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Medicines Q&As
Q&A 226.1
Is it safe to take herbal medicines with non-vitamin K antagonist
oral anticoagulants (NOACs)?
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: 13th July 2015
Background
Herbal medicines have been widely used for thousands of years and have gained increasing
popularity [1]. Many UK patients use herbal medicines, frequently without consulting their
conventional healthcare professionals [2]. As herbal medicines are often taken in combination with
conventional medicines this increases the potential for pharmacokinetic and/or pharmacodynamic
interactions. The clinical implications of any interaction depend on a variety of factors, such as coadministered drugs, the health status of the patient, the composition of the herbal medicine and the
dosage regimens used. Herbal medicines are not subject to the same scrutiny and regulatory
processes that apply to conventional medicines. Exemption from pre-market safety and efficacy
testing may mean that the list of ingredients on the labels of these products might be incomplete or
incorrect, and the composition could vary from batch to batch. Herbal medicine-drug interactions
have been reported in several studies, but there is, in general, a lack of knowledge among patients
and healthcare providers about drug-herb interactions, and a lack of scientific evidence of the safety
and efficacy of herbal medicines together with an under-reporting and underestimation of adverse
effects [1].
Currently, four non-vitamin K antagonist (non-VKA) oral anticoagulant (NOAC) drugs are available on
the UK market as alternatives to warfarin: dabigatran, rivaroxaban, apixaban and edoxaban.
Dabigatran is a direct thrombin inhibitor and rivaroxaban, apixaban and edoxaban are direct factor Xa
inhibitors [3,4].
Answer
There are no studies investigating the co-administration of herbal medicines with dabigatran,
rivaroxaban, apixaban [5] or edoxaban. However the metabolic pathway of these drugs raises
concerns for potential interactions with other substances that are inducers or inhibitors of the
cytochrome P 450 (CYP450) enzyme system or P-glycoprotein (P-gp) transporters [6]. In addition, a
number of herbal medicines might affect antiplatelet activity, or have anticoagulant activity and some
herbal medicines are documented as having caused haemorrhage as a side effect [7]. Concomitant
use of antiplatelet or anticoagulant agents with dabigatran, rivaroxaban, apixaban or edoxaban may
increase the risk of bleeding [4,8]. The clinical significance of any interaction will vary because of
interindividual differences in patient factors e.g. age, sex, nutritional status, metabolising capacity [1],
liver and kidney function.
Dabigatran
Dabigatran is a direct thrombin inhibitor given orally as the mesilate of the prodrug dabigatran
etexilate. After oral administration dabigatran etexilate is rapidly and completely hydrolysed to its
active metabolite, dabigatran, by an esterase-catalysed reaction [9]. Dabigatran etexilate mesilate is
not a substrate, inducer, or inhibitor of CYP450 isoenzymes, so a pharmacokinetic interaction is
unlikely with drugs affecting, or metabolised by hepatic microsomal enzymes [8].
Dabigatran is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors
is expected to result in increased dabigatran concentrations. Close clinical surveillance (looking for
signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp
inhibitors. However the manufacturers contraindicate the concomitant use of some strong P-gp
inhibitors with dabigatran. Caution should also be exercised when used with mild to moderate P-gp
inhibitors [10].
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Concomitant administration of a P-gp inducer is expected to result in decreased dabigatran
concentrations and should be avoided [10].
Dabigatran should be used with caution in conditions with an increased risk of bleeding and in
situations with concomitant use of drugs affecting haemostasis by inhibition of platelet aggregation.
Concomitant treatment with any other anticoagulants, except under specific circumstances (see
SPC), is contraindicated [10].
Rivaroxaban
Rivaroxaban is a direct, selective, reversible, factor Xa inhibitor. It is metabolised via multiple
CYP450 pathways as well as non CYP mediated hydrolysis. Metabolism is primarily mediated through
CYP3A4/3A5, and to a lesser extent CYP2J2, which suggests a potential for drug interactions with
other CYP3A4 or P-gp substrates [5,11]. The manufacturer of rivaroxaban recommends that patients
do not receive concomitant systemic treatment with drugs that are strong inhibitors of both CYP3A4
and P-gp due to the resulting increased rivaroxaban plasma concentrations to a clinically relevant
degree which may lead to an increased risk of bleeding. Active substances strongly inhibiting only one
of the rivaroxaban elimination pathways, either CYP3A4 or P-gp are expected to increase rivaroxaban
plasma concentrations to a lesser extent [11].
The manufacturer advises that the concomitant use of rivaroxaban with strong CYP3A4 inducers may
lead to reduced rivaroxaban plasma concentrations and should be avoided unless the patient is
closely observed for signs and symptoms of thrombosis [11].
Concomitant treatment with any other anticoagulants, except under specific circumstances (see
SPC), is contraindicated. Care is to be taken if patients are treated concomitantly with medicinal
products affecting haemostasis such as platelet aggregation inhibitors [11].
Apixaban
Apixaban is a direct, selective, reversible factor Xa inhibitor. It is predominantly metabolised by
CYP3A4/5 with minor involvement of other enzymes e.g.CYP1A2 and CYP2J2. Therefore
concomitant administration of potent CYP3A4 inhibitors or inducers may affect apixaban
concentrations [5,12].
Apixaban is a substrate of the transport protein P-gp [8,12]. The use of apixaban is not recommended
in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp.
No dose adjustment for apixaban is required when co-administered with less potent inhibitors of
CYP3A4 and/or P-gp [12].
The concomitant use of apixaban with strong CYP3A4 and P-gp inducers may lead to around a 50%
reduction in apixaban exposure [12]. In patients receiving concomitant systemic treatment with strong
inducers of both CYP3A4 and P-gp, apixaban should be used with caution for the prevention of
venous thromboembolic events (VTE) in elective hip or knee replacement surgery, for the prevention
of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and for the
prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE). Apixaban should
not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment
with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised [12].
The concomitant use of apixaban with other anticoagulants is contraindicated and concurrent use with
antiplatelet agents increases the risk of bleeding [12].
Edoxaban
Edoxaban is a highly selective, direct and reversible inhibitors of factor Xa. It is not extensively
metabolised by CYP3A4 [13] but it is a substrate for the efflux transporter P-gp [4].
Concomitant administration of edoxaban and certain P-gp inhibitors has resulted in increased plasma
concentrations of edoxaban (See SPC). The use of edoxaban with other P-gp inhibitors has not been
studied [4].
The concomitant use of edoxaban with P-gp inducers e.g. St John’s wort may lead to reduced
edoxaban plasma concentrations. Edoxaban should be used with caution when co-administered with
P-gp inducers [4].
Available through NICE Evidence Search at www.evidence.nhs.uk
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Coadministration of edoxaban with other anticoagulants is contraindicated due to increased risk of
bleeding. In clinical studies concomitant use of low dose aspirin (≤ 100mg/day), other antiplatelet
agents and thienopyridines resulted in approximately a 2-fold increase in major bleeding in
comparison with no concomitant use [4].
Table 1: The pharmacokinetic / pharmacodynamic activity of some commonly used herbal
medicines which may interact with NOACs.
Black cohosh:
Black cohosh may inhibit CYP3A4 [14,15] so might interact and potentially increase the risk of
adverse effects with drugs that are metabolised by CYP3A4 enzyme [15,16]. However four small
studies in healthy volunteers suggested that black cohosh has a minimal effect on various CYP450
enzymes (CYPs) or P-gp. Further studies are needed to demonstrate the safety of concomitant use of
black cohosh and conventional drugs [1].
Dong quai:
Prolonged use of dong quai can induce CYP3A4 which may reduce the blood levels and effectiveness
of substrate drugs [16].
Dong quai may have anticoagulant activity [16].
Echinacea:
Conflicting results have been reported regarding the effect of echinacea on CYP activity [1].
Flavonoids from Echinacea have been shown to inhibit or induce CYP450 enzymes [15]. It should be
used with caution in patients receiving drugs with a narrow therapeutic range which are substrates of
CYP1A2 and CYP3A enzymes [7]. Echinacea purpurea can also inhibit P-gp activity. Although the
potential for echinacea to inhibit CYPs or P-gp needs further investigation, on the basis of current
evidence echinacea does not appear to pose a risk to patients [1]. However patients concomitantly
taking drugs metabolised by CYP3A4 should be monitored closely [14].
Evening Primrose Oil:
Evening primrose oil can inhibit platelet aggregation and increase bleeding time. It has been
suggested that it may have additive effects with other antiplatelet drugs, but evidence of this is lacking
[17]. Theoretically concomitant use with anticoagulants and antiplatelets may increase the risk of
bleeding [14].
Garlic:
Garlic can inhibit CYP 2C9, 2C19, 3A4 in vitro and theoretically may interact with drugs metabolised
by these enzymes [14,16]. However, studies in volunteers of the effects of garlic products on CYPs
have given conflicting results [1]. Garlic also induces P-gp [16]. Until further data are available,
caution is advised if garlic is taken concomitantly with substrates of CYP2E1, CYP3A4 or P-gp [1].
Garlic has anticoagulant and antiplatelet activity [1]. It inhibits platelet aggregation in a dosedependent fashion. The effect of one of its constituents, ajoene, appears to be irreversible and may
potentiate the effect of other platelet inhibitors [18]. Garlic may enhance existing anticoagulant
therapy; a potential interaction between garlic and warfarin has been documented. Garlic
supplements should be used with caution in patients on anticoagulant therapy [7].
Gingko:
There is conflicting evidence for the ability of ginkgo to induce or inhibit CYP3A4 [14].
Ginkgo biloba has been associated with platelet, bleeding, and clotting disorders, and there are
isolated reports of serious adverse reactions after its concurrent use with antiplatelet drugs such as
aspirin, clopidogrel, and ticlopidine [17]. Ginkgo extract should only be used with caution in patients
taking anticoagulants and/or antiplatelet agents [7], as the risk of bleeding is increased [15].
Ginseng, Panax:
There is conflicting evidence on the effect of Panax ginseng on platelet aggregation [14]. Potential
pharmacodynamic interactions of Panax ginseng with antiplatelet/anticoagulant drugs have been
reported [1]. Until more is known, use with caution in patients concurrently taking anticoagulants or
antiplatelet drugs [14].
Available through NICE Evidence Search at www.evidence.nhs.uk
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Ginseng, Siberian:
Preliminary in vitro research suggests that Siberian ginseng can inhibit P-gp, theoretically increasing
levels of drugs affected by P-gp [14].
A constituent of Siberian ginseng appears to inhibit platelet aggregation. Concomitant use with
anticoagulant or antiplatelet drugs might increase the risk of bleeding [14].
Saw palmetto:
One in vitro study indicated that saw palmetto showed potent inhibition of the activities of CYP3A4,
CYP2D6 and CYP2C9 suggesting the potential for drug interactions. However studies in humans did
not find any significant effects on CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activity [1].
Saw palmetto has been reported to prolong bleeding time. Theoretically saw palmetto might increase
the risk of bleeding when used concomitantly with anticoagulant or antiplatelet drugs [14].
There is one case report of an isolated hemopericardium associated with rivaroxaban in a patient who
was also taking saw palmetto. The concurrent use of this herb may have contributed to the bleed by
increasing rivaroxaban activity [19].
St John’s wort:
St John’s wort is a potent inducer of intestinal and hepatic CYP3A4, CYP2C9, CYP2C19, CYP2E1
and intestinal P-gp [20]. Plasma concentration of dabigatran, rivaroxaban, apixaban and edoxaban
may possibly be reduced by St John's wort. The manufacturer of dabigatran advises avoid
concomitant use [10]. The manufacturer of rivaroxaban states that St John’s wort should be avoided
unless the patient is closely observed for signs and symptoms of thrombosis [11]. St John’s wort
should be used with caution in patients taking apixaban for the prevention of VTE in elective hip or
knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF
and for the prevention of recurrent DVT and PE. St John’s wort should not be used in patients taking
apixaban for the treatment of DVT and treatment of PE, since efficacy may be compromised [12].
Edoxaban should be used with caution when co-administered P-gp inducers such as St John’s wort
[4].
Summary
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There is a lack of scientific evidence of the safety and efficacy of herbal medicines together
with an under-reporting and underestimation of adverse effects. Interactions between herbal
medicines and conventional medicines are poorly studied and may be unpredictable.
A lack of a documented interaction with drugs does not mean that an interaction does not
exist; it may not yet have been reported.
The clinical importance of any interaction depends on a variety of factors, such as other coadministered drugs, the health status of the patient, the composition of the herbal medicine
and the dosage regimens used.
Currently, four non-VKA [vitamin K antagonist] oral anticoagulant (NOAC) drugs are available
on the UK market as alternatives to warfarin: dabigatran, rivaroxaban, apixaban and
edoxaban.
Dabigatran etexilate mesilate is not a substrate, inducer, or inhibitor of CYP450 isoenzymes,
so a pharmacokinetic interaction with herbs affecting, or metabolised by hepatic microsomal
enzymes is unlikely. However, dabigatran is a substrate for the efflux transporter P-gp.
Concomitant administration of P-gp inhibitors or inducers will affect dabigatran plasma
concentrations. The manufacturer of dabigatran contra-indicates concurrent use of some
strong P-gp inhibitors or the concurrent use of St John’s wort.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms and is
a substrate of P-gp. Strong inhibitors of both CYP3A4 and P-gp should be avoided in patients
taking rivaroxaban due to an increased risk of bleeding. The manufacturer of rivaroxaban
states that St John’s wort, which is a potent inducer of intestinal and hepatic CYP3A4,
CYP2C9, CYP2C19, CYP2E1 and intestinal P-gp, should be avoided unless the patient is
closely observed for signs and symptoms of thrombosis.
There is one case report of an isolated hemopericardium associated with rivaroxaban in a
patient who was also taking saw palmetto. The concurrent use of this herb may have
contributed to the bleed by increasing rivaroxaban activity.
Available through NICE Evidence Search at www.evidence.nhs.uk
4
Medicines Q&As
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Apixaban is predominantly metabolised by CYP3A4/5 and is a substrate of P-gp. The
manufacturer advises that St John’s wort should not be used in patients taking apixaban for
the treatment of deep vein thrombosis and treatment of pulmonary embolism, since efficacy
may be compromised.
Edoxaban is not extensively metabolised by CYP3A4, but it is a substrate for the efflux
transporter P-gp. Concomitant administration of edoxaban and P-gp inhibitors may result in
increased plasma concentrations of edoxaban. Concomitant use of edoxaban with P-gp
inducers e.g. St John’s wort may lead to reduced edoxaban plasma concentrations and
should be used with caution.
Other herbs which may affect CYP3A4 or other CYP enzymes, include black cohosh, dong
quai, echinacea, garlic, ginkgo, and saw palmetto. Although the risk of interactions appears
theoretical, patients should be monitored for any adverse effects e.g. bruising, bleeding or
signs and symptoms of thrombosis, if concurrent treatment with the herbal medicine cannot
be avoided.
Concomitant administration of NOACs with herbs which have anticoagulant or antiplatelet
activity e.g. garlic, ginkgo, and ginseng, can increase the risk of bleeding and should be
avoided or used with caution.
Limitations
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Co-administration of dabigatran, rivaroxaban, apixaban or edoxaban with herbal medicines
has not been investigated in clinical studies, consequently a lack of a documented interaction
with a drug may not mean that an interaction does not exist, only that it has not yet been
reported.
Other herbal medicines which are not discussed in this Q&A may also interact with NOACs.
References
1. Shi S, Klotz U. Drug interactions with herbal medicines. Clin Pharmacokinet 2012;51(2):77104
2. Posadzki P, Watson LK, Alotaibi A et al. Prevalence of herbal medicine use by UK
patients/consumers: a systematic review of surveys. Focus on Alternative and
Complementary Therapies 2013;18(1):19-26 Accessed via
http://onlinelibrary.wiley.com/doi/10.1111/fct.12006/abstract on 3/3/2015
3. Khanderia S (managing editor). British National Formulary. Accessed online via:
http://www.evidence.nhs.uk/formulary/bnf/current on 13/3/2015
4. Daiichi Sankyo UK Ltd. Summary of Product Characteristics for Lixiana 30mg Film-Coated
Tablets. Last updated on the eMC 02/7/2015 Accessed online via:
http://www.medicines.org.uk/emc/ on 8/7/2015 [date of first authorisation 19/6/2015]
5. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel
oral anticoagulants: an update. J Thromb Thrombolysis 2011;31:326-343
6. Walenga JM, Adiguzel C. Drug and dietary interactions of the new and emerging oral
anticoagulants. Int J Clin Pract. 2010;64(7):956-967
7. Barnes J, Anderson LA, Phillipson JD. Herbal Medicines. Accessed online at
www.medicinescomplete.com on 6/3/2015, 8/7/2015
8. McEvoy G (Ed in Chief), American Society of Health-System Pharmacists. AHFS Drug
Information. London: Pharmaceutical Press Accessed online via
http://www.medicinescomplete.com/ on 18/3/2015, 8/7/2015
9. Brayfield A (ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press
Accessed online via http://www.medicinescomplete.com/ on 13/3/2015, 8/7/2015
10. Boehringer Ingelheim Ltd. Summary of Product Characteristics for Pradaxa 150mg hard
capsules. Last updated on the eMC 30/1/2015 Accessed online via:
http://www.medicines.org.uk/emc/ on 12/3/2015 [date of revision of the text 12/2014]
Available through NICE Evidence Search at www.evidence.nhs.uk
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11. Bayer plc. Summary of Product Characteristics for Xarelto 15mg film-coated tablets. Last
updated on the eMC 10/7/2015 Accessed online via: http://www.medicines.org.uk/emc/ on
13/7/2015 [date of revision of the text 5/2015]
12. Bristol-Myers Squibb-Pfizer. Summary of Product Characteristics for Eliquis 2.5mg filmcoated tablets. Last updated on the eMC 30/7/2014 Accessed online via:
http://www.medicines.org.uk/emc/ on 12/3/2015 [date of revision of the text 28/7/2014]
13. Minor C, Tellor KB, Armbruster AL. Edoxaban, a novel oral factor Xa inhibitor. Annals of
Pharmacology 2015;49(7):843-850
14. Natural Medicines Comprehensive Database. Assessed online via www.naturaldatabase.com
on 4/3/2015, 8/7/2015
15. Ara T, Viqar M, Arshad J. Use of herbal products and potential interactions in patients with
cardiovascular diseases. J Am Coll Cardiol. 2010;55(6):515-525
16. Memorial Sloan Kettering Cancer Centre. About herbs. Accessed online via
http://www.mskcc.org/cancer-care/integrative-medicine/about-herbs on19/3/2015
17. Pharmaceutical Press. Stockley’s Herbal Interactions Accessed online via:
https://www.medicinescomplete.com on 10/3/2015, 24/3/2015
18. Ang-Lee MK, Moss J, Yuan C-SY. Herbal medicines and perioperative care. JAMA
2001;286:208-216
19. Shivamurthy P, Brar N; Therrien ML. Isolated hemopericardium associated with rivaroxaban:
first case report. Pharmacotherapy: The Journal of Human Pharmacology & Drug Therapy.
2014;34(9):e169-72
20. The Maudsley Prescribing Guidelines in Psychiatry. St John’s wort. Wiley Blackwell 2015 12th
edition p.247
Quality Assurance
Prepared by
Gill Lewis, South West Medicines Information & Training, University Hospitals Bristol NHS Foundation
Trust
Date Prepared
13th July 2015
Checked by
Julia Kuczynska, South West Medicines Information & Training, University Hospitals Bristol NHS
Foundation Trust
Date of check
22nd July 2015
Search strategy
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Medline: “[ANTITHROMBINS AND/OR FACTOR XA INHIBITORS/ AND HERBAL MEDICINE/
OR PLANTS, MEDICINAL], “[dabigatran.ti,ab OR rivaroxaban.ti,ab OR dabigatran.ti,ab AND
herbal.ti,ab]” (date of search 10/3/2015) [edoxaban] (date of search 8/7/2015)
Embase: “[exp DABIGATRAN ETEXILATE or exp RIVAROXABAN OR exp APIXABAN AND
HERBAL MEDICINE]” (date of search 10/3/2015) [edoxaban] (date of search 8/7/2015)
NHS Evidence “[dabigatran, rivaroxaban, apixaban, edoxaban and “herbal medicines]” (date
of search 10/3/2015, 8/7/2015)
DRUGDEX Drug Evaluations: [dabigatran, rivaroxaban, apixaban, edoxaban] Accessed via
www.micromedexsolutions.com (date of search 10/3/2015, 8/7/2015)
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
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AltMedDex® Summary: [dong quai, echinacea, evening primrose oil, garlic, ginkgo biloba,
ginseng, saw palmetto, St John’s wort] Accessed via www.micromedexsolutions.com (date
of search 10/3/2015, 8/7/2015)
Herbal Medicines: [dong quai, echinacea, evening primrose oil, garlic, ginkgo biloba, ginseng,
saw palmetto, St John’s wort] Accessed via www.medicinescomplete.com (date of search
6/3/2015, 8/7/2015)
Stockley’s Herbal Medicines Interactions: [dong quai, echinacea, evening primrose oil, garlic,
ginkgo biloba, ginseng, saw palmetto, St John’s wort] Accessed via
www.medicinescomplete.com (date of search 10/3/2015, 8/7/2015)
Natural Medicines Comprehensive Database [dong quai, echinacea, evening primrose oil,
garlic, ginkgo biloba, ginseng, saw palmetto, St John’s wort] (date of search 4/3/2015,
8/7/2015)
HerbMed; [dong quai, echinacea, evening primrose oil, garlic, ginkgo biloba, ginseng, saw
palmetto, St John’s wort] Accessed via http://www.herbmed.org (date of search 8/4/2015,
8/7/2015)
Available through NICE Evidence Search at www.evidence.nhs.uk
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