Drug Interactions between phenobarbital and tamoxifen

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of tamoxifen and its major metabolite, N-desmethyltamoxifen. According to the product labeling, tamoxifen is primarily metabolized by CYP450 3A4 to N-desmethyltamoxifen, an antiestrogenic metabolite with similar biological activity to tamoxifen but an elimination half-life that is estimated to be approximately 10 to 14 days versus 5 to 7 days for tamoxifen. N-desmethyltamoxifen itself is further metabolized by CYP450 2D6 to endoxifen, a major metabolite that is thought to be primarily responsible for tamoxifen's therapeutic effect. When a single 80 mg oral dose of tamoxifen was administered to 10 healthy volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin at a dosage of 600 mg once daily for 5 days, tamoxifen peak plasma concentration (Cmax), systemic exposure (AUC) and elimination half-life decreased by 55%, 86% and 44%, respectively, compared to pretreatment with placebo. In addition, rifampin decreased the AUC and half-life of N-desmethyltamoxifen by 62% and 36%, respectively, and increased the Cmax by approximately 50% compared to placebo. These changes indicate that rifampin enhanced the metabolism of tamoxifen during both the presystemic and elimination phases. In another study, patients with glioma who received high-dose tamoxifen with phenytoin (n=15) demonstrated a 60% lower mean plasma tamoxifen concentration than patients not on concomitant phenytoin (n=10), although the difference did not reach statistical significance due to high interpatient variability and low patient numbers. The interaction has also been described in case reports of two tamoxifen-treated patients who had significantly reduced and subtherapeutic endoxifen levels during or after coadministration with a potent CYP450 inducer. One of them was receiving phenytoin and the other, rifampin. Induction of endoxifen clearance via P-glycoprotein-mediated efflux and/or uridine diphosphate glucuronosyltransferase (UGT)-mediated metabolism may be involved. The extent to which other potent CYP450 3A4 inducers may affect tamoxifen and its active metabolites is unknown.

MANAGEMENT: Until more information is available, concomitant use of tamoxifen with potent CYP450 3A4 inducers should be avoided when possible, particularly if they are to be administered for a prolonged period. Otherwise, therapeutic drug monitoring of tamoxifen and endoxifen is recommended to optimize therapy.