Drug Interactions
Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inhibitors of CYP3A Enzymes
In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inducers of CYP3A Enzymes
Coadministration of Iclusig with strong CYP3A inducers was not eva luated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

Drugs That Elevate Gastric pH
Coadministration of Iclusig with drugs that elevate the gastric pH was not eva luated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems
In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been eva luated in clinical studies.

USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D

Risk Summary

Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and w