Drug Interactions between tamoxifen and Xenleta

GENERALLY AVOID: Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of tamoxifen. Supportive data are derived primarily from in vitro and animal studies. In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on estrogen-dependent breast cancer cell proliferation. In contrast, high concentrations of genistein greater than 10 microM/L have been found to enhance tamoxifen effects by inhibiting breast cancer cell growth. It is not known if these high concentrations are normally achieved in humans. Plasma concentrations below 4 microM/L have been observed in healthy volunteers given a soy diet for one month or large single doses of genistein. These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals. In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes. No toxicity or recurrence of breast cancer was reported during the 9-week study period.

Green tea does not appear to have significant effects on the pharmacokinetics of tamoxifen or its primary active metabolite, endoxifen. In a study consisting of 14 patients who have been receiving tamoxifen treatment at a stable dose of 20 mg (n=13) or 40 mg (n=1) once daily for at least 3 months, coadministration with green tea supplements twice daily for 14 days resulted in no significant differences in the pharmacokinetics of either tamoxifen or endoxifen with respect to peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) compared to administration of tamoxifen alone. The combination was well tolerated, with all reported adverse events categorized as mild (grade 1) and none categorized as serious or severe (grade 3 or higher) during the entire study. Although some adverse events such as headache, polyuria, gastrointestinal side effects (e.g., constipation, dyspepsia), and minor liver biochemical disturbances were reported more often during concomitant treatment with green tea, most can be attributed to the high dose of green tea used or to the caffeine in green tea. The green tea supplements used were 1000 mg in strength and contained 150 mg of epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea. According to the investigators, the total daily dose of EGCG taken by study participants is equivalent to the amount contained in approximately 5 to 6 cups of regular green tea. However, it is not known to what extent the data from this study may be applicable to other preparations of green tea such as infusions, since the bioavailability of EGCG and other catechins may vary between preparations.

MANAGEMENT: Until more information is available, patients treated with tamoxifen may consider avoiding or limiting the consumption of soy-containing products. Consumption of green tea and green tea extracts during tamoxifen therapy appears to be safe.

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ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of lefamulin. When a single 600 mg oral dose of lefamulin was administered with a high-calorie, high-fat breakfast (800 to 1000 calories; approximately 50% from fat), lefamulin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 23% and 18%, respectively.

GENERALLY AVOID: Grapefruit juice may increase the oral bioavailability of lefamulin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, ketoconazole. When oral lefamulin was administered with oral ketoconazole, mean lefamulin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 58% and 165%, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to lefamulin may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Lefamulin tablets should be taken at least one hour before or two hours after a meal. Patients should preferably avoid or limit the consumption of grapefruit and grapefruit juice during treatment with lefamulin.

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