Drug Interactions between tamoxifen and thioguanine

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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MONITOR: The concomitant or sequential use of other agents known to induce hepatotoxicity may potentiate the risk of liver injury associated with thioguanine. A high risk of liver toxicity characterized by vascular endothelial damage has been reported with long-term continuous use of thioguanine, particularly in children receiving the drug as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Histopathological features include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.

MANAGEMENT: The risk of hepatic injury should be considered when thioguanine is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Baseline and regular monitoring of hepatic function is recommended. Thioguanine therapy should be discontinued if there is evidence of toxic hepatitis or biliary stasis, as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal. Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported, but do not always occur.

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