Drug Interactions between aspirin / caffeine / propoxyphene and osimertinib

MONITOR CLOSELY: Osimertinib may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In two premarketing studies with 411 patients, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis performed in 210 patients from one of the studies suggested a concentration-dependent QTc interval prolongation of 14 msec at a dose of 80 mg daily. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if osimertinib is used in combination with other drugs that can prolong the QT interval. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting osimertinib therapy and periodically during treatment. Osimertinib should not be started if baseline QTc is greater than 500 msec. Likewise, treatment should be interrupted and adjusted in accordance with the product labeling in patients who develop QTc prolongation greater than 500 msec. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Permanently discontinue osimertinib in patients who develop QTc interval prolongation with life-threatening arrhythmia.

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MONITOR: Coadministration with osimertinib may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 1A2. In vitro, osimertinib has been shown to be an inducer of the isoenzyme. However, no pharmacokinetic data are available from drug interaction studies.

MANAGEMENT: Caution is advised when osimertinib is prescribed with drugs that undergo metabolism by CYP450 1A2. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osimertinib is added to or withdrawn from therapy. Sensitive CYP450 1A2 substrates or substrates with narrow therapeutic ranges (e.g., theophylline) should preferably be avoided with osimertinib, if possible.

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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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