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Medicines Q&As
Q&A 214.4
Is there an interaction between St John’s Wort and combined and
progestogen only hormonal contraceptives
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: 23rd 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]. SJW has several active
constituents including hypericin, hyperforin and adhyperforin. Initially it was thought that hypericin was
responsible for its action; however it is now understood that hyperforin, adhyperforin and several other
related compounds are the primary active constituents [1-3].
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 [4, 5]. CYP3A4 is the
major route for inactivation of most contraceptive steroids, including ethinylestradiol and most
progestogens and enzyme inducers, such as anti-epileptics, can affect this enzyme causing a
decrease in serum hormone levels [1, 6-9].
SJW preparations are non-standardised and the exact composition and levels of active constituents,
including hyperforin, varies between different preparations, and patients often switch between
preparations. Therefore the overall effectiveness and level of enzyme induction will vary and change
over time [6-10].
The Committee on Safety of Medicines (CSM) has advised that St John’s Wort (SJW) should not be
used with hormonal contraceptives, except intrauterine devices, as there is a risk of contraceptive
failure and unplanned pregnancy [10, 11].
Answer
Most of the available evidence regarding an interaction between SJW and hormonal contraceptives,
relates to women who were taking a combined oral hormonal contraceptive, although there have been
a few anecdotal reports with other formulations [7, 8]. It has also been reported that SJW can
decrease norethindrone and ethinyl estradiol levels by 13% and 15%, resulting in breakthrough
bleeding, irregular menstrual bleeding or unplanned pregnancy [1]. Bleeding irregularities usually
occur within a week of starting SJW and regular cycles return when SJW is discontinued [1].
In 1999, 3 cases of breakthrough bleeding were reported in patients taking ethinylestradiol and
desogestrel and were attributed to lowered plasma ethinylestradiol concentrations caused by SJW
[12, 13]. By 2000, the Swedish Medical Products Agency, had received 8 reports of inter-menstrual
bleeding and 1 report of changed menstrual bleeding in women on oral contraceptive tablets who
started taking SJW [14, 15].
An unplanned pregnancy in a 36 year old woman taking a regular ethinylestradiol plus dienogestrel
oral contraceptive, was reported by Schwarz et al in 2003 [16]. The woman self medicated with up to
1700mg of hypericin extract daily for approximately 3 months prior to conception.
Up to October 2015, the CSM had received 16 reports of unintended pregnancy in patients taking
SJW [17].
Several studies have assessed the effect of SJW extracts on oral contraceptives. The effect of SJW
300mg three times daily (TDS) in 12 healthy premenopausal women receiving a combined oral
contraceptive pill containing norethindrone and ethinylestradiol was assessed over 3 consecutive 28
day menstrual cycles. SJW was associated with increased clearance of norethindrone (8.2 L/h to
9.5L/h, p=0.04) and a reduction in the half life of ethinylestradiol (23.4 to 12.2, p=0.02). Serum
concentrations of follicle stimulating hormone, luteinising hormone and progesterone were not
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Medicines Q&As
significantly affected by SJW. Breakthrough bleeding occurred in 17% (2/12 women) on COC alone
vs 58% (7/12) women when on COC and SJW together [18].
Seventeen women who had received a low dose oral contraceptive containing ethinylestradiol and
desogestrel for one menstrual cycle, randomly received either 300mg SJW twice daily (BD) or 300mg
SJW three times daily (TDS) for one cycle. The groups were then crossed over. There was no
significant change in follicle maturation, serum estradiol or progesterone concentrations. More
subjects reported intra-cyclic bleeding in the SJW treatment groups, (77% and 88% in the BD and
TDS groups; p<0.001 respectively versus 35% in the COC alone group). The study authors concluded
that there was no evidence of ovulation during concomitant treatment with SJM, but intra-cyclic
bleeding episodes increased which could affect compliance and lead to unintended pregnancies [19].
In a non-randomised, single blind, sequential trial, 16 healthy women received a low dose COC,
containing ethinylestradiol and norethindrone acetate for 21 days and placebo for 7 days for 2
consecutive 28 day cycles. SJW 300mg three times daily was then taken concomitantly for 2
additional 28 day cycles. The Area under the Curve (AUC) decreased, resulting in a 13-15% reduction
in dose exposure to the oral contraceptives. Breakthrough bleeding occurred in more subjects during
the SJW treatment phase than during the control phase (56% vs. 31%; p=0.05). One patient was
thought to have ovulated during the control phase compared with 6 patients in the SJW cycle. The
study authors concluded that SJW is associated with increased metabolism of norethindrone and
ethinylestradiol, breakthrough bleeding, follicle growth and ovulation [20].
In March 2014, the MHRA recommended that women using hormonal contraception, except those
using intrauterine devices, should not take herbal products containing SJW, due to an increased risk
of unplanned pregnancy [10].
Guidance issued by the Clinical Effectiveness Unit of the Faculty of Sexual and Reproductive Health
Care (FSRH), highlights that enzyme inducing drugs, such as SJW have the potential to reduce the
efficacy of combined hormonal contraceptives, progestogen only pills, oral emergency contraception
and the progestogen only implant. The FSRH advise that women using these formulations should
either avoid St John's Wort or they should use an alternative form of contraception, unaffected by
enzyme inducers, which according to the FSRH includes: the progestogen only injectable (depot
medroxyprogesterone acetate), copper bearing intrauterine devices (Cu-IUDs), the levonorgestrel
containing intrauterine device or barrier methods. Health professionals supplying hormonal
contraception should ask women about their current and previous drug use including prescription,
over the counter, herbal, recreational drugs and dietary supplements. Women using hormonal
contraception should be informed about the potential for interactions with other drugs and the need to
seek the advice of a health professional before starting any new drugs [21, 22].
The FSRH advice is available also recommends the following if SJW or any liver enzyme inducing
medication must be continued:
 Women on short term treatment with SJW (defined arbitrarily as ≤2 months) may continue
using the combined patch, ring or standard strength combined pill, but they should be advised
to use additional contraceptive precautions (e.g. condoms) while taking SJW and for 28 days
after stopping [21].
 To minimise the risk of contraceptive failure the FSRH recommends an extended regimen
(taking COC continuously for ≥3 weeks until breakthrough bleeding occurs for 3-4 days) or
tricycling (taking 3 pill packets continuously without a break) and a shortened pill/patch or ring
free interval of 4 days. Only monophasic 21 day pill packs are suitable for extended use or
tricycling and the FSRH recommends a minimum COC strength of 30µg ethinylestradiol (EE)
[21].
 Women who do not wish to use additional contraception or women on long term treatment (>2
months) with an enzyme inducing drug who do not wish to change to another method may be
offered an increased dose of COC containing at least 50µg EE during treatment and for 28
days after stopping [21].
 An extended or tricycling regimen with reduced pill free interval of 4 days is recommended but
additional contraception is not essential. If breakthrough bleeding occurs, and other causes
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


such as chlamydia are excluded, the dose of EE can be increased up to a maximum of 70µg,
use additional precautions or switch to a method unaffected by enzyme inducing drugs [21].
The FSRH also advise that the use of two COCs, extended/tricycling regimens and
shortening the pill free interval are all unlicensed and there is no evidence that such practice
is effective in women on SJW [21].
There do not appear to have been any clinical pharmacokinetic studies of enzyme inducers,
including SJW, with any of the available oral progestogen only contraceptives [8]. There are
isolated reports of pregnancies in women given these contraceptives with SJW [8, 17]. The
progestogen only pill (POP) or implant may be affected by SJW. Alternative methods of
contraception should be used [21].
Concomitant use of SJW with progestogen only injectables does not appear to necessitate
additional precautions, dose adjustment or alteration to the dosing /replacement interval.
Women using a POP or implant with a short term course of SJW could be offered a one-off
injectable progestogen preparation [21].
Summary
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The interaction between oral contraceptives and St John's Wort appears to be established. Its
incidence is not known, but cases of breakthrough bleeding, menstrual irregularity and
unplanned pregnancy have been reported. The Committee on Safety of Medicines (CSM) has
advised that St John’s Wort (SJW) should not be used with hormonal contraceptives, except
intrauterine devices, as there is a risk of contraceptive failure and unplanned pregnancy.
Health professionals supplying hormonal contraception should ask women about their current
and previous drug use including prescription, over the counter, herbal, recreational drugs and
dietary supplements.
Women using hormonal contraception should be informed about the potential for interactions
with other drugs and the need to seek the advice of a health professional before starting any new
drugs including herbal of dietary supplements.
The Faculty of Sexual and Reproductive Health Care (FSRH) in the UK, advise that women
taking oral contraceptives (both combined and progestogen-only pills) should either avoid St
John's Wort or they should use an alternative form of contraception, unaffected by enzyme
inducers [e.g. progestogen only injectable, copper bearing intrauterine devices (Cu-IUDs), the
levonorgestrel containing intrauterine device or barrier methods].
If St John's Wort is continued, the general guidelines, produced by the FSRH for the use of liver
enzyme inducers with hormonal contraceptives should be followed.
Limitations
This document does not consider the effect of SJW on emergency hormonal contraceptives or on
hormonal contraceptives when used for non-contraceptive indications, such as acne or hirsutism.
References
1)
2)
3)
4)
5)
6)
7)
Jellin J, Gregory P, et al, editors. Natural Medicines Comprehensive Database. St John’s Wort.
Last updated 25/01/2016. Accessed 22/02/2016 via http://www.naturaldatabase.com.
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.
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.
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.
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.
Mannel M. Drug interactions with St John’s Wort: Mechanisms and Clinical implications. Drug
Safety 2004; 27: 773-797.
Baxter K (ed). Stockley’s Drug Interactions online. Combined Hormonal Contraceptives + St
John’s wort (Hypericum perforatum). Last updated 21/05/14. Accessed 22/02/2016 via
www.medicinescomplete.com
Available through NICE Evidence Search at www.evidence.nhs.uk
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8)
9)
10)
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13)
14)
15)
16)
17)
18)
19)
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21)
22)
Baxter K (ed). Stockley’s Drug Interactions online. Progestogen only contraceptives; oral +
enzyme inducers. Last updated 21/05/2014. Accessed 22/02/2016 via
www.medicinescomplete.com
Russo E, Scicchitano F, Whalley BJ et al. Hypericum perforatum: Pharmacokinetic, Mechanism
of Action, Tolerability and Clinical Drug-Drug Interactions. Phytotherapy Research 2014; 28: 64355.
Committee on Safety of Medicines (UK): St John’s wort: interaction with hormonal
contraceptives, including implants-reduced contraceptive effect. Drug Safety Update March
2014. https://www.gov.uk/drug-safety-update/st-john-s-wort-interaction-with-hormonalcontraceptives-including-implants
Committee on Safety of Medicine. Reminder: St Johns Wort (Hypericum perforatum) interactions.
Current Problems in Pharmacovigilance May 2000; 26: 6.
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.
Ernst E. Second thoughts about safety of St John’s Wort. Lancet 1999; 354: 2014-2015.
Izzo AA. Drug interactions with St John’s Wort (Hypericum perforatum): a review of the clinical
evidence. International Journal of Clinical Pharmacology and Therapeutics 2004; 139-148.
Yue QY, Bergquist C. Safety of St John’s Wort. Lancet 2000; 355: 576-577.
Schwarz UI, Buschel B, Kirch W et al. Unwanted pregnancy on self medication with St John’s
Wort despite hormonal contraception. British Journal of Clinical Pharmacology 2003; 55:112-113.
Medicines and Healthcare Products Regulatory Agency. Drug Analysis Prints. Hypericum
Accessed 22/02/2016.
http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/TheYell
owCardScheme/YellowCarddata/Druganalysisprints/index.htm
Hall SD, Wang Z, Huang, SM et al. The interaction between St John’s Wort and an oral
contraceptive. Clinical Pharmacology and Therapeutics 2003; 74: 525-535.
Pfrunder A, Schiesser M, Gerber S et al. Interaction of St John’s Wort with low dose oral
contraceptive therapy: a randomised controlled trial. British Journal of Clinical Pharmacology
2003; 56: 683-690.
Murphy PA, Kern SE, Stanczyk FZ et al. Interaction of St John’s Wort with oral contraceptives:
effects on the pharmacokinetics of norethindrone and ethinylestradiol, ovarian activity and
breakthrough bleeding. Contraception 2005; 71: 402-408.
FSRH Clinical Effectiveness unit Clinical Guidance: Drug Interactions with Hormonal
Contraception. January 2011 (updated January 2012). Available at
http://www.fsrh.org/pdfs/CEUGuidanceDrugInteractionsHormonal.pdf Accessed 22/02/2016.
FSRH: Clinical Effectiveness unit. Statement St John’s Wort and Hormonal Contraception March
2014. Available at http://www.fsrh.org/pdfs/CEUStatementStJohnsWort.pdf. Accessed
22/02/2016.
Quality Assurance
Prepared by
Katie Smith, East Anglia Medicines Information Service (based on earlier work by Victoria Gibson)
Date Prepared
23rd February 2016
Checked by
Abigail Scott, East Anglia Medicines Information Service
Date of check
2nd March 2016
Search strategy

Embase: Hypericum perforatum/it + Contraceptive agent

Medline: Hypericum + Contraceptive agents

PubMed: St John’s Wort + hormonal contraceptives + interaction

Cochrane Library: St John’s Wort, contraception
Available through NICE Evidence Search at www.evidence.nhs.uk
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NICE Evidence: St John’s Wort, hormonal contraceptives
Faculty of Sexual and Reproductive Healthcare: St John’s Wort, contraception
Natural Medicines Comprehensive Database: St John’s Wort, depression, oral contraceptives
Clinical Knowledge Summaries: contraception, St John’s Wort
MHRA Drug Analysis Prints website: St John’s Wort, pregnancy
Stockley’s Drug interactions: hormonal contraceptives, St John’s Wort
Drugdex: hormonal contraceptives, St John’s Wort
British National Formulary, Maudsley Guidelines 12th Ed, Psychotropic drug directory 2014,
Martindale, AHFS DI
Available through NICE Evidence Search at www.evidence.nhs.uk
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