Bosutinib

Grapefruit and grapefruit juice may interact with bosutinib and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Many drugs can interact with bosutinib. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• cyclosporine;
• imatinib;
• nefazodone;
• St. John's wort;
• an antibiotic--azithromycin, clarithromycin, erythromycin, telithromycin;
• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;
• heart or blood pressure medicine--amiodarone, captopril, carvedilol, diltiazem, dronedarone, felodipine, nicardipine, quinidine, ranolazine, verapamil;
• antiviral medicine to treat hepatitis or HIV/AIDS--atazanavir, boceprevir, cobicistat, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir;
• seizure medicine--carbamazepine, phenytoin;
• stomach acid reducers--dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; or
• tuberculosis medicine--isoniazid, rifampin.

This list is not complete and many other drugs can interact with bosutinib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Before you take bosutinib, tell your doctor if you:

• have liver problems
• have heart problems
• have any other medical conditions
• are pregnant or plan to become pregnant. Bosutinib can harm your unborn baby. You should not become pregnant while taking bosutinib. Tell your doctor right away if you become pregnant while taking bosutinib.
• are a woman who may become pregnant. Use effective contraception (birth control) during and for at least 30 days after completing treatment with bosutinib. Talk to your doctor about forms of birth control.
• are breastfeeding or plan to breastfeed. It is not known if bosutinib passes into your breast milk or if it can harm your baby. You and your doctor should decide if you will take bosutinib or breastfeed. You should not do both.

Tell your doctor about the medicines you take, including prescription medicines, non-prescription medicines, vitamins, and herbal supplements.

• Take bosutinib exactly as prescribed by your doctor.
• Do not change your dose or stop taking bosutinib without first talking with your doctor.
• Take bosutinib with food.
• Swallow bosutinib tablets whole. Do not crush or cut bosutinib tablets. Do not touch or handle crushed or broken bosutinib tablets.
• You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract while taking bosutinib. Grapefruit products increase the amount of bosutinib in your body.
• Your doctor may change your dose of bosutinib or tell you to stop taking bosutinib depending on how you respond to treatment.
• If you miss a dose of bosutinib, take it as soon as you remember. If it has been more than 12 hours since your last dose, take your next dose at your regular time. Do not take two doses at the same time.

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 4–6 hours.1

Food

Oral administration with a high-fat meal increases peak plasma concentrations and AUC by 1.8- and 1.7-fold, respectively.1

Special Populations

Patients with hepatic impairment (Child-Pugh class A, B, or C): Peak concentrations increased by 2.4-, 2-, or 1.5-fold, respectively; AUCs increased by 2.3-, 2-, or 1.9-fold, respectively, compared with healthy individuals following a 200-mg dose.1

Systemic exposure following bosutinib 200 mg daily in patients with hepatic impairment expected to be similar to that observed in those with normal hepatic function receiving 500 mg daily; efficacy of bosutinib 200 mg daily in patients with hepatic impairment and CML unknown.1 (See Hepatic Impairment under Cautions.)

Patients with moderate (ClCr 30–50 mL/minute) or severe (ClCr <30 mL/minute) renal impairment: AUC increased by 35 or 60%, respectively, compared with healthy individuals following a 200-mg dose.1

Systemic exposure following bosutinib 300 mg daily in patients with severe renal impairment expected to be similar to that observed in those with normal renal function receiving 500 mg daily; efficacy of bosutinib 300 mg daily in patients with renal impairment and CML unknown.1 (See Renal Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

94–96%.1

Elimination

Metabolism

Metabolized principally by CYP3A4 to 3 inactive metabolites, oxydechlorinated (M2), N-desmethylated (M5), and N-oxide (M6) derivatives. 1

Elimination Route

Eliminated in feces (91%) and urine (3%).1

Half-life

Mean terminal half-life: 22.5 hours.1

Special Populations

Patients with mild to severe hepatic impairment: Prolonged elimination half-life expected.3

Patients with renal impairment: Elimination half-life not affected.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For bosutinib, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to bosutinib or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of bosutinib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of bosutinib in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking bosutinib, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using bosutinib with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine

Using bosutinib with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine
• Amprenavir
• Aprepitant
• Atazanavir
• Bacillus of Calmette and Guerin Vaccine, Live
• Boceprevir
• Bosentan
• Carbamazepine
• Ceritinib
• Cholera Vaccine, Live
• Ciprofloxacin
• Clarithromycin
• Cobicistat
• Conivaptan
• Darunavir
• Delavirdine
• Dexamethasone
• Dexlansoprazole
• Diltiazem
• Dronedarone
• Efavirenz
• Enzalutamide
• Erythromycin
• Esomeprazole
• Etravirine
• Fluconazole
• Fosamprenavir
• Fosaprepitant
• Fosphenytoin
• Idelalisib
• Imatinib
• Indinavir
• Influenza Virus Vaccine, Live
• Itraconazole
• Ketoconazole
• Lansoprazole
• Lopinavir
• Mibefradil
• Mifepristone
• Mitotane
• Modafinil
• Nefazodone
• Nelfinavir
• Nevirapine
• Omeprazole
• Oxcarbazepine
• Pantoprazole
• Phenobarbital
• Phenytoin
• Poliovirus Vaccine, Live
• Posaconazole
• Prednisone
• Primidone
• Rabeprazole
• Rifabutin
• Rifampin
• Ritonavir
• Saquinavir
• Smallpox Vaccine
• St John's Wort
• Telaprevir
• Telithromycin
• Typhoid Vaccine
• Verapamil
• Voriconazole
• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using bosutinib with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use bosutinib, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of bosutinib. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia (low red blood cells) or
• Blood or bone marrow problems or
• Diarrhea or
• Edema (fluid retention or swelling) or
• Nausea or vomiting or
• Neutropenia (low white blood cells) or
• Thrombocytopenia (low platelets in the blood)—Use with caution. May make these conditions worse.

• Infection—May decrease your body's ability to fight infection.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Bosulif

Preexisting impairment (mild, moderate, or severe): Child-Pugh class A, B, or C: Reduce initial dose to 200 mg once daily (this dose is predicted to result in an AUC similar to that of patients with normal hepatic function, however, there is no efficacy data for this dose in CML patients with hepatic impairment).

Hepatotoxicity during treatment:

ALT or AST >5 times ULN: Withhold treatment until recovery to ≤2.5 times ULN and resume at 400 mg once daily thereafter. If recovery to ≤2.5 times ULN takes >4 weeks: Discontinue bosutinib.

ALT or AST ≥3 times ULN in conjunction with bilirubin elevation >2 times ULN and alkaline phosphatase <2 times ULN: Discontinue bosutinib.

>10%:

Cardiovascular: Edema (17% to 20%), chest pain (7% to 12%)

Central nervous system: Fatigue (21% to 26%), headache (17% to 21%), dizziness (11% to 13%)

Dermatologic: Skin rash (38% to 42%), pruritus (7% to 12%)

Endocrine & metabolic: Hypophosphatemia (50% [Gambacorti-Passerini 2014]), hypokalemia (18% [Gambacorti-Passerini 2014])

Gastrointestinal: Diarrhea (76% to 85%), nausea (47% to 48%), vomiting (37% to 43%), abdominal pain (31% to 42%), increased serum lipase (15% to 38% [Cortes 2012; Gambacorti-Passerini 2014]), decreased appetite (13% to 14%)

Hematologic & oncologic: Thrombocytopenia (40% to 45%; grades 3/4: 26% to 39%), anemia (27% to 38%; grades 3/4: 11% to 27%), neutropenia (18% to 22%; grades 3/4: 12% to 20%), leukopenia (10% to 15%; grades 3/4: 4% to 12%)

Hepatic: Abnormal hepatic function tests (20% to 26%), increased serum ALT (18%), increased serum AST (15%)

Neuromuscular & skeletal: Arthralgia (14% to 17%), weakness (10% to 13%), back pain (8% to 13%)

Renal: Renal insufficiency (13%)

Respiratory: Respiratory tract infection (38% to 39%), cough (22%), dyspnea (12% to 20%), pleural effusion (9% to 12%)

Miscellaneous: Fever (23% to 37%)

1% to 10%:

Cardiovascular: Hypertension, pericardial effusion, prolonged Q-T interval on ECG

Central nervous system: Pain

Dermatologic: Urticaria

Endocrine & metabolic: Fluid retention (grade 3/4: 5%), dehydration, hyperkalemia

Gastrointestinal: Dysgeusia, gastritis, gastrointestinal hemorrhage, increased serum amylase

Hematologic & oncologic: Febrile neutropenia

Hepatic: Hepatic insufficiency, hepatotoxicity, increased serum bilirubin (grades ≥3: 1% to 3%)

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Increased creatine phosphokinase, myalgia

Otic: Tinnitus

Frequency not defined: Genitourinary: Decreased estimated GFR (eGFR)

<1% (Limited to important or life-threatening): Acute pancreatitis, anaphylactic shock, erythema multiforme, exfoliative dermatitis, fixed drug eruption, granulocytopenia, hepatic injury, pericarditis, pulmonary hypertension, respiratory failure, Stevens-Johnson syndrome

Severe renal dysfunction (CrCl less than 30 mL/min): 300 mg orally once a day

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.