Usual Adult Dose for Chronic Myelogenous Leukemia

Newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP): 300 mg orally twice a day
Resistant or intolerant Ph+ CML-CP and chronic myeloid leukemia in accelerated phase (CML-AP): 400 mg orally twice a day

Comments:

• Doses should be administered about 12 hours apart.
• This drug may be given in combination with hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor [G-CSF]), hydroxyurea, or anagrelide if clinically indicated.

• For the treatment of patients with newly diagnosed Ph+ CML-CP
• For the treatment of patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant/intolerant to prior therapy that included imatinib

Usual Pediatric Dose for Chronic Myelogenous Leukemia

1 year or older: 230 mg/m2 orally twice a day

• Rounded to the nearest 50 mg dose
• Maximum dose: 400 mg/dose

• BSA up to 0.32 m2: 50 mg orally twice a day
• BSA 0.33 to 0.54 m2: 100 mg orally twice a day
• BSA 0.55 to 0.76 m2: 150 mg orally twice a day
• BSA 0.77 to 0.97 m2: 200 mg orally twice a day
• BSA 0.98 to 1.19 m2: 250 mg orally twice a day
• BSA 1.2 to 1.41 m2: 300 mg orally twice a day
• BSA 1.42 to 1.63 m2: 350 mg orally twice a day
• BSA at least 1.64 m2: 400 mg orally twice a day

• Doses should be administered about 12 hours apart.
• Therapy should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.
• This drug may be given in combination with hematopoietic growth factors (e.g., erythropoietin, G-CSF), hydroxyurea, or anagrelide if clinically indicated.

• For the treatment of patients with newly diagnosed Ph+ CML-CP
• For the treatment of patients with chronic phase and accelerated phase Ph+ CML with resistance or intolerance to prior tyrosine-kinase inhibitor therapy

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Adult Patients:
Newly diagnosed Ph+ CML in chronic phase:

• Mild, moderate, or severe liver dysfunction (Child-Pugh A, B, or C): Dosage should be reduced to 200 mg orally twice a day; may increase to 300 mg twice a day based on tolerability

• Mild or moderate liver dysfunction: Dosage should be reduced to 300 mg orally twice a day; may increase to 400 mg orally twice a day based on tolerability
• Severe liver dysfunction: Dosage should be reduced to 200 mg orally twice a day; may increase to 300 mg orally twice a day and then to 400 mg orally twice a day based on tolerability

• If possible, alternative therapies should be considered.
• If this drug must be administered to patients with liver dysfunction, the above dosing regimens should be considered.

Dose Adjustments

DISCONTINUATION OF THERAPY AFTER A SUSTAINED MOLECULAR RESPONSE (MR4.5) ON THIS DRUG:
Eligibility for Discontinuation of Therapy:

• Ph+ CML-CP patients with typical BCR-ABL transcripts who have been taking this drug for at least 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL less than or equal to 0.0032% IS) may be eligible for therapy discontinuation; the manufacturer product information should be consulted for information on US FDA-authorized tests for detection and quantitation of BCR-ABL transcripts.
• Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of therapy. Patients should continue to be monitored for possible loss of molecular remission after therapy discontinuation; the same US FDA-authorized test should be used to consistently monitor molecular response levels while on and off therapy.
• Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have:
• been treated with this drug for at least 3 years
• maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL less than or equal to 0.01% IS) for 1 year prior to discontinuation of therapy
• achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy
• been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)
• no history of accelerated phase or blast crisis
• no history of prior attempts of treatment-free remission discontinuation that resulted in relapse.
• Consider discontinuation in patients with Ph+ CML-CP that are resistant/intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on this drug who have:
• been treated with this drug for at least 3 years
• been treated with imatinib only prior to treatment with this drug
• achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL less than or equal to 0.0032% IS)
• sustained an MR4.5 for at least 1 year immediately prior to discontinuation of therapy
• been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)
• no history of accelerated phase or blast crisis
• no history of prior attempts of therapy-free remission discontinuation that resulted in relapse.
• In patients who have discontinued therapy, BCR-ABL transcript levels and CBC with differential should be monitored monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.
• Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL less than or equal to 0.01% IS) during the therapy-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels remain lower than major molecular response (MMR, corresponding to MR3.0 or = BCR-ABL/ABL less than or equal to 0.1% IS) for 4 consecutive measurements; the patient can then proceed to the original monitoring schedule.

• Newly diagnosed patients who lose MMR should reinitiate therapy within 4 weeks at the dose level prior to discontinuation of therapy; patients who reinitiate therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is reestablished and every 12 weeks thereafter.
• Patients resistant/intolerant to prior therapy that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR should reinitiate therapy within 4 weeks at the dose level prior to discontinuation of therapy; patients who reinitiate therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is reestablished and every 12 weeks thereafter.

• ECGs with QTc greater than 480 msec:
• This drug should be withheld and an analysis of serum potassium and magnesium should be performed; if below lower limit of normal, correction with supplements to within normal limits is recommended. Concomitant medication usage should be reviewed.
• Resumption within 2 weeks at prior dose is recommended if QTcF returns to less than 450 msec and to within 20 msec of baseline.
• If QTcF is between 450 msec and 480 msec after 2 weeks, the dose should be reduced to 400 mg once a day in adults and 230 mg/m2 once a day in pediatric patients.
• This drug should be discontinued if, after dose-reduction to 400 mg once a day in adults and 230 mg/m2 once a day in pediatric patients, QTcF returns to greater than 480 msec.
• An ECG should be repeated about 7 days after any dose adjustment.

• Dosage should be withheld or reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia.
• Adult patients with newly diagnosed Ph+ CML in chronic phase at 300 mg twice a day OR resistant/intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice a day with absolute neutrophil count (ANC) less than 1 x 10(9)/L and/or platelet counts less than 50 x 10(9)/L:
• This drug should be stopped and blood counts should be monitored.
• Resumption within 2 weeks at prior dose is recommended if ANC greater than 1 x 10(9)/L and platelets greater than 50 x 10(9)/L.
• If blood counts remain low for more than 2 weeks, dose should be reduced to 400 mg once a day.
• Pediatric patients with newly diagnosed Ph+ CML in chronic phase at 230 mg/m2 twice a day OR resistant/intolerant Ph+ CML in chronic phase at 230 mg/m2 twice a day with ANC less than 1 x 10(9)/L and/or platelet counts less than 50 x 10(9)/L:
• This drug should be stopped and blood counts should be monitored.
• Resumption within 2 weeks at prior dose is recommended if ANC greater than 1.5 x 10(9)/L and platelets greater than 75 x 10(9)/L.
• If blood counts remain low for more than 2 weeks, dose reduction to 230 mg/m2 once a day may be needed.
• If the event occurs after dose reduction, discontinuation of therapy should be considered.

• Elevated Serum Lipase or Amylase At Least Grade 3:
• Adult patients: This drug should be withheld and serum lipase or amylase should be monitored. Resumption of therapy at 400 mg once a day is recommended if serum lipase or amylase returns to Grade 1 or less.
• Pediatric patients: This drug should be interrupted until the event returns to Grade 1 or less. Resumption of therapy at 230 mg/m2 once a day is recommended if prior dose was 230 mg/m2 twice a day; therapy should be discontinued if prior dose was 230 mg/m2 once a day.
• Elevated Bilirubin At Least Grade 3 in Adult Patients and At Least Grade 2 in Pediatric Patients:
• Adult patients: This drug should be withheld and bilirubin should be monitored. Resumption of therapy at 400 mg once a day is recommended if bilirubin returns to Grade 1 or less.
• Pediatric patients: This drug should be interrupted until the event returns to Grade 1 or less. Resumption of therapy at 230 mg/m2 once a day is recommended if prior dose was 230 mg/m2 twice a day; therapy should be discontinued if prior dose was 230 mg/m2 once a day, and recovery to Grade 1 or less takes longer than 28 days.
• Elevated Hepatic Transaminases At Least Grade 3:
• Adult patients: This drug should be withheld and hepatic transaminases should be monitored. Resumption of therapy at 400 mg once a day is recommended if hepatic transaminases return to Grade 1 or less.
• Pediatric patients: This drug should be interrupted until the event returns to Grade 1 or less. Resumption of therapy at 230 mg/m2 once a day is recommended if prior dose was 230 mg/m2 twice a day; therapy should be discontinued if prior dose was 230 mg/m2 once a day, and recovery to Grade 1 or less takes longer than 28 days.

• Other Clinically Moderate or Severe Nonhematologic Toxicity:
• Adult patients: This drug should be withheld until toxicities resolve. Resumption of therapy at 400 mg once a day is recommended if previous dose was 300 mg twice a day in patients newly diagnosed with CML-CP or 400 mg twice a day in patients with resistant/intolerant CML-CP and CML-AP; therapy should be discontinued if the prior dose was 400 mg once a day. If clinically appropriate, re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant/intolerant Ph+ CML-CP and CML-AP) twice a day should be considered.
• Pediatric patients: This drug should be interrupted until toxicities resolve. Resumption of therapy at 230 mg/m2 once a day is recommended if previous dose was 230 mg/m2 twice a day; therapy should be discontinued if prior dose was 230 mg/m2 once a day. If clinically appropriate, re-escalation of the dose to 230 mg/m2 twice a day should be considered.

• Concomitant use of strong CYP450 3A4 inhibitors should be avoided; if treatment with any of these agents is required, therapy with this drug should be interrupted.
• If coadministration with a strong CYP450 3A4 inhibitor is required, dosage should be reduced to 300 mg once a day in patients with resistant/intolerant Ph+ CML or to 200 mg once a day in patients with newly diagnosed Ph+ CML-CP; however, no clinical data are available regarding this dose adjustment in patients receiving strong CYP450 3A4 inhibitors.
• If the strong inhibitor is discontinued, a washout period should be allowed before the dose of this drug is adjusted upward to the indicated dose.
• Patients who cannot avoid use of strong CYP450 3A4 inhibitors should be monitored closely for prolongation of the QT interval.

Precautions

US BOXED WARNING:

• QT PROLONGATION AND SUDDEN DEATHS: This drug prolongs the QT interval; before drug administration and periodically, patients should be monitored for hypokalemia or hypomagnesemia and deficiencies should be corrected; ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and after any dose adjustments. Sudden deaths have been reported in patients receiving this drug; this drug should not be administered to patients with hypokalemia, hypomagnesemia, or long QT syndrome. Concomitant use of drugs known to prolong the QT interval and strong CYP450 3A4 inhibitors should be avoided. Food should be avoided 2 hours before and 1 hour after taking the dose.

Dialysis

Data not available

Other Comments

Administration advice:

• Administer on an empty stomach; do not consume food for at least 2 hours before the dose and for at least 1 hour after the dose.
• Swallow capsules whole with water.
• If unable to swallow capsules, disperse the contents of each capsule in 1 teaspoon of applesauce and swallow the mixture immediately (within 15 minutes); do not store for future use.
• If a dose is missed, administer the next scheduled dose at its regular time; do not administer 2 doses at the same time.

• Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F).

• Cardiovascular: ECG (at baseline, 7 days after starting therapy, after dose adjustments, and periodically during therapy)
• Hematologic: CBC (every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated)
• Hepatic: Hepatic function tests (monthly or as clinically indicated)
• Metabolic: Chemistry panels, including electrolytes, calcium, and magnesium (before starting and periodically during therapy); glucose (before starting and periodically during first year of therapy; at least yearly during chronic therapy); serum lipase levels (monthly or as clinically indicated); lipid profile (before starting, at 3 and 6 months after starting therapy, and at least yearly)

• Read the US FDA-approved patient labeling (Medication Guide).
• Seek immediate medical attention if symptoms suggestive of low blood counts (e.g., fever/chills/other signs of infection, unexplained bleeding/bruising, unexplained weakness, shortness of breath), pancreatitis (e.g., sudden stomach area pain with nausea and vomiting), or hemorrhage (e.g., uncontrolled bleeding, changes in eyesight, unconsciousness, sudden headache/sudden confusion in surroundings) occur.
• Seek immediate medical attention if symptoms of abnormal heartbeat (e.g., feeling lightheaded, faint, irregular heartbeat) occur.
• Seek immediate medical attention if any symptoms suggestive of a cardiovascular event (e.g., chest/leg pain, numbness/weakness, problems walking/speaking occur suddenly), hepatotoxicity (e.g., stomach pain, yellow skin and eyes, dark-colored urine), tumor lysis syndrome (e.g., abnormal heartbeat, less urine production), or fluid retention (e.g., shortness of breath, rapid weight gain, swelling) occur.
• Take this medication on an empty stomach; do not consume any food for at least 2 hours before the dose and at least 1 hour after the dose. Do not consume grapefruit products and other foods known to inhibit CYP450 3A4 at any time during therapy.
• Do not breastfeed during therapy and for 14 days after the last dose.
• Females of childbearing potential: Notify health care provider of known/suspected pregnancy; use effective contraception during therapy and for 14 days after the last dose.
• Monitor growth and development in pediatric patients.

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