Drug Interactions between celecoxib / tramadol and phenytoin

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of tramadol, which is primarily metabolized by CYP450 3A4 and 2D6. Reduced opioid efficacy can occur, including opioid withdrawal in physically dependent patients. After discontinuing a CYP450 3A4 inducer, the tramadol plasma concentration will increase, which could increase and/or prolong opioid efficacy and adverse reactions, including seizures, serotonin syndrome, and respiratory depression. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Caution is advised when tramadol is used with CYP450 3A4 inducers. Patients should be monitored for opioid efficacy and signs of withdrawal. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. If a CYP450 3A4 inducer is discontinued, monitor for seizures, serotonin syndrome, sedation, and respiratory depression. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.

MONITOR: Coadministration with inducers of CYP450 2C9 may decrease the plasma concentrations of celecoxib, which is primarily metabolized by the isoenzyme. When a single 200 mg dose of celecoxib was administered to 12 healthy volunteers following pretreatment with the moderate CYP450 2C9 inducer rifampin 600 mg once daily for 5 days, celecoxib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 56% and 64%, respectively, while clearance increased by 185%. Reduced efficacy of celecoxib may occur.

MANAGEMENT: The potential for diminished pharmacologic effects of celecoxib should be considered during coadministration with CYP450 2C9 inducers. Dose adjustments or alternative treatments may be required if an interaction is suspected.

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.