Bosutinib – Uses, Dosage, Side Effects, Interaction

Use in Cancer

Bosutinib is approved to treat:

• Chronic myelogenous leukemia (CML) is Philadelphia chromosome positive. It is used:
  • In adults with newly diagnosed chronic phase CML. This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that bosutinib provides a clinical? benefit in these patients.
  • In adults with chronic phase, accelerated phase, or blastic phase CML that cannot be treated with or that did not respond to other treatments.

Bosutinib is also being studied in the treatment of other types of cancer.

Contraindication?

• are allergic to bosutinib or any ingredients of the medication
• have a history of irregular heartbeat, particularly long QT syndrome?
• have reduced liver function
• have untreated low potassium or low magnesium in your blood
• anemia?
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• fluid in the covering of the heart or pericardium?
• chronic heart failure?
• escape of fluid into the lungs
• fluid in the lungs
• liver problems
• fluid retention in the legs, feet, arms or hands
• high amount of bilirubin? in the blood
• excessive diarrhea?
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• reactivation of hepatitis? B infection?
• chronic kidney disease? stage 3A (moderate?)
• chronic kidney? disease stage 3B (moderate)
• chronic kidney disease stage 4 (severe?)
• Child-Pugh class A liver impairment
• Child-Pugh class B liver impairment
• Child-Pugh class C liver impairment

Dosage?

Strengths: 100 mg; 500 mg; 400 mg

Chronic Myelogenous Leukemia

Newly-diagnosed:

• 400 mg orally once daily
• Duration of therapy: Until disease progression? or patient intolerance

Chronic/accelerated/blast phase:

• 500 mg orally once daily
• Duration of therapy: Until disease progression or patient intolerance
• Take this drug with food.
• If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.

Renal? Dose Adjustments

RECOMMENDED STARTING DOSE for newly-diagnosed chronic phase Ph+ CML:

• Normal renal function: 400 mg orally once a day
• Moderate renal dysfunction (CrCl 30 to 50 mL/min): 300 mg orally once a day
• Severe renal dysfunction (CrCl less than 30 mL/min): 200 mg orally once a day

RECOMMENDED STARTING DOSE for Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy:

• Normal renal function: 500 mg orally once a day
• Moderate renal dysfunction (CrCl 30 to 50 mL/min): 400 mg orally once a day
• Severe renal dysfunction (CrCl less than 30 mL/min): 300 mg orally once a day

Liver Dose Adjustments

RECOMMENDED STARTING DOSE for newly-diagnosed chronic phase Ph+ CML:

• Normal liver function: 400 mg orally once a day
• Mild?, moderate, or severe liver dysfunction (Child-Pugh A, B, or C): 200 mg orally once a day (There are no clinical data for efficacy at the dose of 200 mg once daily in patients with CML)

RECOMMENDED STARTING DOSE for Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy:

• Normal liver function: 500 mg orally once a day
• Mild, moderate, or severe liver dysfunction (Child-Pugh A, B, or C): 200 mg orally once a day (There are no clinical data for efficacy at the dose of 200 mg once daily in patients with CML)

Dose Adjustments

DOSE ESCALATION:

• The dose can be escalated by increments of 100 mg once daily to a maximum of 600 mg once daily in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage.

NON-HEMATOLOGIC ADVERSE REACTIONS:
Elevated liver transaminases:

• Liver transaminases greater than 5 times the institutional upper limit of normal (ULN): Withhold therapy until recovery to less than or equal to 2.5 x ULN and resume at 400 mg orally once daily thereafter. If recovery takes longer than 4 weeks, discontinue therapy.
• Liver transaminases greater than or equal to 3 x ULN concurrently with bilirubin greater than 2 x ULN and alkaline phosphatase less than 2 x ULN (Hy’s law case definition): Discontinue therapy

Diarrhea:

• For NCI CTCAE Grade 3 to 4 diarrhea (an increase of greater than or equal to 7 stools/day over baseline?/pretreatment): Withhold therapy until recovery to Grade 1 or less. Treatment may be resumed at 400 mg orally once a day.

Other Moderate or Severe Non-Hematologic Adverse Reactions:

• Withhold therapy until resolved, then consider resuming therapy at a dose reduced by 100 mg orally once a day.
• If appropriate, consider re-escalating the dose to the starting dose once a day.
• Doses less than 300 mg/day have been used in patients; however, efficacy has not been established

MYELOSUPPRESSION:

• Absolute neutrophil count (ANC) less than 1000 x 10(6)/L OR platelets less than 50,000 x 10(6)/L: Withhold therapy until ANC is greater than or equal to 1000 x 10(6)/L AND platelets are greater than or equal to 50,000 x 10(6)/L.
• Resume therapy at the same dose if recovery occurs within 2 weeks. If blood counts remain low for more than 2 weeks, upon recovery, reduce the dose by 100 mg and resume therapy.
• If cytopenia recurs, reduce the dose by an additional 100 mg upon recovery and resume therapy.
• Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.

Side Effects

The Most Common

• headache
• loss of appetite
• tiredness or weakness
• change in the ability to taste food
• ringing in the ears
• nausea
• vomiting
• diarrhea
• sudden stomach area pain
• unexplained bleeding or bruising
• blood in urine or stool
• change in the frequency of urination
• increase or decrease in the amount of urine
• dizziness
• fever, sore throat, chills, or other signs of infection
• shortness of breath and cough
• chest pain
• swelling of the face, hands, ankles, feet, or lower legs
• sudden weight gain
• yellowing of the skin and eyes
• dark or tea-colored urine
• hives
• rash
• itching
• difficulty breathing or swallowing

More Common

• abnormal heart rhythms (such as fast or slow heart rate, palpitations), fainting, or seizures
• chest pain
• dizziness
• fever
• generalized pain (back pain, muscle pain)
• increased blood pressure
• shortness of breath
• changed sense of taste
• cold symptoms (e.g., sore throat, runny nose)
• decreased appetite
• diarrhea
• fatigue
• flu-like symptoms (sudden lack of energy, fever, cough, sore throat)

Rare

• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of breathing problems (e.g., shortness of breath, troubled breathing, wheezing, or tightness in chest, fast or irregular breathing)
• signs of dehydration (e.g., decreased urine, dry skin, dry and sticky mouth, sleepiness, dizziness, headache, thirst, confusion)
• signs of fluid build-up around the lungs (e.g., chest pain, cough, hiccups, rapid breathing)
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• signs of kidney failure (e.g., decreased urine production, swelling, fatigue, abdominal pain)
• signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
• signs of pneumonia (e.g., fever, chills, shortness of breath, cough)
• swelling of the hands, feet, or face
• symptoms of fluid build-up around the heart (e.g., fever, fatigue, muscle aches, shortness of breath, nausea, vomiting, diarrhea, fast or pounding heartbeat, light-headedness)
• symptoms of inflammation of the tissue surrounding the heart (pericarditis; e.g., chest pain, cough, fast or irregular heartbeat, shortness of breath, weakness, or fatigue)
• symptoms of respiratory failure (e.g., dizziness, trouble breathing, shortness of breath, fast, shallow breathing, wheezing, bluish coloration to the skin and lips from lack of oxygen)
• symptoms of too little phosphorus in the blood (e.g., muscle weakness, fatigue, bone pain, fractures, numbness, confusion)
• symptoms of too much potassium in the body (e.g., muscle fatigue, weakness, difficulty moving, abnormal heart rhythms, nausea)
• signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
• signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
• signs of bleeding in the stomach (e.g., bloody, black, or tarry stools, spitting up of blood, vomiting blood or material that looks like coffee grounds)

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

This medication should not be taken during pregnancy. Bosutinib may cause severe harm to a developing baby if it is taken by the mother while she is pregnant. Female partners of men taking this medication should not become pregnant. Both women and men must use a reliable method of birth control (e.g., condoms, birth control pill) during treatment and for at least 4 weeks after treatment is finished. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

No information is available on the clinical use of bosutinib during breastfeeding. Because bosutinib is 96% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 22 hours and it might accumulate in the infant. National Comprehensive Cancer Network guidelines recommend avoiding breastfeeding during bosutinib therapy and the manufacturer recommends withholding breastfeeding until 2 weeks following the last dose.

References