Drug Interactions between aspirin / butalbital / caffeine and ponatinib

MONITOR CLOSELY: Coadministration of ponatinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Treatment with ponatinib is associated with severe, sometimes fatal hemorrhage including cerebral and gastrointestinal hemorrhage. In clinical trials, hemorrhagic events occurred in 24% of patients treated with ponatinib, and serious events occurred in 5% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with ponatinib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. The INR should be monitored more frequently during coadministration of warfarin. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ponatinib. In vitro, ponatinib has been shown to undergo Phase I metabolism primarily via CYP450 3A4 and to a lesser extent, CYP450 2C8, 2D6 and 3A5. When a single 45 mg dose of ponatinib was administered to healthy subjects following 7 days of continuous daily dosing of 600 mg rifampin, a potent CYP450 3A4 inducer, mean ponatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 42% and 62%, respectively, compared to ponatinib administered alone. Similar results were observed with thrice daily administration of 100 mg oral phenytoin, another potent CYP450 3A4 inducer, using physiologically based pharmacokinetic modeling. The extent to which other, less potent CYP450 3A4 inducers may interact with ponatinib is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of ponatinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.