Estradiol Patch and Alcohol: Full Interaction Profile

Does the estradiol patch label list alcohol as an interaction?

No. The drug interactions section of the Climara label and the Vivelle-Dot label names only inducers and inhibitors of CYP3A4, the enzyme that metabolizes estrogens in part [1][2]. Inducers such as St. John's wort, phenobarbital, carbamazepine and rifampin may lower estrogen plasma levels, reducing effect or changing the uterine bleeding pattern; inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may raise estrogen levels and cause adverse reactions [1][2]. Alcohol appears in neither list.

What exists instead is two small pharmacokinetic studies by Ginsburg and colleagues.

What the two human studies found

Transdermal estradiol: slower clearance once the patch comes off

In a randomized, placebo-controlled crossover study published in Fertility and Sterility in 1995, 12 healthy postmenopausal women had 0.15 mg transdermal estradiol patches applied 13 hours before they drank either 1 mL/kg of 95% ethanol or a carbohydrate placebo punch; the patch was removed immediately after the drink [3].

After alcohol, the calculated estradiol half-life was 378 minutes. After the placebo punch it was 245 minutes [3]. Estrone concentrations did not differ significantly between the two conditions [3]. The authors concluded that ethanol may decrease estradiol clearance after removal of transdermal estradiol patches [3].

Because this study tracked how fast estradiol levels fell once the patch was off, it cannot say how much levels change when someone drinks while wearing a patch.

Oral estradiol: a rise lasting at least five hours

The second study, published in JAMA in 1996, compared 12 postmenopausal women taking oral estradiol 1 mg a day plus medroxyprogesterone with 12 postmenopausal women not using estrogen replacement [4]. Each group drank 0.7 g/kg of alcohol and an isocaloric placebo on consecutive days in randomized, double-blind order, and the women on estrogen were studied during the estrogen-only part of their cycle [4].

In the women taking estrogen, estradiol rose from 297 to 973 pmol/L, or 81 to 265 pg/mL, within 50 minutes (P<0.001) and stayed significantly above baseline for 5 hours (P<0.001) [4]. Estrone did not rise significantly in either group, and fell after both the alcohol and the placebo drink in the estrogen users (P<0.05) [4]. Estradiol did not change significantly in the women who were not using estrogen replacement, and blood alcohol levels were similar between groups [4]. The authors wrote that the levels reached were 300% higher than those targeted in clinical use of estrogen replacement [4].

How the patch is described in its label

The Climara label states that systemic availability of estradiol after transdermal use is about 20 times higher than after oral use because there is no first-pass metabolism, and that the patch delivers estradiol steadily over 7 days [1]. The label does not address alcohol in this context.

Does alcohol change clot risk with a patch?

Both patch labels still carry a boxed warning covering cardiovascular disorders, and both state that only daily oral conjugated estrogens 0.625 mg were studied in the WHI estrogen-alone substudy, so the relevance of those findings to lower doses or other routes of administration is not known [1][2]. The VTE rates quoted in the Climara label come from WHI conjugated estrogens, not from estradiol patches [1].

Observational studies did not find a statistically significant increase in clot risk with transdermal estrogen. In the French ESTHER case-control study, 271 women with a first idiopathic VTE and 610 matched controls gave an adjusted odds ratio of 0.9 (95% CI 0.4 to 2.1) for current transdermal estrogen use and 4.2 (1.5 to 11.6) for oral estrogen [6]. A BMJ meta-analysis of eight observational studies and nine randomized trials reported pooled observational odds ratios of 1.2 (0.9 to 1.7) for transdermal and 2.5 (1.9 to 3.4) for oral estrogen [7]. A UK nested case-control study of 80,396 women with VTE and 391,494 controls found an adjusted odds ratio of 0.93 (0.87 to 1.01) for transdermal preparations [8].

These are observational estimates, and none of them tests whether drinking changes clot risk with a patch [6][7][8]. The labels still contraindicate active DVT or PE and a history of either [1][2].

Breast cancer risk from alcohol, independent of the patch

Alcohol carries its own dose-dependent breast cancer signal. In the Million Women Study, 1,280,296 UK women were followed for an average of 7.2 years, during which 68,775 invasive cancers occurred; each additional 10 g of alcohol a day, roughly one standard drink, was associated with a 12% increase in breast cancer incidence (95% CI 9% to 14%) [9]. A collaborative reanalysis of 53 studies including 58,515 women with breast cancer found a 7.1% increase in relative risk per 10 g a day (95% CI 5.5% to 8.7%) [5].

Estradiol has its own breast cancer language in labeling. The patch boxed warnings describe an increased risk of invasive breast cancer in the WHI estrogen-plus-progestin substudy, and note that relevance to other doses or routes is not known [1][2]. Breast cancer or a history of it is a contraindication to the patch [1][2].