Q&A 233.3
Does St John’s Wort interact with Emergency Hormonal Contraception?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 22nd February 2016
Background
St John’s Wort (SJW) is the common name for the plant Hypericum perforatum and is a popular herbal remedy for the management of mild to moderate depression [1, 2].
Emergency contraception also known as postcoital contraception is used to prevent pregnancy after an unprotected or inadequately protected act of sexual intercourse [3, 4].
Oral hormonal emergency contraceptives available in the UK include a progestogen; levonorgestrel (e.g. Levonelle™) and the progesterone receptor modulator, ulipristal acetate (EllaOne™) [5-9].
Answer
No single mechanism of action has been established for emergency contraception, the mode of action varies according to the day of the menstrual cycle on which intercourse occurs and emergency contraception is administered. Both levonorgestrel and ulipristal acetate appear to inhibit or delay ovulation. In addition, ulipristal may alter the endometrium and inhibit implantation of a fertilised egg. Emergency contraception is only effective before implantation has occurred and pregnancy is established [3, 4].
Most of the available evidence regarding an interaction between SJW and hormonal contraceptives, relates to women who were taking a combined oral hormonal contraceptive. (See Medicines Q&A 214.4 for further discussion regarding this [10].) The Medicines & Healthcare products Regulatory Agency (MHRA) and Committee on Safety of Medicines (CSM) has advised that St John’s Wort should not be used with oral contraceptives as there is a risk of contraceptive failure and unplanned pregnancy [11, 12].
SJW has several active constituents including hypericin, hyperforin and adhyperforin. In vitro studies have shown that hyperforin is a potent inducer of the cytochrome P450 enzymes, particularly CYP3A4, CYP1A2 and CYP2C9, as well as affecting the P-glycoprotein cellular transport system. Small short term studies in human volunteers have failed to confirm this [13-16]. The isoenzyme CYP3A4 appears to be the major route for inactivation of most contraceptive steroids, including levonorgestrel and ulipristal [17, 18].
There is very little information relating to the effect of SJW on oral emergency hormonal contraception. Between 2000 and 2002, the Committee on Safety of Medicines in the UK received 2 reported cases of unwanted pregnancy occurring in women taking St John’s Wort who became pregnant despite taking levonorgestrel based emergency hormonal contraception [19].
In a small pharmacokinetic study, 36 participants received either 6 weeks of placebo, herb or SJW 900mg or 1500mg daily; followed by either one 1.5mg or 2.25mg dose of the emergency hormonal contraceptive, levonorgestrel, taken between days 9-12 of a normal menstrual cycle. Serum progesterone levels were measured at weekly intervals. Pharmacokinetic modeling showed that levonorgestrel clearance increased with increasing amounts of SJW. The study authors reported that the trend was consistent but not statistically significant and concluded dosing with SJW may have effects on the clearance of levonorgestrel, however larger studies are needed to determine the risk of emergency contraceptive failure when using P450 enzyme inducers such as SJW [20].
In vitro data indicate that ulipristal is predominantly metabolised by CYP3A4, and to a small extent by CYP1A2 and CYP2A6. Therefore enzyme inducers, such as SJW which induce the CYP3A4 enzyme, may decrease plasma concentrations and the effectiveness of ulipristal acetate [21].
The Summary of Product Characteristics (SPC) for levonorgestrel containing oral hormonal emergency contraceptives indicate that these products may be affected by SJW, resulting in reduced efficacy of the hormonal contraceptive [5-8].
The SPC for ulipristal acetate confirms that concomitant administration with enzyme inducers such as SJW can reduce plasma concentrations of ulipristal resulting in decreased efficacy. Enzyme induction wears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even if a woman has stopped taking an enzyme inducer within the last 2-3 weeks. Concomitant administration with enzyme inducers including SJW is therefore not recommended [9].
The Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynecologists’ (FSRH) advise that the effectiveness of emergency hormonal contraceptives will be reduced in women taking liver enzyme inducers including SJW. Women who require emergency contraception whilst using SJW or within 28 days of stopping should be advised that a copper intra-uterine device (Cu-IUD) is the most effective method [4].
Women who decline or who are not eligible to have a Cu-IUD should be offered a total of 3mg of levonorgestrel as a single dose as soon as possible and within 120 hours of unprotected sexual intercourse (UPSI). Using levonorgestrel between 72 and 120 hours after UPSI and doubling the standard dose are unlicensed and there is limited evidence in relation to the efficacy. In the UK, it is possible to buy the progestogen-only emergency hormonal contraception without a prescription; however, the FSRH advise that all women taking enzyme inducers should be referred to a doctor or family planning service. The FSRH recommend that ulipristal acetate should not be used in patients currently taking SJW or who have taken SJW within the last 28 days [4].
Summary
· Levonorgestrel is a progestogen commonly used in hormonal contraceptives to inhibit ovulation. Ulipristal acetate is a selective progesterone receptor modulator.
· St John’s Wort (SJW) is the common name for the plant Hypericum perforatum and is a popular herbal remedy for the management of mild to moderate depression.
· SJW has several active constituents including hypericin, hyperforin and adhyperforin. Hyperforin is a potent inducer of the cytochrome P450 enzymes, particularly CYP3A4, which appears to be the major route for inactivation of most contraceptive steroids, including levonorgestrel and also ulpristal acetate.
· There is very little information relating to the effect of SJW on oral emergency hormonal contraception. The FSRH advises that the effectiveness of oral emergency hormonal contraception will be reduced by St John’s wort.
· The FSRH advises that all women who require emergency contraception whilst using SJW or within 28 days of stopping, should be advised that a copper intra-uterine device (Cu-IUD) is the most effective method.
· Women who decline or who are not eligible to have a Cu-IUD should be offered a total of 3mg of levonorgestrel as a single dose as soon as possible and within 120 hours of unprotected sexual intercourse. This is unlicensed and there is limited evidence in relation to efficacy.
· Ulipristal acetate should not be used in patients taking SJW or who have stopped it within the last 28 days.
Limitations
This document does not consider the effect of SJW on combined hormonal or progestogen only contraceptives. See UKMI Q and A 214.4: Is there an interaction between St John’s Wort and combined and progestogen only hormonal contraceptives?
References
1) Jellin J, Gregory P, Batz F, Bonakdar R, editors. Natural Medicines Comprehensive Database. St John’s Wort. Last updated 25/01/2016. Accessed 18/02/2016 via http://www.naturaldatabase.com.
2) Taylor D, Paton C, Kerwin R. The South London and Maudsley NHS Foundation Trust & Oxleas NHS Foundation Trust Prescribing Guidelines. 12th ed. London: Informa Healthcare; 2015: 246-9.
3) Cleland K, Raymond EG et al. Emergency Contraception Review: Evidence-based recommendations for Clinicians. Clinical Obstetrics & Gynecology 2014; 57 (4): 741-750.
4) FSRH Clinical Effectiveness Unit Clinical Guidance: Emergency Contraception. August 2011 (Updated January 2012). Accessed 18/02/2016 at http://www.fsrh.org/pdfs/CEUguidanceEmergencyContraception11.pdf
5) Summary of Product Characteristics - Levonelle 1500 microgram tablet, Bayer Plc. Last updated 20/10/2014. Accessed 18/02/2016 via http://www.emc.medicines.org.uk
6) Summary of Product Characteristics - Levonelle One Step. Bayer PLC. Last updated 10/12/2015. Accessed 18/02/2016 via http://www.emc.medicines.org.uk
7) Summary of Product Characteristics – Emergency Contraceptive Consilient 1500 microgram tablet. Consilient Health Ltd. Last updated 13/01/2016. Accessed 18/02/2016 via http://www.emc.medicines.org.uk
8) Summary of Product Characteristics – Upostelle 1500microgram tablet. Last updated 13/01/2016. Accessed 18/02/2016 via http://www.emc.medicines.org.uk
9) Summary of Product Characteristics. EllaOne 30mg HRA Pharma UK Limited. Last updated 28/01/2015. Accessed 18/02/2016 via http://www.emc.medicines.org.uk
10) UKMI Medicines Q&A 214.4. Is there an interaction between St John’s Wort and combined and progestogen only hormonal contraceptives? East Anglia Medicines Information Service. Last updated 23/02/2016.
11) Medicines & Healthcare products Regulatory Agency. St John’s wort: interaction with hormonal contraceptives, including implants. Drug Safety Update March 2014. https://www.gov.uk/drug-safety-update/st-john-s-wort-interaction-with-hormonal-contraceptives-including-implants
12) Committee on Safety of Medicine. Reminder: St John’s Wort (Hypericum perforatum) interactions. Current Problems in Pharmacovigilance May 2000; 26: 6. http://webarchive.nationalarchives.gov.uk/20080804194642/http://mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON007462&RevisionSelectionMethod=LatestReleased
13) Will-Shahab L, Bauer S, Kunter U et al. St John’s Wort extract (Ze117) does not alter the pharmacokinetics of a low dose oral contraceptive. European Journal of Clinical Pharmacology 2009; 65: 287-294.
14) Henderson L, Yue QY, Bergquist C et al. St John’s Wort (Hypericum perforatum): drug interaction and clinical outcomes. British Journal of Clinical Pharmacology 2002; 54: 349-356.
15) Barnes J, Anderson LA et al. St John’s Wort (Hypericum perforatum L.): A review of its chemistry, pharmacology and clinical properties. Journal of Pharmacy and Pharmacology 2001; 53: 583-600.
16) Madabushi R, Frank B, Drewelow B et al. Hyperforin in St. John’s Wort drug interactions. European Journal of Clinical Pharmacology 2006; 62: 225-233.
17) DRUGDEX® System (electronic version). Levonorgestrel. Last modified 27/01/2016. Truven Health Analytics, Greenwood Village, Colorado, USA. Accessed 18/02/2016 via http://www.micromedexsolutions.com
18) DRUGDEX® System (electronic version). Ulipristal. Last modified 22/12/2015. Truven Health Analytics, Greenwood Village, Colorado, USA. Accessed 18/02/2016 via http://www.micromedexsolutions.com
19) Baxter K (ed). Stockley’s Drug Interactions online. Emergency hormonal contraceptives + Enzyme inducers. Last updated 21/05/2014. Accessed 18/02/2016 via www.medicinescomplete.com
20) Murphy P. Effects of St John’s Wort on the pharmacokinetics of levonorgestrel in emergency contraceptive (EC) dosing. Contraception 2010; 83: 191.
21) Baxter K (ed). Stockley’s Drug Interactions online. Emergency hormonal contraceptives: Ulipristal + Miscellaneous. Last updated 21/05/2014. Accessed 18/02/2016 via www.medicinescomplete.com
Quality Assurance
Prepared by
Katie Smith, East Anglia Medicines Information Service (based on earlier work by Vicky Gibson)
Date Prepared
22/02/2016
Checked by
Abigail Scott, East Anglia Medicines Information Service
Date of check
09/03/2016
Search strategy
· Embase: Hypericum + levonorgestrel/ulipristal/emergency contraception.
· Medline: Hypericum + levonorgestrel/ulipristal/contraception, postcoital
· PubMed: levonorgestrel/ulipristal acetate/emergency contraception + St John’s Wort/hypericum
· Cochrane Library: St John’s Wort, levonorgestral, ulipristal
· NHS Evidence: emergency hormonal contraception, St John’s wort, levonorgestrel, ulipristal
· Faculty of Sexual and Reproductive Healthcare: emergency hormonal contraception
· Clinical Knowledge Summaries: emergency hormonal contraception
· Natural Medicines Comprehensive Database: St John’s Wort, levonorgestrel, ulipristal
· Drugdex: St John’s Wort, levonorgestrel, ulipristal
· Stockleys Drug Interactions: St John’s Wort, levonorgestrel, ulipristal
· EMC, BNF, Martindale, AHFS DI, Maudsley Guidelines 12th Ed, Psychotropic Drug Directory 2014, Drug Safety Update, Current Problems in Pharmacovigilance
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Available through NICE Evidence Search at www.evidence.nhs.uk