Iclusig (ponatinib HCl)

Dosage of ponatinib hydrochloride is expressed in terms of ponatinib.

Avoid concomitant use of ponatinib with strong inhibitors of cytochrome P-450 (CYP) 3A when possible. If concomitant use cannot be avoided, reduce the dosage of ponatinib as described in Table 3. After discontinuing a strong CYP3A inhibitor for 3-5 elimination half-lives, resume the dosage of ponatinib that was tolerated prior to initiating the strong CYP3A inhibitor.

Table 3. Recommended Dosage for Ponatinib Coadministered with Strong CYP3A Inhibitors.

Current Ponatinib Dosage Recommended Ponatinib Dosage with a Strong CYP3A Inhibitor 45 mg once daily 30 mg once daily 30 mg once daily 15 mg once daily 15 mg once daily 10 mg once daily 10 mg once daily Avoid coadministration of ponatinib with a strong CYP3A inhibitor

If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or discontinuance of ponatinib may be necessary. If dosage modification is required, reduce the dosage of ponatinib as described in Table 1. Permanently discontinue ponatinib in patients who are unable to tolerate the lowest dosage described in Table 1.

Table 1. Recommended Dosage Reduction for Ponatinib Toxicity.

Dosage Reduction Chronic Phase CML Accelerated Phase Newly Diagnosed or Blast Phase Ph+ ALL CML, or Ph+ ALL Monotherapy First 30 mg once daily 30 mg once daily 15 mg once daily Second 15 mg once daily 15 mg once daily 10 mg once daily Third 10 mg once daily Permanently Permanently discontinue if discontinue if patient is unable patient is unable to tolerate 15 mg to tolerate 10 mg once daily once daily Subsequent Permanently Permanently Permanently reduction discontinue if discontinue if discontinue if patient is unable patient is unable patient is unable to tolerate 10 mg to tolerate 15 mg to tolerate 10 mg once daily once daily once daily

If an adverse reaction occurs, reduce ponatinib dosage, or interrupt or permanently discontinue therapy as described in Table 2.

Table 2. Recommended Dosage Modification for Ponatinib Toxicity.

Adverse Reaction and Severity Modification Cardiovascular or Cerebrovascular Withhold ponatinib until resolved, Arterial Occlusive Event (Grade 1) then resume at the same dosage Cardiovascular or Cerebrovascular Withhold ponatinib until grade 0 or Arterial Occlusive Event (Grade 2) 1, then resume at the next lower dosage; discontinue ponatinib if event recurs Cardiovascular or Cerebrovascular Discontinue ponatinib Arterial Occlusive Event (Grade 3 or 4) Peripheral Vascular or Other Withhold ponatinib until resolved, Arterial Occlusive Event (Grade 1) then resume at the same dosage Peripheral Vascular or Other Withhold ponatinib until grade 0 or Arterial Occlusive Event (Grade 2) 1, then resume at the same dosage; if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage Peripheral Vascular or Other Withhold ponatinib until grade 0 or Arterial Occlusive Event (Grade 3) 1, then resume at the next lower dosage; discontinue ponatinib if event recurs Peripheral Vascular or Other Discontinue ponatinib Arterial Occlusive Event (Grade 4) Venous Thromboembolism (Grade 1) Withhold ponatinib until resolved, then resume at the same dosage Venous Thromboembolism (Grade 2) Withhold ponatinib until grade 0 or 1, then resume at the same dosage; if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage Venous Thromboembolism (Grade 3) Withhold ponatinib until grade 0 or 1, then resume at the next lower dosage; discontinue ponatinib if event recurs Venous Thromboembolism (Grade 4) Discontinue ponatinib Heart Failure (Grade 2 or 3) Withhold ponatinib until grade 0 or 1, then resume at the next lower dosage; discontinue ponatinib if event recurs Heart Failure (Grade 4) Discontinue ponatinib Hepatotoxicity (AST or ALT >3 times Withhold ponatinib until grade 0 or ULN) 1, then resume at the next lower dosage Hepatotoxicity (AST or ALT >=3 times Discontinue ponatinib ULN concurrent with bilirubin >2 times ULN and alkaline phosphatase <2 times ULN) Elevated Serum Lipase (Serum lipase Consider withholding ponatinib until >1 to 1.5 times ULN) resolution, then resume at same dosage Pancreatitis or Elevated Serum Withhold ponatinib until grade 0 or Lipase (Serum lipase >1.5 to 2 times 1 (<1.5 times ULN), then resume at ULN, serum lipase 2 to 5 times ULN next lower dosage and asymptomatic, or asymptomatic radiologic pancreatitis) Pancreatitis or Elevated Serum Withhold ponatinib until complete Lipase (Serum lipase >2 to 5 times resolution of symptoms and after ULN and symptomatic, symptomatic recovery of lipase elevation to grade 3 pancreatitis, or serum grade 0 or 1; then resume at the lipase >5 times ULN and next lower dosage asymptomatic) Symptomatic pancreatitis and serum Discontinue ponatinib lipase >5 times ULN Myelosuppression (ANC <1000/mm3 or Withhold ponatinib until ANC platelets <50,000/mm3) >=1500/mm3 and platelets >=75,000/mm3, then resume at the same dosage; if myelosuppression recurs, withhold ponatinib until resolution, then resume at the next lower dosage Other Non-Hematologic Adverse Events Withhold ponatinib until resolved, (Grade 1) then resume at the same dosage Other Non-Hematologic Adverse Events Withhold ponatinib until grade 0 or (Grade 2) 1, then resume at the same dosage; if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage Other Non-Hematologic Adverse Events Withhold ponatinib until grade 0 or (Grade 3 or 4) 1, then resume at the next lower dosage; if event recurs, discontinue ponatinib

Ponatinib hydrochloride is administered orally once daily without regard to food. The tablets should be swallowed whole and should not be crushed, broken, cut, or chewed. If a dose is missed, the next dose should be taken at the regularly scheduled time the next day.

No dosing information is available for this tab.

No dosing information is available for this tab.

Ponatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5. In vitro studies indicate that ponatinib does not inhibit the metabolism of substrates for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce the metabolism of substrates for CYP1A2, 2B6, or 3A.

In vitro studies indicate that ponatinib inhibits the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP); the drug is a weak substrate for P-gp and BCRP. In vitro, the drug is not a substrate for organic anion transport polypeptide (OATP) 1B1, OATP1B3, or organic cation transporter (OCT) 1. Ponatinib does not inhibit OATP1B1, OATP1B3, OCT1, OCT2, organic anion transporter (OAT) 1, or OAT3.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*None.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions reported in >20% of patients receiving ponatinib as monotherapy include rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction, cardiac arrhythmias, and arterial occlusive events. Grade 3 or 4 laboratory abnormalities reported in more than 20% of patients include decreased platelet count, decreased neutrophil count, and decreased white blood cell count.

The most common adverse reactions reported in patients receiving ponatinib in combination with chemotherapy include hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. Grade 3 or 4 laboratory abnormalities reported in more than 20% of patients include decreased white blood cell count, decreased neutrophil count, decreased platelet count, decreased lymphocytes, decreased hemoglobin, increased lipase, and increased ALT.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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

Based on its mechanism of action and findings from animal studies, ponatinib may cause fetal harm. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose. There are no available data in human pregnancy.

Verify the pregnancy status of females of reproductive potential prior to initiating ponatinib. If used during pregnancy or if the patient becomes pregnant while receiving ponatinib, apprise the patient of the potential fetal hazard.

There are no data on the presence of ponatinib in human milk or the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions to ponatinib in breastfed children, advise patients to avoid breastfeeding during ponatinib treatment and for 1 week following the last dose.

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, caution is advised in dose selection for geriatric patients.

Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 17% were 65 years of age or older and 2.1% were 75 years of age or older. Patients 65 years of age or older had lower rates of BCR-ABL1IS <=1% at 12 months compared to younger patients (27% versus 47%); this continued at 60 months with rates of 40% and 64%, respectively. Patients 65 years of age or older were also more likely to experience arterial occlusive events compared to younger patients (38% versus 14%).

In the PACE trial, 35% of patients were 65 years of age or older and 8% were 75 years of age or older. In patients with chronic phase CML, the major cytogenetic response rate was 40% in those 65 years of age and older compared with 65% in those younger than 65 years of age. In patients with accelerated or blast phase CML or with Ph+ ALL, the major hematologic response rate was 45% in those 65 years of age and older compared with 44% in those younger than 65 years of age. Arterial occlusive events occurred in 35% of patients 65 years of age or older and 21% of patients younger than 65 years of age.

In the PhALLCON trial, 21% of patients were 65 years of age or older and 7% were 75 years of age or older. No differences in efficacy were seen in patients 65 years of age or older and younger patients. Arterial occlusive events occurred more frequently in patients 65 years of age and older as compared to those less than 65 years of age (21% versus 2.3%).

Adverse reactions associated with ponatinib therapy (e.g., vascular occlusion, thrombocytopenia, peripheral edema, elevated serum lipase concentration, dyspnea, asthenia, muscle spasm, decreased appetite) may occur more frequently in patients 65 years of age or older. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, caution is advised in dose selection for geriatric patients.