Drug Interactions between Butalbital Compound and Imbruvica

MONITOR CLOSELY: Coadministration of ibrutinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. In clinical trials, 5% of patients with mantle cell lymphoma had Grade 3 or higher bleeding events such as subdural hematoma, gastrointestinal bleeding, and hematuria. Overall, bleeding events including bruising of any grade occurred in 48% of patients treated with ibrutinib 560 mg daily. The mechanism for the bleeding events is not well understood, although treatment with ibrutinib is associated with a high frequency of thrombocytopenia. Treatment-emergent grade 3 or 4 thrombocytopenia was reported in 17% of patients during clinical trials, while thrombocytopenia of all grades was reported in 57%. Fatal bleeding events have been reported during postmarketing use.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with ibrutinib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. The INR should be monitored more frequently during coadministration of warfarin. In addition, some authorities recommend avoiding the use of supplements that have an inhibitory effect on platelet function such as fish oil (omega-3 polyunsaturated fatty acids), flaxseed, and vitamin E preparations (AU, CA, UK) because of an increased risk of bleeding. 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.

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MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ibrutinib, which is primarily metabolized by the isoenzyme. Preliminary pharmacokinetic data from an ongoing dedicated drug interaction trial and simulations using physiologically based pharmacokinetic models indicate that rifampin, a potent CYP450 3A4 inducer, can decrease ibrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) by more than 10-fold. Pharmacokinetic modeling also suggests that a moderate CYP450 3A4 inducer such as efavirenz may decrease the AUC of ibrutinib up to 3-fold.

MANAGEMENT: The potential for diminished therapeutic effects of ibrutinib should be considered when prescribed in combination with CYP450 3A4 inducers. Patients should be closely monitored, and the dosage of ibrutinib adjusted as necessary in accordance with product labeling.

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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.

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