Interaction of St John's wort with low‐dose oral contraceptive therapy: a randomized controlled trial

Abstract

Aims Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. Methods Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. Results During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and C max of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and C max of 3-ketodesogestrel decreased significantly from 31.2 ng ml -1 h to 17.7 ng ml -1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng ml -1 to 3.0 ng ml -1 (17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. Conclusions There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

“…This adverse event has been observed also in clinical studies (28,68,69) that have shown a higher incidence of intracyclic bleeding episodes after coadministration of SJW and oral contraceptive pills. Most importantly, reports of women becoming pregnant while using oral contraceptives and SJW have been reported by UK, German, and Swedish authorities.…”

“…It is well known that drugs inducing CYP3A4 such as rifampicin may cause reduced efficacy of oral contraceptives and breakthrough bleeding (71). Clinical studies have shown that SJW increases the clearance of oral pill components such as ethinylestradiol, norethindrone, and ketodesogestrel, and this effect is associated to breakthrough bleeding (28,68,69); interestingly, SJW extracts with low hyperforin content were found not to alter the pharmacokinetics of ethinylestradiol and 3-ketodesogestrel, the hormonal components of the oral contraceptive (45). This further highlights the concept that hyperforin is the chemical ingredient responsible of SJWinduced pharmacokinetic interactions.…”

Gender-Differences in Mice Hypericin Plasma Levels Upon Long-Term Hypericum Administration

“…Co-administration of Hypericum and oral contraceptives may increase unintended pregnancy risk [1], seven cases being reported by the United Kingdom authorities [2]. The Medical Products Agency from Sweden received eight reports of intermenstrual bleedings and one of changed menstrual bleeding from manufacturers of St John's wort products [3]; in Switzerland have been reported similar clinical cases [1].…”

“…The Medical Products Agency from Sweden received eight reports of intermenstrual bleedings and one of changed menstrual bleeding from manufacturers of St John's wort products [3]; in Switzerland have been reported similar clinical cases [1].…”

Which medications used in paediatric practice have demonstrated natural health product-drug interactions?

“…Significant decreases in the AUC were demonstrated in trials with warfarin (when administered with American ginseng) (13), midazolam (with echinacea) (14), saquinavir (with garlic) (15) and alprazolam (with ginkgo biloba) (16). In addition, St John's wort significantly decreased the AUC or C max when administered with alprazolam (AUC [17,18]), amitriptyline (AUC [19]), cyclosporin A (AUC [20]), digoxin (AUC [21,22]), fexofenadine (AUC and C max [23]), indinavir (AUC [24]), midazolam (AUC and C max [23]), omeprazole (AUC [25]), oral contraceptive (3-ketodesogestrel) (AUC [26]), simvastatin Figure 1) Sequential first-pass elimination of a theoretical drug through metabolism by the cytochrome P450 isoenzyme CYP3A4 and/or transport by P-glycoprotein (P-gp) in enterocytes of the small intestine and then hepatocytes of the liver. The percentage of the initial drug dose that is available before and after passage through the gut wall and liver is presented.…”