Potential Interaction between Warfarin and Boldo-Fenugreek

1. Potential Interaction between Warfarin and
Boldo-Fenugreek
Jean-Philippe Lambert, B.Pharm., M.Sc., and Julie Cormier
A patient was treated with warfarin for atrial fibrillation. During treatment,
an increase in international normalized ratio (INR) and her admission that
she was taking a variety of natural products, to include boldo and fenugreek,
led us to suspect that some of these natural products could alter the effect of
warfarin. When she stopped the culpable products, the INR returned to
normal after 1 week. The herb-drug interaction was observed a second time
after both products were reintroduced a few days later. The imputability of
this interaction to both natural products, as determined by the Naranjo
algorithm, suggests a probable association between boldo-fenugreek and
increased bleeding time in patients treated with warfarin. No undesirable
reaction was reported during telephone discussions with the patient.
Nevertheless, we recommend that clinicians treating patients with
anticoagulant therapy be vigilant when patients also take herbal agents.
(Pharmacotherapy 2001;21(4):509–512)
Identifying and managing drug interactions are
daily challenges to pharmacists. Fundamental
research and clinical experience contribute to
better documentation of known interactions.
However, interactions between drugs and natural
products are difficult to predict, and they are
discussed infrequently in the medical and
pharmaceutical literature. American and
Canadian laws, although different, are quite
permissive where alternative agents are
concerned, including treatment with medicinal
herbs and other natural products. These
substances need not go through the regulation
process to determine efficacy and harmlessness,
as regular drugs do.1, 2
Furthermore, deficiencies
exist with identification and nomenclature of the
products, some of which may contain
impurities.1–3
It is therefore difficult to document
potential interactions between natural products
and drugs. Pharmacists and other clinicians
must be alert to detect undesirable effects when
they identify a patient consuming natural
substances concomitantly with a prescribed drug.
Interactions may be dangerous if the drug in
question has a small therapeutic index.
Interactions implicating warfarin and natural
products have appeared in the literature.4, 5
Case Report
A 67-year-old Caucasian woman with a history
of hypertension was admitted to the hospital after
a diagnosis of de novo atrial fibrillation. She was
referred to our clinic by her cardiologist to begin
warfarin treatment. After reviewing her medical
record and contacting her pharmacy, we
determined that the only prescribed drug she was
taking other than warfarin was metoprolol 50 mg
twice/day. It was difficult to make a precise list of
over-the-counter and natural products consumed
because the patient had some memory confusion.
Before hospitalization, she admitted to taking
several products, such as vitamin C 500 mg/day, a
calcium supplement (unknown dosage), garlic
(which she had stopped taking), and evening
primrose oil. It seemed that she had taken no
other over-the-counter, prescription, or natural
product before the fibrillation episode.
From the Pharmacy Department, CHAUQ, St-Sacrement
Hospital and Faculty of Pharmacy, Laval University, Québec
City, Québec, Canada (both authors).
Address reprint requests to Jean-Philippe Lambert,
CHAUQ, St-Sacrement Hospital, 1050, chemin Ste-Foy,
Québec City, Québec G1S 4L8 Canada.

2. PHARMACOTHERAPY Volume 21, Number 4, 2001
During the first year of anticoagulant therapy,
the woman’s international normalized ratios
(INRs) were invariably in the therapeutic range
between 2.0 and 3.0, with a daily dose of
warfarin 2 mg. At the beginning of therapy she
began taking a zinc supplement and a
multivitamin (brand name unknown), as well as
a product containing an unknown artichoke
extract. No significant variations of INR or other
health problems were noted during this period.
On routine analysis a few months later, the INR
increased to slightly above the desired level (3.4).
The patient denied new prescription drugs,
alcohol consumption, modification of her usual
dietary habits, or health problems. However, she
explained that in the past few weeks she had
been taking 10 drops of boldo (Vaugel) after
meals and one capsule of fenugreek (Swiss)
before meals to “help her liver.” She added a
supplement (FLW) containing vitamin E 400 IU
about 4 months earlier with no apparent effect on
INR.
After discussion, the patient agreed to
withdraw the two natural products for a while
but continue vitamin E at the same dose. A week
later the INR was normal (2.6). The patient then
decided of her own accord to resume taking
boldo and fenugreek, which led to new increases
in INR: 3.1 after 1 week and 3.4 after the second.
Due to the woman’s refusal to stop the herbal
agents, the weekly warfarin dosage was reduced
almost 15%, and therapeutic INR again was
reached. Figure 1 illustrates the patient’s INR
variations over time.
Discussion
Boldo (Peumus boldus), also known as boldine,
is a dioecious tree, about 5–8 meters high, with
white flowers that produce translucent fruit.6–8
The plant contains many active ingredients
including boldine and isoquinolines, as well as
bolden and boldoglucine, both glycosides,
eucalyptol, flavonoids, and asconiodol (a volatile
oil).6–9
All these substances confer a variety of
properties to boldo, especially in the digestive
system.8, 9
One study concluded that boldine has
antiplatelet effects due to inhibition of
thromboxane A2 production.10
However, boldo is
not taken for an antiplatelet effect.9, 11
It is taken
mainly as a choleretic and cholagog in bile
ailments and to stimulate digestion but may have
antiinflammatory, helminthic, spasmolytic,
antioxidant, diuretic, and carminative effects.8, 9,
11
This product should not be recommended to
patients with kidney failure (if it contains
510
Figure 1. The patient’s INR values from February–November 1999.
0
1
2
3
4
2.7
2.3
2.1 2.1
2.3
3.4
2.6
3.1
3.4
2.1
2.3
1.9
2.6
2.5
2.2
2.5
Feb23
Mar16
Apr13
May12
June10
Jul8
Jul15
Jul22
Jul29
Aug5
Aug12
Aug27
Sep9
Sep30
Oct21
Nov17
Dates of blood draws (1999)
INR
Boldo-fenugreek
stopped
Boldo-fenugreek
restarted

3. BOLDO-FENUGREEK–WARFARIN INTERACTION Lambert and Cormier
ascaridole) or hepatitis.11
Self-medication with
boldo is not recommended for those with biliary
obstructions such as stones.11
It seems harmless
when consumed in small quantities such as those
present in foods. When taken orally in greater
quantities for medicinal purposes, its main
known undesirable side effects are diarrhea and
disorders of the nervous system, and skin
irritation when applied externally.9, 11
At higher
dosages, central nervous system effects can lead
to increased reflexes, bad coordination, and
convulsions.9, 11
Boldo can provoke a paralysis of
motor and sensory neurons followed by paralysis
of muscular neurons, which could lead to
respiratory failure and death.9
The usual oral dosage is 0.5–2 ml tincture
(1:10 in 60% alcohol) or 0.1–0.3 ml liquid
extract (1:1 in 45% alcohol) 3 times/day.11
It also
comes in capsules containing dried leaf powder
or tea.11
We were unable to determine precisely
which type of formulation and which exact dose
of boldo (10 drops) our patient was taking.
Fenugreek (Trigonelle foenum-graecum) is a
bush, about 20–50 cm high, with white-yellow
flowers producing yellow to brown pod-shaped
fruit.6, 7, 12
The plant contains alkaloids including
trigonelle, gentian, and carpaine, as well as
proteins rich in lysine, nucleoproteins rich in
iron and phosphate, lecithin, steroids, coumarin
glucosides, carbohydrates, mucilage, lipids, and
saponins capable of hemolysis in aqueous
solution.6, 7, 9, 12
Taken orally, fenugreek has many
properties, including stimulating the appetite,
lowering blood sugar in diabetics, and reducing
high cholesterol and triglyceride levels.13, 14
It
also could be effective in treating symptomatic
dyspepsia and constipation, and has
antihypertensive and diuretic properties.9, 12, 13
This plant can be used in topical applications to
improve local inflammatory symptoms, asthenia
and myalgia, boils, wounds, chapping aphthous
ulcers, abscesses, and cellulitis.9, 13
One of
fenugreek’s characteristics is its maple syrup
odor, and it may be used as a flavoring agent in
food preparations.9, 13
Among its unwanted
effects are body odor similar to maple syrup,
diarrhea, flatulence, hypoglycemia when large
doses are taken, systemic reactions, and allergic
skin reactions.9, 13
The typical dosage of
fenugreek is 1–2 g of the seed or equivalent 3
times/day.13
A tea preparation and a topical form
are available.13
Prescribing warfarin as preventive treatment of
thromboembolism associated with atrial
fibrillation is well documented and frequently
recommended.15
Warfarin activity in the
coagulation cascade is situated in factors II, VII,
IX, and X, all of which are dependent on vitamin
K.16
Pharmacokinetic properties and drug
interactions implicating warfarin are widely
studied, and reviews are available elsewhere.17–19
A change in metabolism caused by modifications
in nutrition habits, drug therapy, or general
health can greatly affect the efficacy and
harmlessness of warfarin. Some substances can
inhibit or compete with certain cytochrome P450
isoenzymes (3A, 1A2, 2C19), thus increasing the
risk of bleeding secondary to warfarin therapy.17,
19
Products modifying the serum protein bond of
warfarin or that themselves contain coumarinic
derivatives or agents inhibiting platelet
aggregation are also often implicated in increased
bleeding in anticoagulated patients.17
In contrast,
source products of vitamin K can reverse the
effect of warfarin.3, 16
Boldo and fenugreek are not recognized or
administered for their antiplatelet or
anticoagulant properties. A review of scientific
reports (MEDLINE January 1966–November
2000, EMBASE January 1970–November 2000,
International Pharmaceutical Abstract January
1970–November 2000) revealed no interaction
between warfarin and the two natural products.
This does not exclude, however, the risk of
interaction with warfarin by diverse mechanisms.
As mentioned, boldo could have certain
antiplatelet activities.10
We did not find
documentation of anticoagulant or antiplatelet
properties of fenugreek, apart from the possibility
that it may contain coumarinic derivatives.
Whether or not its constituents could have an
effect on coagulation, particularly in patients
taking warfarin, is unknown. However,
monographs of both products caution against
concomitant use of other medicinal herbs and
drugs that increase bleeding time to reduce the
risk of bleeding.11, 13
Using the Naranjo algorithm20
to define the
link between boldo and fenugreek and the
increased INR, we determined that it is probable
that the natural products caused the increase in
INR. Of note is that INR variations corresponded
to modifications in the use of both products. We
must consider, however, the possibility of a bias,
linked to the patient’s memory as to dates of
beginning and ending the products. We did
experience some difficulty in obtaining the exact
names of the various over-the-counter products
the woman consumed. It is not impossible that
she may have omitted or forgotten to mention
511

4. PHARMACOTHERAPY Volume 21, Number 4, 2001
some change in nutrition such as decreased
consumption of foods rich in vitamin K or
excessive consumption of alcohol that could be
associated with an increased INR.
Conclusion
The small amount of information available
concerning interactions with natural products is
no guarantee of their safety. As well, popular
belief tends to overestimate the safety of these
compounds, increasing the risk of interactions
with prescribed drugs. This risk is increased in
persons taking agents with a narrow therapeutic
index such as warfarin. It seems probable that
use of boldo and fenugreek by our patient
contributed to the increased bleeding time
outside the therapeutic window. In part thanks
to early detection of the interaction and the
intervention of pharmacists at the clinic, no
negative consequences resulted. However, the
importance of the undesirable effect of this
combination should be recognized, and use of
these products by patients receiving anticoagu-
lation discouraged. When such consumption
cannot be avoided, bleeding times should be
monitored closely. These recommendations
should apply to all drugs and natural products
likely to produce an interaction that could
modify warfarin’s effect.
Finally, health professionals, particularly those
most likely to care for patients taking natural
products, should have access to references
allowing them to advise patients on the
consumption of these products. We also
encourage clinicians to note use of natural
products by all patients and to follow their effects
systematically.
References
1. Miller LG, Hume A, Harris IM, Jackson EA, Kanmaz TJ,
Cauffield JS. White paper on herbal products.
Pharmacotherapy 2000;20(7):877–91.
2. Boullata JI, Nace AM. Safety issues with herbal medicine.
Pharmacotherapy 2000;20(3):257–69.
3. Lambert JP. Des interactions «naturelles.» Québec Pharmacie
1999;46(8):789–97.
4. Janetzky K, Morreale AP. Probable interaction between
warfarin and ginseng. Am J Health-Syst Pharm 1997;54:692–3.
5. Yu CM, Chan JCN, Sanderson JE. Chinese herbs and warfarin
potentiation by “danshen.” J Int Med 1997;241:337–9.
6. Wallis TE. Textbook of pharmacognosy, 4th ed. London: J & A
Churchill, 1960:124, 222.
7. Youngken WP. A textbook of pharmacognosy, 6th ed.
Philadelphia: Blakiston, 1952:47, 360, 446.
8. Speisky H, Cassels BK. Boldo and boldine: an emerging case of
natural drug development. Pharmacol Res 1994;29(1):1–12.
9. Der Marderosian A, ed. The review of natural products. St.
Louis: Facts and Comparisons, 1996.
10. Teng CM, Hsueh CM, Chang YL, Ko FN, Lee SS, Liu KC.
Antiplatelet effects of some aporphine and phenanthrene
alkaloids in rabbits and man. J Pharm Pharmacol
1997;49(7):706–11.
11. Anonymous. Boldo monograph. Natural Medicines
comprehensive database serial online. Available from
http://www.naturaldatabase.com. Accessed November 7, 2000.
12. Tyler VE, Brady LR, Robbers JE. Pharmacognosy, 9th ed.
Philadelphia: Lea & Febiger, 1988:472.
13. Anonymous. Fenugreek monograph. Natural Medicines
comprehensive database serial online. Available from
http://www.naturaldatabase.com. Accessed September 9, 2000.
14. Gori M, Campbell RK. Natural products and diabetes
treatment. Diabetes Educ 1998;24(2):201–8.
15. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants;
mechanism of action, clinical effectiveness, and optimal
therapeutic range. Chest 1998;114:445S–69.
16. O’Reilly RA. Drugs used in disorders of coagulation. In:
Katzung BG, ed. Basic and clinical pharmacology, 6th ed.
Norwalk, CT: Appleton & Lange, 1995:507–21.
17. Harder S, Thurmann P. Clinically important drug interactions
with anticoagulants. An update. Clin Pharmacokinet
1996;30(6):416–44.
18. Fugh-Berman A. Herb-drug interactions. Lancet 2000;
355(9198):134–8.
19. Michalets EL. Update: clinically significant cytochrome P-450
drug interactions. Pharmacotherapy 1998;18(1):84–112.
20. Naranjo CA, Busto U, Sellers EM, et al. A method for
estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30(2):239–45.
512