Ponatinib Dosage

Usual Adult Dose for Chronic Myelogenous Leukemia

Initial Dose: 45 mg orally once a day

Comments: The optimal dose has not been identified. The starting dose in clinical trials was 45 mg once a day; however, 68% of phase 2 trial patients required dose reductions to 30 mg or 15 mg once a day.

Uses: Treatment of:
-Chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
-T315I-positive CP/AP/BP CML or T315I-Ph+ ALL

Renal Dose Adjustments

Data not available.

Liver Dose Adjustments

ANY LEVEL OF HEPATIC IMPAIRMENT (CHILD-PUGH A, B, OR C): Reduce the initial dose to 30 mg once a day; monitor for adverse reactions.

IF HEPATOTOXICITY DEVELOPS DURING TREATMENT:
Elevation of Liver Transaminase Greater Than 3 x ULN (Grade 2 or Higher):
-Occurrence at 45 mg: Interrupt dosing and monitor hepatic function; resume treatment at 30 mg after recovery to Grade 1 or less (less than 3 x ULN).
-Occurrence at 30 mg: Interrupt dosing and resume treatment at 15 mg after recovery to Grade 1 or less.
-Occurrence at 15 mg: Discontinue treatment.

Elevation of AST or ALT 3 x ULN or Greater WITH an Elevation of Bilirubin Greater Than 2 x ULN AND Alkaline Phosphatase Less Than 2 x ULN: Discontinue treatment.

Dose Adjustments

-Chronic Phase (CP) and Accelerated Phase (AP) CML Patients Who Have Achieved a Major Cytogenetic Response: Consider reducing the dose.

-If Response to Treatment Has Not Occurred By 3 Months (90 Days): Consider treatment discontinuation.

-Concomitant Use of Strong CYP450 3A Inhibitor: Reduce the initial dose to 30 mg once a day.

-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.

ELEVATED LIPASE/PANCREATITIS:
ASYMPTOMATIC GRADE 1 or 2 ELEVATION of SERUM LIPASE: Consider treatment interruption or dose reduction.
ASYMPTOMATIC GRADE 3 or 4 ELEVATION of LIPASE (GREATER THAN 2 x ULN) or ASYMPTOMATIC RADIOLOGIC PANCREATITIS (GRADE 2 PANCREATITIS):
-Occurrence at 45 mg: Interrupt dosing and resume treatment at 30 mg after recovery to Grade 1 or less (less than 1.5 x ULN).
-Occurrence at 30 mg: Interrupt dosing and resume treatment at 15 mg after recovery to Grade 1 or less.
-Occurrence at 15 mg: Discontinue treatment.
SYMPTOMATIC GRADE 3 PANCREATITIS:
-Occurrence at 45 mg: Interrupt dosing and resume treatment at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to Grade 1 or less.
-Occurrence at 30 mg: Interrupt dosing and resume treatment at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to Grade 1 or less.
-Occurrence at 15 mg: Discontinue treatment.
GRADE 4 PANCREATITIS: Discontinue treatment.

NEUTROPENIA and THROMBOCYTOPENIA:
ANC less than 1 x 10(9)/L or Platelets less than 50 x 10(9)/L:
-First Occurrence: Interrupt treatment and resume initial 45 mg dose after recovery to ANC 1.5 x 10(9)/L or greater and Platelets 75 x 10(9)/L or greater.
-Second Occurrence: Interrupt treatment and resume at 30 mg after recovery to ANC 1.5 x 10(9)/L or greater and Platelets 75 x 10(9)/L or greater.
-Third Occurrence: Interrupt treatment and resume at 15 mg after recovery to ANC 1.5 x 10(9)/L or greater and Platelets 75 x 10(9)/L or greater.

SERIOUS NON-HEMATOLOGIC ADVERSE REACTIONS:
-Modify dose or interrupt treatment; do not restart treatment until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.
-In the event of arterial or venous occlusive reactions, do not restart treatment unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options.

Precautions

US REMS: The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for ponatinib. It includes a communication plan. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:
-Arterial occlusions, venous thromboembolism, heart failure, and hepatotoxicity/liver failure have occurred.
-There were fatalities among the reported arterial occlusion, heart failure, and hepatotoxic cases.
-Monitor cardiac function, hepatic function, and for evidence of arterial occlusion and venous thromboembolism.
-Consider dose modification or discontinuation in patients who develop serious venous thromboembolism; interrupt treatment if hepatotoxicity is suspected; interrupt or stop treatment immediately for arterial occlusion and for new or worsening heart failure.
-A benefit-risk consideration should guide a decision to restart therapy.
-ARTERIAL OCCLUSION: Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Some patients experienced more than 1 type of event, including myocardial infarction, stroke, stenosis of large arterial brain vessels, severe peripheral vascular disease, and the needs for urgent revascularization procedures.

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

Consult WARNINGS section for additional precautions.

Dialysis

Data not available.

Other Comments

Administration Advice:
-Administer this drug with or without food, and at the same approximate time each day.
-Swallow tablets whole; do not crush or dissolve the tablets.
-Instruct patients not to take 2 doses on the same day to make up for a missed or vomited dose from the previous day.

Storage Requirements:
-Store at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit); excursions are permitted from 15 to 30 degrees (59 to 86 Fahrenheit).
-To protect from light and moisture, keep tablets in the original container and do not remove the desiccant.

Monitoring:
-Cardiovascular (CV): CV status/function; evidence of arterial and vascular occlusion; signs/symptoms of heart failure; QT (at baseline); blood pressure (every clinic visit); thromboembolism
-Gastrointestinal: Serum lipase (every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated)
-General: Major or complete hematological/cytogenic response to therapy
-Hematologic: CBC (every 2 weeks for the first 3 months and then monthly or as clinically indicated)
-Hepatic: LFTs (at baseline, then at least monthly or as clinically indicated)
-Metabolic: Fluid retention
-Nervous System: Symptoms of neuropathy
-Ocular: Ocular toxicities (conduct comprehensive eye exams at baseline and periodically during treatment)


Patient Advice:
-Avoid drinking grapefruit juice and taking St. John's Wort during treatment.
-This drug may cause side effects such as lethargy, dizziness, and blurred vision that can affect your ability to perform certain activities; avoid driving and activities such as operating machinery until you know how this drug affects you.