form that was opened and the contents mixed with applesauce or yogurt immediately before use. A high-fat meal consisted of 800 to 1000 total calories consisting of approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories.
-Special Populations
Hepatic Impairment
Following a single 200-mg dose of bosutinib, the Cmax and AUC values increased by 2.4-fold and 2.3-fold, respectively, in subjects with mild (Child-Pugh class A) hepatic impairment, 2-fold (for both Cmax and AUC) in subjects with moderate (Child-Pugh class B) hepatic impairment, and 1.5-fold and 1.9-fold, respectively, in subjects with severe (Child-Pugh class C) hepatic impairment compared with subjects who had normal hepatic function.
Renal Impairment
Following a single 200-mg dose of bosutinib, the Cmax value increased by 1.4-fold in subjects with moderate renal impairment (creatinine clearance (CrCl), 30 to 50 mL/min) and 1.6-fold in subjects with severe renal impairment (CrCl, less than 30 mL/min) compared with subjects who had normal renal function; there was no clinically significant difference in the pharmacokinetic parameters of bosutinib in patients with mild renal impairment (CrCl, 51 to 80 mL/min). Bosutinib has not been studied in patients receiving hemodialysis.
Pediatrics
In pediatric patients with newly diagnosed, chronic phase chronic myelogenous leukemia (CP-CML) or resistant/intolerant CP-CML, the steady-state Cmax and AUC values were 159 (coefficient of variation (CV), 42%) nanograms (ng)/mL and 2,027 (CV, 47%) ng X hour/mL, respectively, in 15 patients aged 4 to less than 17 years who received 300 mg/m2 PO daily (with food) and 198 (CV, 37%) ng/mL and 2,514 (CV, 47%) ng X hour/mL, respectively, in 6 patients aged 6 to less than 17 years who received 400 mg/m2 PO daily (with food). Exposures increased in a dose proportional manner over the dose range of 300 mg/m2 to 400 mg/m2. The median Tmax was about 3 (range, 1 to 8) hours. Following the approved recommended body surface area (BSA)-based dosage, an increase in BSA correlated with an increase in the apparent clearance of bosutinib.