Adult Dosing

Chronic myeloid leukemia (CML) resistant or intolerant to prior tyrosine kinase inhibitor therapy

• 45 mg PO once daily with or without food

Philadelphia chromosome-positive Acute lymphoblastic leukemia resistant or intolerant to prior tyrosine kinase inhibitor therapy

• 45 mg PO once daily with or without food

Pediatric Dosing

• Safety and efficacy in patients <18 years of age have not been established

[Outline]

• Adult Dosing
• Pediatric Dosing

• Chronic myeloid leukemia (CML) resistant or intolerant to prior tyrosine kinase inhibitor therapy
• Philadelphia chromosome-positive Acute lymphoblastic leukemia resistant or intolerant to prior tyrosine kinase inhibitor therapy

• Hypersensitivity to any of the ingredients of the product

• Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal MI and stroke has been reported. In clinical trials, serious arterial thrombosis occurred in 8% of patients. Interrupt therapy and consider discontinuation if arterial thrombotic events develop
• Hepatotoxicity, liver failure, and death have been reported. Monitor hepatic function before and during treatment. Interrupt and then reduce or discontinue for hepatotoxicity

Renal Dose Adjustment (Based on CrCl)

• Renal impairment: Dose adjustments not defined
• It is unknown if moderate or severe renal impairment would affect hepatic elimination

Hepatic Dose Adjustment

• AST or ALT 2 times or higher than normal with concurrent elevation of bilirubin more than 2 times normal and alkaline phosphatase less than 2 times normal discontinue therapy
• Avoid use in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions

Use with CYP3A inhibitors

• Reduce dose to 20 mg orally once daily

Myelosuppression

• ANC less than 1 x 10(9)/L or platelets less than 50 x 10(9)/L: interrupt therapy and resume after recovery to ANC 1.5 and platelets to 75 or greater. Resume at a dose of 45 mg after first occurrence, 30 mg after second occurrence and 15 mg after third occurrence.

Pancreatitis

• Asymptomatic grade 1 or 2 serum lipase increase: consider interrupting therapy or reducing dose
• Asymptomatic grade 3 or 4 serum lipase increase, more than 3 times normal or asymptomatic radiologic pancreatitis grade 2: interrupt therapy and resume after recovery to grade 1. For occurrence on 45 mg resume to 30 mg. For occurrence on 30 mg resume to 15 mg. For occurrence on 15 mg discontinue therapy
• Symptomatic grade 3: Interrupt therapy and resume after resolution to grade 1 or less. For occurrence on 45 mg resume to 30 mg. For occurrence on 30 mg resume to 15 mg. For occurrence on 15 mg discontinue therapy
• Grade 4: Discontinue therapy

Serious ischemic or nonhematologic nonischemic reactions

• Modify or interrupt therapy. Resume based on assessment of benefits and risks.

• Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal MI and stroke has been reported. In clinical trials, serious arterial thrombosis occurred in 8% of patients. Interrupt therapy and consider discontinuation if arterial thrombotic events develop [US black box warning]
• Hepatotoxicity, liver failure, and death have been reported. Monitor hepatic function before and during treatment. Interrupt and then reduce or discontinue for hepatotoxicity [US black box warning]
• Therapy may lead to serious congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated. Consider discontinuation of therapy in patients who develop serious congestive heart failure
• Serious peripheral arterial events, arterial thrombosis and venous thromboembolic events have occured in patients treated with ponatinib. Consider dose modification or discontinuation of therapy in patients developing serious events
• Therapy may result in elevation in ALT, AST, or both. Monitor LFT at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue therapy as clinically indicated
• Hypertensive crisis including hypertension may occur as a serious adverse reaction. Monitor for hypertension and treat as clinically indicated
• Clinical pancreatitis has occured in patients treated with ponatinib. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse
• Serious bleeding events and hemorrhagic events such as cerebral hemorrhage and gastrointestinal hemorrhage including fatalities have occured in patients with AP-CML, BP-CML, and Ph+ALL. Discontinue therapy if serious bleeding occurs
• Fluid retention events such as peripheral edema, pleural effusion and pericardial effusion have occured. Monitor patients for fluid retention and manage patients as clinically indicated
• Gastrointestinal perforation and fistula formation have been reported
• May compromise wound healing or increase risk for GI perforation; temporarily interrupt therapy in patients undergoing major surgical procedures
• Symptomatic bradyarrhythmias, complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses have been reported with use of ponatinib. Advise patients to report signs and symptoms suggestive of slow heart rate
• Thrombocytopenia, neutropenia, and anemia may require dose interruption, or reduction; monitor CBC q2weeks x 3 months and then monthly and as clinically indicated; interrupt for ANC < 1000/mm³ or thrombocytopenia < 50,000/mm³
• Severe (grade 3 or 4) myelosuppression has occured with use of ponatinib. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended
• Ensure adequate hydration and correct high uric acid levels prior to initiating therapy to decrease risk for tumor lysis syndrome
• Therapy can cause fetal harm; advise women of potential risk to a fetus
• Avoid use with strong CYP3A inducers and drugs which elevate gastric pH

Pregnancy Category:D

Breastfeeding: It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of the drug to the mother.

• CNS: Headache, fatigue, pyrexia
• CV: Hypertension, arterial ischemia, bradyarrhythmias, supraventricular tachycardia, cardiac failure
• GI: Abdominal pain, constipation, nausea, diarrhea, vomiting, oral mucositis, GI hemorrhage
• HEMA: Febrile neutropenia, thrombocytopenia, anemia, lymphopenia, leukopenia, pancreatitis
• RESP: Nasopharyngitis, pneumonia, upper respiratory tract infection
• HEP: Hepatoxicity
• LAB TESTS: ALT, AST, or GGT increased
• GU: Urinary tract infection
• MUSC: Arthralgia, myalgia, pain in extremity, fluid retention, hyperuricemia, back pain, muscle spasms, bone pain, tumor lysis syndrome
• DERM: Dry skin, Rash

• Kinase inhibitor; inhibits o tyrosine kinase activity of ABL and T315I mutant ABL; inhibits additional kinases including VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3
• Metabolized by CYP3A4, and to a lesser extent CYP2C8, CYP2D6, and CYP3A5
• Excretion: 87% feces, 5% urine
• Half-life: 24 hours (Range: 12-66)

US Trade Name(s)

• Iclusig

US Availability

Iclusig

• TABS: 15, 45 mg

Canadian Trade Name(s)

• N/A

Canadian Availability

• N/A

UK Trade Name(s)

• N/A

UK Availability

• N/A

Australian Trade Name(s)

• N/A

Australian Availability

• N/A

[Outline]

Hematology/Oncology

Antineoplastics

Tyrosine Kinase Inhibitors