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Potential Interactions Between Alternative Therapies and

Warfarin
Amy M. Heck, Beth A. Dewitt, and Anita L. Lukes

Am J Health Syst Pharm. 2000;57(13)

Abstract and Introduction

Abstract

Potential and documented interactions between alternative therapy agents and warfarin are discussed.

An estimated one third of adults in the United States use alternative therapies, including herbs. A major safety concern
is potential interactions of alternative medicine products with prescription medications. This issue is especially
important with respect to drugs with narrow therapeutic indexes, such as warfarin. Herbal products that may potentially
increase the risk of bleeding or potentiate the effects of warfarin therapy include angelica root, arnica flower, anise,
asafoetida, bogbean, borage seed oil, bromelain, capsicum, celery, chamomile, clove, fenugreek, feverfew, garlic,
ginger, ginkgo, horse chestnut, licorice root, lovage root, meadowsweet, onion, parsley, passionflower herb, poplar,
quassia, red clover, rue, sweet clover, turmeric, and willow bark. Products that have been associated with documented
reports of potential interactions with warfarin include Coenzyme Q10 , danshen, devil's claw, dong quai, ginseng, green
tea, papain, and vitamin E. Interpretation of the available information on herb- warfarin interactions is difficult because
nearly all of it is based on in vitro data, animal studies, or individual case reports. More study is needed to confirm and
assess the clinical significance of these potential interactions.

There is evidence that a wide range of alternative therapy products have the potential to interact with warfarin.
Pharmacists and other health care professionals should question all patients about use of alternative therapies and
report documented interactions to FDA's MedWatch program.

Introduction

Alternative medicine therapies have become increasingly popular, and it has been estimated that one third of all
Americans use herbal products.[1] In 1997, herbal medicine sales increased nearly 59%, reaching an estimated total of
$3.24 billion.[1,2] Despite widespread use of alternative therapies, scientific data about their safety and efficacy are
lacking in most cases. This makes it very difficult for pharmacists to advise patients appropriately about safe
concomitant use of alternative therapies and prescription medications. New information about therapeutic efficacy,
adverse effects, and potential drug interactions of alternative therapies is frequently reported in the medical literature.
Therefore, it is important for pharmacists to have current knowledge in order to remain a reliable source of drug
information for patients and other health care professionals.

One particular safety concern is potential interactions of alternative medicine products with prescription medications.
This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin. More food
and drug interactions have been reported for warfarin than for any other prescription medication.[3,4] Multiple pathways
exist for interference with warfarin, and interactions may lead to either hemorrhage or thrombotic episodes by
increasing or reducing this agent's effect. Therefore, close monitoring of therapy and knowledge of potential
interactions of herbs with warfarin are extremely important.

This article discusses potential and documented herb-warfarin interactions.

Potential Interactions of Herbs with Warfarin

Several herbs may have the potential to interfere with warfarin therapy. However, because information about the
pharmacologic activity, therapeutic efficacy, and adverse effects of most alternative medicine products is limited, the
clinical significance of potential warfarin-herb interactions is unknown. Herbs that have been identified as having the
theoretical potential to interfere with warfarin therapy are listed in . [5-11] Further study is needed to confirm these
potential interactions and assess their clinical significance.

Table Potential and Documented Interactions of Herbs with Warfarin

a Excessive amounts are necessary for this interaction to occur.

Herbs with Coumarin, Salicylate, or Antiplatelet Properties

Several natural products contain substances that have coumarin, salicylate, or antiplatelet properties. Therefore, a
theoretical risk for potentiation of the pharmacologic activity of warfarin exists when these herbs are taken with
warfarin. Herbs thought to contain coumarin or coumarin derivatives include angelica root, arnica flower, anise,
asafoetida, celery, chamomile, fenugreek, horse chestnut, licorice root, lovage root, parsley, passionflower herb,
quassia, red clover, and rue.[5-9] Meadowsweet, poplar, and willow bark contain high concentrations of salicylates,
while bromelain, clove, onion, and turmeric have been reported to exhibit antiplatelet activity.[5,8] Borage seed oil
contains glinoleic acid, which may increase coagulation time.[10] Bogbean has been noted to demonstrate hemolytic
activity,[8] and capsicum has been reported to cause hypocoagulability. [11] There have been no documented case
reports of an interaction of warfarin with any of these herbs. However, patients taking any products containing these
herbs concurrently with medications that have anticoagulant effects, such as warfarin, should be closely monitored for
signs or symptoms of bleeding.

Sweet clover also contains coumarin derivatives and therefore poses an increased risk of bleeding if given with
warfarin.[5] There have been no reports of an interaction between sweet clover and warfarin or hemorrhagic disease in
humans. However, several cases of severe hemorrhage and death have been reported in cattle. [12,13] Patients taking
both sweet clover and an anticoagulant should be monitored closely for signs and symptoms of bleeding, and the
International Normalized Ratio (INR) should be closely monitored.

Feverfew

Feverfew (Tanacetum parthenium) is commonly used for the treatment of migraine headaches, arthritis, and various
type of allergies. [5,14,15] This herb is thought to exert its pharmacologic activity by inhibiting serotonin release,
histamine release, prostaglandin synthesis, and platelet release and aggregation.[5,16] Several in vitro studies have
shown feverfew to interfere with hemostasis and platelet aggregation by neutralizing platelet sulfhydryl groups, as well
as preventing prostaglandin synthesis.[17-20] Parthenolide, one of the many sesquiterpene lactone constituents of
feverfew extract, has been shown to exert the greatest pharmacologic activity.[20] However, a recent study found that
most commercially available feverfew products do not contain substantial amounts of parthenolide. [21]

Although there are no documented reports of feverfew interacting with warfarin in humans, pharmacologic data
suggest the potential for additive anticoagulant effects in the presence of warfarin. The clinical significance of this
potential interaction has not been determined. Until more data are available, it is recommended that patients taking
warfarin avoid products containing feverfew in order to prevent potentially serious bleeding.

Garlic

Garlic (Allium sativum) is thought to provide several cardiovascular benefits, such as blood pressure lowering, serum
lipid lowering, and antithrombotic activity.[6,14] Garlic oil has been reported to interrupt thromboxane synthesis, thereby
inhibiting platelet function.[22] One author reported that in vitro platelet aggregation decreased within five days when
blood samples from six healthy adults were mixed with essential garlic oil.[23] An elderly man developed a
spontaneous epidural hematoma after he ingested approximately 2000 mg of garlic daily (equivalent to about four
cloves) for an undetermined period.[24] The man denied use of aspirin, nonsteroidal anti-inflammatory drugs, and any
other medications that may precipitate a bleeding event.

There have been no reports of potentiation of warfarin's activity with concomitant administration of garlic, but the
available information suggests that a serious interaction is possible. Patients taking warfarin should be advised to
avoid garlic supplements. However, they should also be aware that regular ingestion of food products containing small
amounts of garlic should not pose a problem. If excessive garlic consumption and warfarin use occur concomitantly,
the patient's INR should be closely monitored.

Ginger

Ginger (Zingiber officinale), promoted for use in motion sickness and arthritis, has been reported to reduce platelet
aggregation through the inhibition of thromboxane synthetase. [25] Ginger supplements, containing amounts of ginger
much greater than regularly found in food products, may lead to an increased risk of bleeding when taken with
warfarin. Therefore, patients taking warfarin and ginger supplements concurrently should have their INR checked
regularly and be advised to watch for symptoms of bleeding.

Ginkgo

Ginkgo (Ginkgo biloba) is a common herbal product available in the United States and advertised to improve cognitive
function.[5,6,14] Ginkgolide B, one component of ginkgo, inhibits platelet-activating factor by displacing it from its
receptor- binding site, resulting in reduced platelet aggregation.[26] Several cases of bleeding thought to be secondary
to ginkgo ingestion have been reported. [27-29] A 70-year-old man ingested 40 mg of concentrated ginkgo extract twice
daily for one week. He complained of blurred vision and was diagnosed with a spontaneous hyphema. [27] He was
also taking 325 mg of aspirin daily. A second report involved a 33-year-old woman who complained of diffuse
headaches and was later diagnosed with bilateral subdural hematomas.[28] The patient's medication list included
occasional acetaminophen use, a brief trial of ergotamine- caffeine tablets, and 60 mg of ginkgo twice daily for two
years. Yet another report described a 72- year-old woman diagnosed with a left frontal subdural hematoma after taking
50 mg of ginkgo three times daily for at least six months.[29]

Currently, there are no reports of bleeding associated with concomitant administration of warfarin and ginkgo.
However, it is recommended that patients taking warfarin, or any other anticoagulant, not take ginkgo-containing
products because of an increase in the risk of serious bleeding.

Documented Reports of Possible Herb-warfarin Interactions

Herbal products that have been associated with published case reports of possible interactions with warfarin include
danshen, devil's claw, dong quai, green tea, ginseng, and papain. Dietary supplements such as Coenzyme Q 10 and
vitamin E have also been reported to adversely affect warfarin therapy. It should be noted that the following information
is derived primarily from individual case reports; further study is needed to identify the exact mechanism, time of onset,
severity, and appropriate management of these potential interactions.

Coenzyme Q10

Coenzyme Q10 (also known as ubiquinone or ubidecarenone) is a provitamin found in the mitochondria of plant and
animal cells. It is involved in electron transport and may act as a free-radical scavenger, an antioxidant, or a
membrane stabilizer.[30] Coenzyme Q10 supplementation is primarily promoted to treat a variety of cardiovascular
disorders, including heart failure, hypertension, stable angina, and ventricular arrhythmias.[30] Many patients with
these conditions may also be prescribed warfarin.

Coenzyme Q10 is structurally related to menaquinone (vitamin K 2 ) and may have procoagulant effects.[31] The
vitamin K-like effects of Coenzyme Q10 have been demonstrated in vitro and in four case reports describing possible
warfarin and Coenzyme Q10 interactions. [32-34] In Denmark, a 72-year-old woman had a decreased response to
warfarin while she was taking Coenzyme Q10. [33] Appropriate anticoagulation was achieved only when she stopped
taking the product. A 68-year-old man who had a history of several episodes of pulmonary and cerebrovascular emboli
and whose condition had been stabilized with warfarin (INR, 2-3) for six years had a reduction in his INR to 1.31 after
consuming 30 mg of Coenzyme Q10 daily for two weeks.[34] The other case reports involved (1) a 72-year-old man
with pulmonary embolism and repeated low INR measurements (1.46 and 1.27) while taking warfarin and
undetermined doses of Coenzyme Q10 and (2) a 70-year-old woman with thromboemobolic disease stabilized on
warfarin (INR, 2-3) for several months who had a reduction in her INR to 1.46 within two weeks of starting Coenzyme
Q10. [34] In each of these patients the INR, which had been stable and therapeutic, fell below the therapeutic range
during co-enzyme Q10 use and subsequently returned to the therapeutic range after the provitamin was discontinued.

Until more is known about the effect of the combination of Coenzyme Q10 and warfarin, patients should be advised to
avoid the combination because of the possible risk of thrombotic complications. If warfarin and Coenzyme Q10 are
used concomitantly, the patient's INR should be monitored periodically within the first two weeks.

Danshen

Although not commonly used in the United States, danshen (the root of Salvia miltiorrhiza), also known as tan seng, is
a very popular herb recommended in the Chinese community for various cardiovascular diseases. The pharmacologic
effects of danshen have been described primarily in vitro and in animals and include hypotensive effects, positive
inotropic effects, coronary artery vasodilation, and inhibition of platelet aggregation.[35-37] Pharmacokinetic and
pharmacodynamic studies in rats indicate that danshen root extracts increase the absorption rate, area under the
plasma concentration-versus-time curve, and maximum concentration of warfarin, as well as reduce the elimination
half-life.[38,39]

There have been several case reports of a warfarin-danshen interaction. [40-43] A 62-year-old man who had been
receiving 5 mg of warfarin daily after a mitral valve replacement and who had had a stable INR for several weeks was
admitted to a Hong Kong hospital with pleural and pericardial effusion; his hemoglobin concentration was 7.6 mg/dL
and his INR was >8.4. [41] The man reported consuming a danshen extract daily for two weeks before his admission.
The INR of a 48-year-old woman taking warfarin 4 mg/day increased to 5.6 after she consumed danshen every other
day for about one month.[42] A 66-year-old man who had been receiving warfarin 2-2.5 mg/day for nearly a year and
had an INR stabilized at 2.0 was hospitalized for bleeding from a gastric carcinoma; the associated INR was 5.5. [43]
He reported consuming danshen three and five days before admission and using a Chinese medicated topical oil
containing methyl salicylate. Both this man and the 48- year-old woman in the previous example achieved a
therapeutic INR after discontinuing danshen.
The available evidence contraindicates concurrent use of danshen and warfarin.

Devil's Claw

Devil's claw (Harpagophytum procumbens) is an expensive herbal product that has been promoted for use as an
analgesic in the treatment of arthritis, gout, and myalgia.[5,8] Although information about the pharmacologic effects of
devil's claw is limited, one case of purpura was reported in a patient receiving warfarin and devil's claw.[44] This case
was uncovered during a toxicology review conducted between 1991 and 1995 by the National Poisons Information
Service, which provides emergency information for poisonings throughout the United Kingdom. However, key details of
this case, including the patient's medical conditions, other medications, and the doses and duration of warfarin and
devil's claw ingestion, were not reported. Until more is known about this possible interaction, patients taking warfarin
should be advised to avoid devil's claw.

Dong quai

Dong quai (Angelica sinensis) is a Chinese herbal supplement promoted in the United States for use in the treatment
of menopausal complaints and menstrual disorders. [6,45] Dong quai contains at least six coumarin derivatives; these
substances are believed to promote vasodilation and uterine stimulation and to have anti-inflammatory, antipyretic,
antispasmodic, immunosuppressant, and estrogen-like effects.[6,46] Dong quai may also exert an antithrombotic effect
by inhibiting platelet activation and aggregation. [47] On the basis of the known pharmacologic effects of dong quai and
a small pharmacokinetic study in rabbits that suggested the potential for increased prothrombin times when this herb is
administered with warfarin, a potentially dangerous interaction was theorized.[7,48] A recent case report supports this
idea. A 46-year-old woman who had been taking warfarin 5 mg/day for nearly two years and had an INR stabilized at
2-3 experienced a sudden increase in her INR to 4.9. [49] The patient denied any changes in her medication regimen,
diet, alcohol consumption, or other lifestyle factors that may affect her INR except for the recent addition of dong quai
565 mg once or twice daily during the preceding four weeks for the management of menopausal symptoms (her
herbalist had recommended this). The patient was instructed to discontinue dong quai, and within four weeks her INR
declined to the therapeutic range. In view of this information, patients receiving warfarin should be advised to avoid
dong quai.

Ginseng

Three ginseng species: American ginseng (Panax quinquefolius), Oriental ginseng (Panax ginseng), and Siberian
ginseng (Eleutherococcus senticosus) have been promoted as enhancing energy, reducing the effects of stress, and
improving mood, among several other claims.[7,14] The active components of ginseng are known as ginsenosides,
more than 20 of which have been identified. The pharmacologic activity of each ginsenoside appears to vary
depending on where the plant grew and the extraction techniques used.[50] Also, data suggest that the ginsenoside
composition varies widely among commercially available ginseng products.[51] This variability makes it difficult to
evaluate the safety and efficacy of ginseng products. Although the exact pharmacologic actions of ginsenosides in
humans are not fully understood, studies in vitro and in animals suggest that these substances may increase adrenal
hormone synthesis, decrease blood glucose concentrations, and promote immunomodulation.[52-54]

One published case report suggests that Oriental ginseng (Ginsana) may antagonize the anticoagulant effects of
warfarin.[55] The INR of a 47- year-old man who had been receiving warfarin for nine months (7.5 mg every Tuesday
and 5 mg on all other days) to prevent thrombotic complications associated with a mechanical heart valve was
stabilized at 3.0-4.0. The patient began taking Oriental ginseng, and within two weeks his INR fell to 1.5. The patient
denied any other changes in his medication regimen (including other nonprescription or herbal products), diet, alcohol
consumption, or other lifestyle factors that may have affected his response to warfarin. The patient's INR returned to
therapeutic level (3.3) two weeks after he stopped using ginseng.

The possible mechanism for this interaction has not been identified, and it is not known which ginsenoside or
ginsenosides may be responsible. A 1999 pharmacokinetic study in rats did not reveal a significant interaction
between warfarin and pure ginseng extract. [56] Nevertheless, because of the potential seriousness of thrombotic
complications resulting from a subtherapeutic INR, patients receiving warfarin should avoid ginseng until more is
known.

Green Tea

Green tea (Camellia sinensis), also known as Chinese tea, is a popular beverage purported to prevent various
cancers, treat gastrointestinal disorders, and enhance cognition.[8,57] Although dried green tea leaves have been
found to contain substantial amounts of vitamin K, brewed green tea is generally not considered a significant source of
the vitamin. [58,59] However, large amounts of brewed green tea may potentially antagonize the effects of warfarin. The
INR of a 44-year-old warfarin recipient with a mechanical heart valve decreased substantially when he started
consuming large amounts of brewed green tea.[60] The patient reported to the outpatient clinic with an INR of 1.37; his
INR 22 days prior to this visit had been 3.79. The patient was unable to be reached until his return visit to the clinic
one month later, at which time his INR was 1.14. In an interview, the patient disclosed that he had begun drinking 0.5-1
gallon of brewed green tea daily approximately one week before the INR measurement of 1.37. There were no other
identifiable causes of the dramatic decrease in the INR, including changes in the patient's medications, dietary intake,
medication compliance, or medical conditions.

A significant drop in the INR would not generally be expected to result from usual consumption of moderate amounts
of brewed green tea. It is probably not necessary to advise patients receiving warfarin therapy to avoid green tea.
However, patients should be advised that large quantities of green tea might decrease the effectiveness of warfarin.

Papain

Papain is a mixture of proteolytic enzymes found in extract of papaya, the fruit of the papaya tree (Carica papaya).[8] It
is taken orally in the belief that it reduces edema, inflammation, herpes zoster symptoms, diarrhea, and psoriasis
symptoms.[8] The pharmacologic mechanisms by which papain may affect coagulation are not known. However, one
case of an interaction between warfarin and papain was identified in the 1991-95 toxicology review conducted
throughout the United Kingdom by the National Poisons Information Service.[44] A patient who had maintained a
therapeutic INR while receiving warfarin began taking papaya extract containing papain as a weight-loss aid. The
patient was admitted for cardiac surgery with an INR of 7.4. After withdrawal of both papaya extract and warfarin, the
patient's INR decreased to 2.0. The details of the case have not been published, however.

Patients receiving warfarin should be advised to avoid papain supplementation until further information about this
potential interaction becomes available.

Vitamin E

Vitamin E has received much publicity as one of several antioxidants that may be useful in treating a variety of
disorders, including cardiovascular diseases. Vitamin E may inhibit the oxidation of reduced vitamin K.[61] Vitamin K
oxidation is necessary for carboxylation of vitamin K-dependent clotting factors, which must occur for these clotting
factors to be fully functional. Conflicting information exists about the effect of vitamin E on prothrombin time.

A 55-year-old man taking warfarin and 1200 units of vitamin E daily developed ecchymoses and hematuria, and his
prothrombin time increased. After a two-month period of stable clinical and hematologic status without concomitant
vitamin E intake, the patient was rechallenged with vitamin E 800 units/day. Again, multiple ecchymoses appeared on
his extremities. His prothrombin time began to increase at four weeks and continued to increase over the next two
weeks. Within a week after the patient stopped taking vitamin E, his prothrombin time returned to the value reported
before he had begun the vitamin. [62]

Studies in animals and humans consuming adequate vitamin K and not receiving warfarin have found no effect of
vitamin E on coagulation. However, vitamin K-deficient animals have demonstrated bleeding diatheses associated with
vitamin E.[63,64] A study in 12 patients undergoing warfarin treatment who received 100 or 400 units of vitamin E daily
for one month found that neither dose induced a clinical bleeding state.[64] Kim and White [65] conducted a
randomized, double-blind study in which four patients received 1200 units of vitamin E daily, three patients received
800 units/day, and four received placebo, all for four weeks.[65] During the study's second phase, which was single-
blind and not randomized, six subjects were told they would receive placebo or vitamin E, but all were given vitamin E
1200 units/day for an additional four weeks. The INR did not increase to a level necessitating warfarin dosage
adjustments in either treatment group. Although these studies indicated no interaction between vitamin E and warfarin,
both were small and limited to only one month.

Vitamin E up to 400 units/day does not appear to affect prothrombin time in patients receiving warfarin. Although
higher dosages appeared to be safe in the study by Kim and White,[65] some conflicting information suggests the
potential for certain patients to be adversely affected by the combination of vitamin E and warfarin. The characteristics
of those patients have not been determined. Therefore, patients receiving warfarin who are beginning vitamin E
therapy, particularly dosages greater than 400 units/day, should have INR measurements conducted one to two weeks
after starting vitamin E. This should be followed by INR monitoring every two to four weeks during the first two months
of combination therapy. Increased prothrombin times induced by combined vitamin E and warfarin therapy may be
managed by discontinuing vitamin E, and, if necessary, by administering vitamin K.

Limitations of the Literature

Several limitations exist for health care professionals attempting to use these data to make clinical decisions. Nearly
all available information on potential drug interactions between warfarin and herbal products is based on in vitro data,
animal studies, or individual case reports. Definitive cause-and-effect relationships have not been proven. The findings
to date may be confounded by several patient- specific variables, including the presence of other concomitant
medications, diseases, and lifestyle factors. Information from in vitro or animal studies may not always predict
responses in humans. In addition, the available reports provide only limited information about the onset or severity of
the potential interactions, which further limits the development of sound recommendations for managing patients.
These problems are further complicated by the lack of information about the safety and therapeutic efficacy of most
herbal products and the lack of regulations governing the purity and potency of herbal products during manufacturing.
Because the pharmacokinetic and pharmacodynamic properties of most herbal products are poorly understood,
potential interactions with warfarin cannot be predicted with any confidence. Therefore, the list presented in this review
cannot be considered all-inclusive, and continued vigilance and reporting of potential interactions are needed.

Discussion

Increases in alternative medicine use in the United States have made information about potential drug and herb
interactions very important, especially for medications with a narrow therapeutic index, such as warfarin. More
information is needed about the severity, onset, and therapeutic management of these potential interactions.

Because nearly 70% of patients who use alternative therapies do not inform their health care providers about these
products,[66] pharmacists and other health care professionals should question all patients about their use of alternative
therapies. Health care professionals should remain vigilant for potential interactions between alternative therapies and
prescription medications, especially medications with a narrow therapeutic index, and should report suspected
interactions to FDA's MedWatch program. FDA recently established the Special Nutritionals Adverse Event Monitoring
System, a searchable database including information about suspected adverse events associated with dietary
supplements or nutritional products. This database includes reports that have been submitted to MedWatch and can
be accessed via the Internet (http:// vm.cfsan.fda.gov/~dms/aems.html). Continued efforts by health care professionals
to recognize and report suspected interactions between prescription medications and herbal and other alternative
therapies should ultimately increase knowledge and awareness of interactions and improve the quality of patient care.

Conclusion

There is evidence that a wide range of herbal products have the potential to interact with warfarin. Pharmacists and
other health care professionals should question all patients about use of alternatives and report documented
interactions to FDA's MedWatch program.

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Address reprint requests to Dr. Heck at the Purdue Pharmacy Programs Office, D711 Myers Building, Wishard
Memorial Hospital, 1001 West Tenth Street, Indianapolis, IN 46202, or to amheck@iupui.edu.

Am J Health Syst Pharm. 2000;57(13) © 2000 American Society of Health-System Pharmacists

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