Drug Interactions between celecoxib / tramadol and tamoxifen

GENERALLY AVOID: Chronic coadministration of potent or moderate CYP450 2D6 inhibitors including certain antidepressants may reduce the effectiveness of tamoxifen. The proposed mechanism is inhibition of tamoxifen bioactivation via CYP450 2D6 to endoxifen (4-hydroxy-N-desmethyltamoxifen), the active metabolite that may be responsible for much of tamoxifen's antiestrogenic activity. This is consistent with studies that reported poorer clinical outcome (e.g., increased breast cancer recurrence; shorter relapse-free periods; lower rates of event-free survival) and decreased incidence/severity of hot flashes in patients treated with tamoxifen who have genetic polymorphisms of CYP450 2D6 resulting in reduced or absent enzyme activity. A similar relationship has been observed between endoxifen exposure and alterations in CYP450 2D6 metabolic status, whether due to CYP450 2D6 genetic variants or use of CYP450 2D6 inhibitors such as quinidine or SSRI antidepressants. In a study of 12 patients receiving tamoxifen adjuvant therapy, mean plasma concentrations of endoxifen decreased by more than 50% after four weeks of paroxetine 10 mg/day for hot flashes, and the effect was evident primarily in patients who carried the wild-type genotype for CYP450 2D6 (i.e., extensive metabolizers). In vitro, quinidine reduced the conversion to endoxifen by 79%. Potential clinical implications of this interaction were reported in a retrospective analysis of nearly 1,300 female breast cancer patients who were newly prescribed tamoxifen between 2003 and 2005 and were monitored for at least two years (mean 2.7 years). Women who used a moderate to potent CYP450 2D6 inhibitor (n=353) during tamoxifen therapy had a two-year breast cancer recurrence rate of 13.9%, compared to 7.5% for those not taking any CYP450 2D6 inhibitors (n=945). The average duration of concomitant tamoxifen and CYP450 2D6 inhibitor use was 340 days. In a subset analysis of patients taking tamoxifen with SSRI antidepressants, a breast cancer recurrence rate of 16% was reported for 213 women who used fluoxetine, paroxetine, or sertraline--SSRIs that are considered moderate to potent inhibitors of CYP450 2D6. This rate was 2.2 times higher than that for women taking tamoxifen without CYP450 2D6 inhibitors. In contrast, the breast cancer recurrence rate was 8.8% for 137 women using citalopram, escitalopram, or fluvoxamine, which was not statistically different than controls. An earlier, smaller study conducted by a group of Danish researchers also reported no reduction of tamoxifen effectiveness in association with citalopram or escitalopram use for up to five years. It is important to note that not all studies have found an association between CYP450 2D6 activity and tamoxifen clinical effects. In fact, a couple of studies even reported decreased risk of recurrence in patients treated with tamoxifen who have a common genetic variant of CYP450 2D6. Investigators suggest that the discrepancies may be due to differences in study designs, including sample size, different genetic models for the assessment of phenotypes, and stratification effects.

MANAGEMENT: Based on available data, patients treated with tamoxifen should avoid the chronic use of potent CYP450 2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine whenever possible, and preferably also moderate inhibitors such as adagrasib, duloxetine, and sertraline. If an antidepressant is required during treatment with tamoxifen, agents such as desvenlafaxine, fluvoxamine, milnacipran, levomilnacipran, mirtazapine, and venlafaxine may be considered, since they have mild to no effects on CYP450 2D6. Alternatively, aromatase inhibitors such as anastrozole, exemestane, and letrozole may be appropriate substitutes for tamoxifen in certain patients. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may reduce the effectiveness of tamoxifen for at least 28 days after administration of rolapitant.

MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk of an individual agent or a combination of these 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). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. 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.

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.