Usual Adult Dose for Chronic Myelogenous Leukemia

Chronic phase chronic myeloid leukemia (CP-CML):

• Initial Dose: 45 mg orally once a day
• Upon achievement of 1% BCR-ABL1 or less (standardized according to International Scale): 15 mg orally once a day
• For loss of response: Re-escalate to a previously tolerated dosage of 30 mg or 45 mg orally once a day
• Treatment duration: Until loss of response at the re-escalated dose or unacceptable toxicity; consider discontinuation if response has not occurred after 3 months.

• Initial dose: 45 mg orally once a day
• The optimal dose has not been identified for AP-CML, BP-CML, and Ph+ ALL.
• Consider dose reduction for AP-CML patients who have achieved major cytogenic response.
• Treatment duration: Until loss of response at the re-escalated dose or unacceptable toxicity; consider discontinuation if response has not occurred after 3 months.

• This drug is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML).

• For the treatment of adult patients with CP-CML with resistance or intolerance to at least two prior kinase inhibitors
• For the treatment of adult patients with AP-CML, or BP-CML or Ph+ ALL for whom no other kinase inhibitors are indicated
• For the treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL

Usual Adult Dose for Acute Lymphoblastic Leukemia

Chronic phase chronic myeloid leukemia (CP-CML):

• Initial Dose: 45 mg orally once a day
• Upon achievement of 1% BCR-ABL1 or less (standardized according to International Scale): 15 mg orally once a day
• For loss of response: Re-escalate to a previously tolerated dosage of 30 mg or 45 mg orally once a day
• Treatment duration: Until loss of response at the re-escalated dose or unacceptable toxicity; consider discontinuation if response has not occurred after 3 months.

• Initial dose: 45 mg orally once a day
• The optimal dose has not been identified for AP-CML, BP-CML, and Ph+ ALL.
• Consider dose reduction for AP-CML patients who have achieved major cytogenic response.
• Treatment duration: Until loss of response at the re-escalated dose or unacceptable toxicity; consider discontinuation if response has not occurred after 3 months.

• This drug is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML).

• For the treatment of adult patients with CP-CML with resistance or intolerance to at least two prior kinase inhibitors
• For the treatment of adult patients with AP-CML, or BP-CML or Ph+ ALL for whom no other kinase inhibitors are indicated
• For the treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL

Renal Dose Adjustments

Data not available.

Liver Dose Adjustments

ANY LEVEL OF LIVER DYSFUNCTION (CHILD-PUGH A, B, OR C):

• Reduce the initial dose to 30 mg once a day in patients with preexisting liver dysfunction (Child-Pugh A, B, or C) and monitor for adverse reactions.
• The safety of multiple doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.

• Occurrence at 45 mg: Interrupt dosing and monitor hepatic function; and resume treatment at 30 mg after recovery to Grade 1 or less (less than 3 x ULN)
• AST or ALT at least 3 times ULN with an elevation of bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN: Discontinue treatment

Dose Adjustments

• Patients with chronic phase myeloid leukemia who have achieved a 1% BCR-ABL1 or less (standardized according to International Scale) or patients with accelerated phase chronic myeloid leukemia who achieve a major cytogenetic response: Consider reducing the dose
• If response to treatment has not occurred by 3 months: Consider treatment discontinuation

• Concomitant use of strong CYP450 3A inducer: Avoid unless the benefit outweighs the risk and monitor for reduced efficacy; select a concomitant medication with no or minimal CYP450 3A induction potential if possible
• Concomitant use of strong CYP450 3A inhibitors: Avoid coadministration, but if it cannot be avoided reduce dosage as follows:
• If current dose 45 mg once a day: Reduce dose to 30 mg once a day
• If current dose 30 mg once a day: Reduce dose to 15 mg once a day
• If current dose is 15 mg once a day: Reduce dose to 10 mg once a day
• If current dose is 10 mg once a day: Avoid use
• Resume the dosage that was tolerated prior to initiating the strong CYP450 3A inhibitor after the strong CYP450 3A inhibitor has been discontinued for 3 to 5 elimination half-lives.

• First Reduction: 30 mg orally once a day for CP-CML, AP-CML, BP-CML, and Ph+ ALL
• Second Reduction: 15 mg orally once a day for CP-CML, AP-CML, BP-CML, and Ph+ ALL
• Third reduction: 10 mg orally once a day for CP-CML and permanently discontinue for AP-CML, BP-CML, and Ph+ ALL patients unable to tolerate the second dose reduction
• Subsequent reduction: Permanently discontinue treatment for CP-CML, AP-CML, BP-CML, and Ph+ ALL

• Occurrence at 45 mg: Interrupt dosing and monitor hepatic function; and resume treatment at 30 mg after recovery to Grade 1 or less (less than 3 x ULN)
• AST or ALT at least 3 times ULN with an elevation of bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN: Discontinue treatment

• Serum lipase greater than 1 to 1.5 x ULN: Consider treatment interruption until resolution and then resume at same dose
• Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis: Interrupt until Grade 0 or 1 (less than 1.5 times ULN) and then resume at next lower dose
• Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic: Interrupt until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose
• Symptomatic pancreatitis and serum lipase greater than 5 times ULN: Discontinue treatment

• ANC less than 1 x 10(9)/L or platelets less than 50 x 10(9)/L and if:
• First Occurrence: Interrupt treatment and resume at same dose after recovery to ANC 1.5 x 10(9)/L or greater and platelets 75 x 10(9)/L or greater
• Recurrence: Interrupt treatment until resolution and then resume at next lower dose

• Grade 1: Interrupt treatment until resolved, then resume at same dose
• Grade 2: Interrupt treatment until Grade 0 or 1, then resume at next lower dose and discontinue if recurrence
• Grade 3 or 4: Discontinue treatment

• Grade 1: Interrupt treatment until resolved, resume at same dose
• Grade 2: Interrupt treatment until Grade 0 or 1, then resume at same dose and if recurrence, interrupt treatment until Grade 0 or 1, then resume at next lower dose
• Grade 3: Interrupt treatment until Grade 0 or 1, then resume at next lower dose and discontinue if recurrence
• Grade 4: Discontinue treatment

• Grade 2 or 3: Interrupt treatment until Grade 0 or 1, then resume at next lower dose and discontinue if recurrence
• Grade 4: Discontinue treatment

• Grade 1: Interrupt treatment until resolved, then resume at same dose
• Grade 2: Interrupt treatment until Grade 0 or 1, then resume at same dose, and if recurrence, interrupt until Grade 0 or 1, then resume at next lower dose
• Grade 3 or 4: Interrupt treatment until Grade 0 or 1, then resume at next lower dose and discontinue if recurrence

Precautions

US BOXED WARNING:
ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, AND HEPATOTOXICITY:

• Arterial occlusive events (AOEs): AOEs including fatal myocardial infarction, stroke, stenosis of large vessels of the brain, severe peripheral vascular disease, and the need of urgent revascularization procedures have occurred in patients treated with this drug. Events occurred in patients with and without cardiovascular risk factors, including patients aged 50 years old and younger. Monitor patients closely for evidence of AOEs, interrupt or discontinue treatment as needed and consider risks and benefits to decide if treatment should be restarted.
• Venous Thromboembolic Events (VTEs): Patients should be monitored for evidence of VTEs. Treatment should be interrupted or discontinued based on severity.
• Heart Failure: Cases have been reported, including fatalities. Monitor patients and manage as clinically indicated. Interrupt or discontinue treatment for new or worsening heart failure.
• Hepatotoxicity: Hepatotoxicity, liver failure and death have been reported in patients using this drug. Monitor liver function tests, and interrupt or discontinue based on severity.

Dialysis

Data not available.

Other Comments

Administration Advice:

• This drug may be taken with or without food, and at the same approximate time each day.
• Swallow tablets whole; do not crush, break, cut, chew, or dissolve the tablets.
• If a dose is missed, take the next dose at the regularly scheduled time the next day.
• Do not take 2 doses at the same time to make up for a missed dose.
• This drug contains lactose monohydrate, care and close monitoring is recommended for intolerant patients.

• Store at 68F to 77F (20C to 25C)
• Excursion permitted to 59F to 86F (15C to 30C)

• Monitor for evidence of arterial occlusive events and venous thromboembolic events.
• Monitor for heart failure.
• Monitor liver function tests at baseline, then at least monthly or as clinically indicated.
• Monitor blood pressure at baseline and as clinically in indicated.
• Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated.
• Monitor for symptoms of peripheral and cranial neuropathy.
• Monitor for vision at baseline and periodically during treatment.
• Monitor for hemorrhage.
• Monitor for fluid retention.
• Monitor for signs and symptoms of arrhythmias.
• Monitor blood counts every 2 weeks for the first 3 months and then monthly or as indicated for myelosuppression.

• Advise the patient to read the approved patient labeling (Medication Guide).
• Advise females of the potential risk to a fetus and inform their healthcare provider of a known or suspected pregnancy.
• Advice females of reproductive potential to use effective contraception during treatment and for at least 3 weeks after the last dose.
• Advise females of the potential for reduced fertility.
• Advise not to breastfeed during treatment and for 6 days after the last dose.
• Advise patients to inform of any planned surgical procedure.
• Advise patients to immediately report any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, or leg swelling.
• Advise patients to report any signs and symptoms suggestive of hemorrhage such as unusual bleeding or easy bruising.
• Advise patients to report symptoms suggestive of heart complications such as chest pain, shortness of breath, hypertension, palpitations, dizziness, or fainting.
• Advise patients to report any symptoms suggestive of pancreatitis such as nausea, vomiting, abdominal pain, or abdominal discomfort.
• Advise patients to report any developing fluid retention such as leg swelling, abdominal swelling, weight gain, or shortness of breath.
• Advice patients to report fever, infection, headache, seizure, altered mental status, and neurological disturbances.
• Advise patients to report symptoms of liver problems such as jaundice, anorexia, bleeding or bruising.
• Advise patients to avoid drinking grapefruit juice or eating grapefruit during treatment.
• Inform patients that the tablets contain lactose monohydrate.
• Advise patients to report symptoms of neuropathy such as hypo- and hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.
• Advise patients to report symptoms of ocular toxicity such as blurred vision, dry eye, or eye pain.