Life threatening interaction between tamoxifen and warfarin.

Abstract

This considerably reduced requirement for warfarin prompted a retrospective review of medical records at our hospital for the period 1981-6 to examine whether there might be an interaction between tamoxifen and warfarin. The records of women with breast cancer and a subsequent admission for a serious thromboembolism were examined. There were 18 such women: seven who had had deep venous thrombosis and 11 who had had a pulmonary embolus with probable deep venous thrombosis. Five of them were taking tamoxifen when they started taking warfarin. Two of them had complications after loading doses of warfarin: in one the prothrombin time after three daily doses of warfarin (10 mg, 10 mg, and 5 mg) rose to 50 seconds, and she developed a left subdural haematoma requiring warfarin to be withdrawn; in the other a similar loading dose regimen resulted in a prothrombin time of 49 seconds on day 7, the patient developed severe haematuria, and her anticoagulant treatment was changed to phenindione. The three other patients taking tamoxifen required daily doses of 2 mg, 2 mg, and 3 mg to maintain appropriate prothrombin times.The dose of warfarin that maintained appropriate prothrombin times in the 13 patients not taking tamoxifen varied from 4 to 10 mg (mean 6 25 mg) daily. None of these patients had complications in the first month of treatment with warfarin. CommentOur observations suggest that women with breast cancer requiring warfarin need a lower dose if they are taking tamoxifen. The mechanism of the interaction between the two drugs is unclear, but protein binding and competition for metabolic pathways may both play a part. Both warfarin and tamoxifen are metabolised by the microsomal enzyme systems in the liver. Warfarin is a racemic mixture and the (S) isomer is four to five times more physiologically active than the (R) isomer. This more active (S) isomer is converted to the 7-hydroxy metabolite, which is inactive, by the cytochrome P450 enzyme system.2 Three metabolites have been detected in the serum ofpatients taking tamoxifen. Normally tamoxifen accounts for 36% of the drug and metabolites present, desmethyltamoxifen for 58%, metabolite Y for 4%, and 4-hydroxytamoxifen for 1-5%.3 All of these metabolites have some affinity for the oestrogen receptor, but the affinity of the 4-hydroxy metabolite is 50-100 times greater than that of the parent drug.4 Accordingly, 4-hydroxytamoxifen is about 100 times more potent than tamoxifen in inhibiting the growth of MCF7 breast cancer cells in culture.5The hydroxylations are probably carried out by similar enzyme systems. In the case of warfarin competition for the enzymes may increase the concentration of the active parent drug and decrease the concentration of inactive metabolites. In the case of tamoxifen, however, the resultant changes in the amounts of metabolites present may have important implications for the activity of the drug. Altering the percentage of the 4-hydroxy metabolite present may have an effect on the response of the tumour.The hazards of an increased pha...

Clinical Pharmacokinetics of Endocrine Agents Used in Advanced Breast Cancer

“…Life-threatening interactions between tamoxifen and warfarin have been reported (Lodwick et al 1987;Ritchie & Grant 1989;Tenni et al 1989). This suggests that tamoxifen may inhibit warfarin metabolism, but this has not been properly documented and the clinical relevance of tamoxifen enzyme inhibition is unclear.…”

Risk of breast cancer among patients with bioprosthetic or mechanical valve replacement: a population-based study in Sweden

“…A few previous studies found that estrogen can enhance the effect of warfarin [23,24]; it is, however, not known whether warfarin medication can affect the activity of estrogen, which may further affect the development of breast cancer. Tamoxifen can interact with warfarin by competition for plasma protein binding [25]; thus, patients with warfarin treatment may be prescribed less tamoxifen to prevent relapse of breast cancer compared to those without warfarin treatment. Patients with long-term medication of warfarin are recommended not to eat or eat less of foods that contain relatively a large amount of vitamin K, such as broccoli, spinach, soya bean products, and green tea [26].…”

Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens

“…Life-threatening interactions between tamoxifen and warfarin have been reported (LODWICK et al 1987;TENNI et al 1989;RITCHIE and GRANT 1989), but the underlying mechanisms are not clear. In these cases, co-administration of tamoxifen to patients who were adjusted to a stable prothrombin time with warfarin, led to a serious increase in prothrombin time.…”