Review Article

Journal of Pharmacy Practice

2015, Vol. 28(6) 561-571
A Comprehensive Review of ª The Author(s) 2014
Reprints and permission:
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Potential Warfarin-Fruit Interactions DOI: 10.1177/0897190014544823
jpp.sagepub.com

Daryl A. Norwood, PharmD1, Crystal K. Parke, PharmD2,

and Leonard R. Rappa, PharmD, BCPP3

Abstract
Purpose: The aim of this review is to discuss possible interactions that may occur between warfarin and fruit products. Methods: A
literature search was conducted using the search terms: ‘‘warfarin (Coumadin1) and fruit interactions, warfarin and fruit, warfarin
and fruit juice, case reports and clinical trials’’. Results: A total of 23 citations (15 case reports and 7 controlled clinical trials) were
reviewed. The majority of cases involved cranberry products, while pomegranate juice, avocado, grapefruit juice, mango, and
papain were also implicated in reports of suspected warfarin-fruit interactions. Cranberry juice was also the most frequently
studied fruit product. Other fruit products evaluated with warfarin in controlled clinical trials were cranberry concentrate and
grapefruit juice. Conclusion: Although a number of case reports have been published that suggest warfarin has the potential to
interact with several fruit products, it is difficult to determine their relevance, as scientific evidence is scarce. Until further
information is available, clinicians may want to encourage patients to consume cranberry products and grapefruit juice in small to
moderate quantities and to inquire about the recent consumption of mangos, pomegranate juice, and avocados when taking a
dietary history or when assessing possible causes for international normalized ratio (INR) instability.

Keywords
ambulatory care, medication safety

Introduction susceptible to several different types of interactions including

Warfarin is the most frequently prescribed oral anticoagulant in
the United States.1 It is characterized by a unique mechanism
of action that involves the hepatic inhibition of vitamin
K-dependent coagulation factors II, VII, IX, and X.2 The use
of warfarin requires periodic monitoring of the prothrombin
time (PT) and international normalized ratio (INR). Tradition-
ally, the PT has been the most frequently used test to monitor
warfarin therapy, but thromboplastins used during the PT assay
tend to vary in their response to warfarin and can lead to incon-
sistent results. Therefore, the INR has become the standard
laboratory value for monitoring and adjusting warfarin ther-
apy.3,4 Most patients receiving warfarin will require a target
therapeutic INR range of 2 to 3. An alternative range of 2.5
to 3.5 may be indicated for patients with certain hypercoagul-
able disease states or who have a mechanical heart valve.5
Two optical isomers, an R and S enantiomer, make up war-
farin; they are both metabolized by the cytochrome P450 (CYP)
pathway. The S enantiomer is approximately 2 to 5 times more
potent than the R enantiomer and is primarily metabolized by
CYP2C9 and to a lesser degree, CYP3A4. The CYP isoenzymes,
1A2 and 3A4, are mainly responsible for the metabolism of the R
enantiomer. Other enzymes involved in the metabolism of war-
farin include CYP2C8, CYP2C18, and CYP2C19.6-8 Due to its
mechanism of action and pharmacokinetic profile, warfarin is
therapeutic duplication, protein displacement, metabolism induc-
tion or inhibition, altered absorption, and therapeutic interference
by vitamin K. It is important for both clinicians and patients to be
aware of those substances that may interact with warfarin to avoid
serious complications such as excessive bleeding and thrombosis
due to suboptimal anticoagulation. The numerous drug–drug
interactions that exist with warfarin are well documented. Less
is known, however, about the potential interactions that may
occur between warfarin and certain foods, especially fruits.9
1
Primary Care, College of Pharmacy and Pharmaceutical Sciences, Florida
A&M University (FAMU) Davie Instructional Site and Clinical Pharmacy Spe-
cialist in Primary Care, Davie, FL, USA
2
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University
(FAMU) Tampa Instructional Site and a Clinical Pharmacy Specialist in Internal
Medicine, Tampa, FL, USA
3
Psychiatric Medicine, College of Pharmacy and Pharmaceutical Sciences,
Florida A&M University(FAMU) Davie Instructional Site and Clinical Pharmacy
Specialist in Primary Care, Davie, FL, USA
Corresponding Author:
Daryl A. Norwood, College of Pharmacy and Pharmaceutical Sciences, Florida
A&M University (FAMU) Davie Instructional Site and Clinical Pharmacy
Specialist in Primary Care, Davie, FL 33324, USA Davie, Florida Instructional
Site, 10650 Suite # 200 State Road 84, Davie, FL 33324, USA.
Email: darylnorwood@gmail.com
562 Journal of Pharmacy Practice 28(6)

Table 1. Modified Drug Interaction Probability Scale Form.a

Unknown or
Questions Yes No NA

Are there previous credible reports of this interaction in humans? þ1 1 0

Is the observed interaction consistent with the known interactive properties of precipitant drug (fruit product)? þ1 1 0
Is the observed interaction consistent with the known interactive properties of object drug (warfarin)? þ1 1 0
Is the event consistent with the known or reasonable time course of the interaction (onset and/or offset)? þ1 1 0
Did the interaction remit upon dechallenge of the precipitant drug (fruit product) with no change in the object drug (warfarin)? þ1 2 0
(if no dechallenge, use Unknown or NA and skip Question 6)
Did the interaction reappear when the precipitant drug (fruit product) was readministered in the presence of continued use þ2 1 0
of object drug (warfarin)?
Are there reasonable alternative causes for the event? 1 þ1 0
Was the object drug (warfarin) detected in the blood or other fluids in concentrations consistent with the proposed þ1 0 0
interaction?
Was the drug interaction confirmed by any objective evidence consistent with the effects on the object drug (warfarin), þ1 0 0
other than drug concentrations from question 8?
Was the interaction greater when the precipitant drug dose (fruit product amount) was increased or less when the þ1 1 0
precipitant drug dose (fruit product amount) was decreased?

Abbreviation: NA, not applicable.

a
Total score: highly probable (total score > 8), probable (total score ¼ 5-8), possible (total score ¼ 2-4), or highly doubtful (total score < 2).

One fruit product, cranberry juice, has been frequently pur-
ported to interact with warfarin. In October 2004, the United
Kingdom’s Medicines and Healthcare Products Regulatory
Agency had received several reports of a suspected cranberry
juice–warfarin interaction and issued a statement that patients
taking warfarin should avoid cranberry products unless the
benefits clearly outweigh the risks.10 One year later, the pre-
scribing information for Coumadin1 (warfarin sodium tablets,
USP) was changed in the United States to include a statement
that patients taking warfarin should avoid cranberry juice and
cranberry products.11 These warnings were later removed in
2012, and currently there are no recommendations regarding
the use of cranberry products in the prescribing information for
Coumadin. Adding to the uncertainty are popular drug informa-
tion resources, such as Micromedex1, that lists major drug–
food interactions between warfarin and some fruit products
(eg, cranberry juice and pomegranate juice), with little to no
scientific evidence to support the claims.12 A clearer under-
standing of the literature is necessary to help clinicians assess
the potential for a warfarin-fruit interaction and advise patients
accordingly. In this article, possible interactions between war-
farin and various fruit products commonly consumed in the
United States are reviewed.
Methods
To further examine which fruit products may interact with war-
farin, a literature search was conducted within the date range of
January 1950 to January 2014, using Medline (PubMed),
OvidSP, IDIS/Web, International Pharmaceutical Abstracts,
and The Cochrane Library. The following MeSH terms and key
words were used: ‘‘warfarin (Coumadin) and fruit interactions,
warfarin and fruit, warfarin and fruit juice, case reports and
clinical trials’’. Articles were considered eligible for evaluation
if they contained original information regarding interactions
between warfarin and fruit products in humans. In addition, the
fruit products had to be currently recognized by the United
States Department of Agriculture. Non-English language liter-
ature was excluded, and references from published articles
were reviewed for additional sources.
Currently, there is not a standardized assessment tool for
determining the probability of a drug–food interaction. There-
fore, to establish the likelihood of a warfarin-fruit interaction in
the case reports reviewed, the Drug Interaction Probability
Scale (DIPS) was utilized.13 The DIPS is a modified version
of the Naranjo adverse drug reaction probability scale14 and
is intended to evaluate the probability of a drug–drug interac-
tion occurring in a specific patient. For the purpose of this lit-
erature review, the DIPS was modified so that warfarin was
labeled as the object drug, and the fruit products purported to
interact with warfarin were considered the precipitant drug.
An example of the modified DIPS form used in this review is
located in Table 1. In each report, the probability of an interac-
tion was rated as highly probable (total score > 8), probable
(total score ¼ 5-8), possible (total score ¼ 2-4), or highly
doubtful (total score < 2).
Results
Of the 10 307 citations identified, 23 (15 case reports and 7
controlled clinical trials) met the criteria and were eligible for
review. The majority of cases involved cranberry products (8
cases), while pomegranate juice (2 cases), avocado fruit (2
cases), grapefruit juice (1 case), mango fruit (1 case), and
papain (1case) were also implicated in reports of suspected
warfarin-fruit interactions. Thus far, cranberry juice, cran-
berry concentrate, and grapefruit juice are the only fruit prod-
ucts to be evaluated with warfarin in controlled clinical trials.
Of the trials, 5 involved cranberry juice, 1 used cranberry
concentrate, and 1 study examined the effects of grapefruit
Norwood et al 563

Table 2. Fruit Products Suspected to Interact With Warfarin.

Potential Proposed mechanism No. clinical trials

Fruit product effect of interaction No. case reports (results) Patient considerations

Avocado # INR Warfarin reversal by 2 0 Eat in moderation as

vitamin K part of consistent
vitamin K intake
Cranberry products " INR CYP3A4/CYP2C9 8 (CJ ¼ 6, CS ¼ 2) 7 (No significant Eat/drink in moderation;
inhibition and/or interaction w/CJ; CJ < 8 oz up to 3
platelet inhibition pharmacodynamic times/d
and/or protein- interaction w/CC)
binding displacement
Grapefruit juice " INR CYP3A4 inhibition 1 1 (No significant Drink in moderation; GJ
interaction) < 8 oz up to 3 times/d
Mangos " INR CYP2C19 inhibition 1 (13 pts) 0 Inquire about
consumption
w/ unstable INRs
Papain (papaya " INR Unknown 1 0 Encourage pts to eat
enzyme) ripe papaya fruit
Pomegranate juice " INR CYP3A4 and/or 2 0 Inquire about ingestion
CYP2C9 inhibition w/ unstable INRs

Abbreviations: CJ, cranberry juice, CC, cranberry concentrate capsules, CS, cranberry sauce; CYP, cytochrome P450; GJ, grapefruit juice; INR, international
normalized ratio; No., number; oz, ounces; pts, patients; w/, with.

juice on warfarin. Although cranberry concentrate capsules
were shown to affect the pharmacodynamic properties of
warfarin, neither cranberry juice nor grapefruit juice demon-
strated a statistically significant interaction with warfarin in
any of the other trials.
The case reports and clinical trials reviewed are summar-
ized subsequently. Patient considerations are also provided to
help aid pharmacists and other health care professionals in
counseling patients who are on warfarin. In addition, a brief
overview of suspected warfarin-fruit interactions is listed in
Table 2.
Discussion
Cranberry (Vaccinium macrocarpon)
As mentioned, cranberry products have been the most fre-
quently reported fruit products to interact with warfarin. Eight
different case reports describing an interaction between war-
farin and cranberry products have been published.15-23
Although an exact mechanism to explain this potential drug–
food interaction has yet to be determined, it has been sug-
gested that cranberries may increase the anticoagulant effect
of warfarin by inhibiting CYP3A4 and CYP2C9, 2 of the pri-
mary enzymes responsible for warfarin’s metabolism.24-26 In
addition, cranberries contain salicylic acid, which may
potentiate the anticoagulant effect of warfarin by inhibiting
platelet aggregation and by displacing warfarin from protein
binding sites.27,28
Case reports. In the first case, Suvarna et al described an elderly
male in his 70s on warfarin who developed a poor appetite and
started consuming almost nothing but cranberry juice.15 Six
weeks after he started drinking cranberry juice, he was admitted
to the hospital with an INR >50 and later died of gastrointestinal
and pericardial hemorrhage. Prior to the admission, the patient’s
INR had been stable and he was not taking any medications other
than digoxin, phenytoin, warfarin, and cephalexin for a chest
infection. Griffiths et al later published a more detailed account
of this case several years later and noted that prior to his death
the patient had been drinking 2 cups (300-400 mL) of pure cran-
berry juice daily for approximately 6 weeks.16 It was also men-
tioned that the patient was compliant with his medications and
had been using a tablet dispenser. According to the autopsy
report, the patient had a fatal hemorrhage into the pericardial sac
and gut. The authors of this report mentioned that hemorrhaging
in 2 different sites was indicative of a systemic coagulation
abnormality most likely due to an increase in the anticoagulant
effect of warfarin. The autopsy report also showed that hemosi-
derin (iron pigment) and an organizing fibrin clot were present
on the outer surface of the heart which suggests that the bleeding
in the pericardial sac was not spontaneous and must have
occurred over several days before the patient died. This finding
was consistent with the theory that the anticoagulant effect of
warfarin was potentiated in this patient. In addition, information
from the toxicology report revealed that although the patient had
a massive hemorrhage and received 5 L of intravenous (IV)
fluids, warfarin still remained at detectable levels in his system.
In the absence of an overdose, this could indicate that the meta-
bolism of warfarin was impaired. Based on the DIPS, it is pos-
sible that a warfarin–cranberry juice interaction occurred in
this case (DIPS score ¼ 3 [þ1 þ 0 þ 0 þ 1 þ 0 þ 0  1 þ
1 þ 1 þ 0]).
In the next report, a 69-year-old male taking warfarin was
admitted to the hospital in preparation for a sigmoid colectomy
564
and bladder repair and was found to have an INR of 12.17 After
holding multiple doses of warfarin and receiving vitamin K, his
INR eventually stabilized at 2 and he had surgery without any
complications. Several days after his surgery and after restart-
ing warfarin, his INR once again increased to 8 and then to 11
and was accompanied by frank hematuria from his catheter and
postrectal bleeding from the anastomosis site. Besides war-
farin, the only other medication the patient was taking was
digoxin and acetaminophen/codeine (postsurgery). The patient
was not known to have any bleeding complications in the past
and denied any changes to his medication regimen or diet but
did admit to drinking almost 2 L/d of cranberry juice over the
2 weeks prior to his hospitalization to prevent urinary tract
infections. He was instructed to discontinue drinking cranberry
juice, and 3 days later, his INR decreased to 3 and all bleeding
episodes stopped. According to the DIPS, it is probable that an
interaction between warfarin and cranberry juice led to the
events in this case (DIPS score ¼ 6 [þ1 þ 0 þ 0 þ 1 þ 1 þ
2  1 þ 0 þ 1 þ 1]).
The third case describes a 71-year-old man on warfarin
therapy for stroke prophylaxis who was admitted to the hos-
pital with a 2 day history of hemoptysis, hematochezia, and
shortness of breath.18 Upon admission, his INR and PT were
found to be >18 and >120 seconds, respectively. The patient
denied any alcohol use or changes to his diet and health but
did state that 2 weeks prior to his admission, he began drink-
ing 24 ounces (oz; 710 mL) of cranberry juice daily as a
source of vitamin C. While hospitalized, the patient received
packed red blood cells, fresh frozen plasma, subcutaneous
vitamin K, and gatifloxacin for a presumed chronic bronchitis
exacerbation. After several days, his INR eventually
decreased to 2.6 and he was restarted on warfarin upon dis-
charge. After alleviating cranberry juice from his diet, he had
2 subsequent INRs between 2 and 3. Although a cranberry
juice–warfarin interaction appears to be a likely contributor
to the elevated INR in this patient, another potential factor
that must be considered was the presence of an active infec-
tion. Some infections can reduce the activity of several drug-
metabolizing enzymes, including CYP2C9, which could
potentially enhance the anticoagulant effect of warfarin.29
Using the DIPS, a cranberry juice–warfarin interaction was
determined to be possible in this report (DIPS score ¼ 3
[þ1 þ 0 þ 0 þ 1 þ 1 þ 0  1 þ 0 þ 1 þ 0]).
Another case report described a 78-year-old male on chronic
warfarin therapy for atrial fibrillation that was found to have an
INR of 6.45 during a regular follow-up visit with his provi-
der.19 The patient denied alcohol use or any changes to his
medication regimen (warfarin, isosorbide mononitrate,
digoxin, flunisolide, and loratadine) but did apparently take
an extra dose of warfarin by accident during the previous week.
The patient also admitted to taking a homemade cough prepara-
tion consisting of honey, vinegar, and water. The only known
change in his diet was that he began drinking nearly a half-
gallon (1893 mL) of cranberry–apple juice during the previous
week. He was instructed to hold multiple doses of warfarin, dis-
continue drinking the cranberry juice cocktail, and then to
Journal of Pharmacy Practice 28(6)
restart warfarin therapy at a lower dose. After 2 weeks, the
patient’s warfarin dose was titrated back to his regular weekly
dose and his INR stabilized 1 week later at 2.4. Although the
DIPS indicates there was a possible warfarin–cranberry juice
interaction in this case, the likelihood of an interaction was
weakened by the patient taking an extra dose of warfarin (DIPS
score ¼ 3 [þ1 þ 0 þ 0 þ 1 þ 1 þ 0  1 þ 0 þ 1 þ 0]).
In this case, a 75-year-old caucasian man who had been on
warfarin for 10 months went to a follow-up visit at an anticoa-
gulation clinic 1 week after thanksgiving and was noted to have
an INR of 4.8.20 After extensive questioning, the patient admit-
ted to eating *113 g of cranberry sauce daily for 1 week prior
to the visit. He denied any alcohol consumption or changes to
his diet, health, and medication regimen (calcium carbonate,
cyanocobalamin, digoxin, cholecalciferol, metoprolol tartrate,
simvastatin, and furosemide). The patient was instructed to dis-
continue eating cranberry sauce, hold warfarin for 2 days, and
then to decrease his warfarin dose from 22.5 mg/week to 20
mg/week. Approximately 7 days later, the patient’s INR was
within therapeutic range at 2.2 and continued to be stable over
the next month. Based on the DIPS, it is possible that an inter-
action between warfarin and cranberry sauce resulted in the
patient’s supratherapeutic INR (DIPS score ¼ 3 [þ1 þ 0 þ 0
þ 1 þ 0 þ 0  1 þ 0 þ 1 þ 1]).
In a recently documented case, a 64-year-old male who was
stabilized on warfarin therapy (60 mg/week for > 1 year) was
found to have a supratherapeutic INR of 5.5 during a clinic
visit.21 According to the patient, he was only taking his usual
medications which included captopril, furosemide, gabapentin,
pravastatin, metoprolol, sertraline, and hydrocodone 5 mg/
acetaminophen 500 mg (2 tablets at bedtime). He also denied
any alcohol or tobacco use and had been eating a consistent
amount of vitamin K-containing foods (a serving of coleslaw
or an iceberg salad once per week) prior to the elevated INR.
Apparently, the only change in his dietary habits was that he
started drinking 2 glasses of cranberry juice daily over the past
month. The patient was instructed to stop drinking cranberry
juice, hold 2 doses of warfarin, and then to resume his normal
dose of 60 mg per week. Two weeks later, his INR was elevated
at 3.6 which was attributed to a recent increase in his hydroco-
done/acetaminophen dose from 2 tablets/d (1000 mg of aceta-
minophen) to 6 tablets/d (3000 mg of acetaminophen). Use of
the DIPS indicated a possible warfarin–cranberry juice interac-
tion for the initial elevated INR in this case (DIPS score ¼ 4
[þ1 þ 0 þ 0 þ 1 þ 1 þ 0  1 þ 0 þ 1 þ 1]).
In the next report, a 46-year-old woman with an average INR
of 2.0 (INR range was 1.6-2.2 for 4 months) experienced an ele-
vated INR of 4.6 after drinking approximately 1.5 quarts (1420
mL) of cranberry juice cocktail daily for 2 days.22 Although the
patient reported using acetaminophen rarely, she denied any
alcohol or herbal medication use or any changes in her medica-
tion regimen. She was instructed to hold warfarin for 1 day, dis-
continue drinking cranberry juice, and then to resume her
normal weekly dose of warfarin. Two weeks later her INR was
2.3 and continued to remain within the range of 1.4 to 2.5 (aver-
age INR 2.1) for the next 3 months. At a follow-up visit, the
Norwood et al
patient’s INR had once again increased, this time to 6.5. She
admitted to drinking approximately 2 quarts (1893 mL) of cran-
berry juice cocktail for 3 to 4 days prior to the measurement.
After holding warfarin for 3 days and discontinuing cranberry
juice, her INR decreased to 1.86. She then resumed her usual
warfarin dose and 1 week later her INR was 3.2. No signs or
symptoms of bleeding were noticed at any time during the
supratherapeutic INR results. The possibility of a drug–food
interaction was strengthened in this case due to an elevation in
the patient’s INR on 2 separate occasions after consuming cran-
berry juice. Based on the DIPS, a probable interaction between
warfarin and cranberry juice occurred in this report (DIPS
score ¼ 6 [þ1 þ 0 þ 0 þ 1 þ 1 þ 2  1 þ 0 þ 1 þ 1]).
The most recent case to date involved an 85-year-old
woman on chronic warfarin therapy who’s INR was found to
be 5.1, 4 days after ingesting approximately 2 tablespoons of
homemade cranberry sauce.23 Two months prior, her INR was
2.3 (target range 2-3) and her total weekly warfarin dose was
increased from 50 mg to 52.5 mg. The patient’s chronic med-
ications included lisinopril, hydrochlorothiazide, metoprolol
succinate extended release, digoxin, and 2 homeopathic reme-
dies (Naja Tripudia and Cactus Grandiflorus). She denied any
changes in her medications or dietary habits and did not use
tobacco or alcohol. She was instructed to hold warfarin for 4
days and then to decrease her total warfarin dose to 50 mg
weekly. Eleven days later, her INR was 1.7 and she was
instructed to continue on the same dose of warfarin. Seventeen
days later, her INR was found to be 6.7 (using a point of care
finger testing device) and 7.1 (confirmed by a laboratory per-
formed venipunture). According to the patient, she did not
make any changes to her warfarin dose but did again consume
cranberry sauce 3 days earlier. She was instructed to hold
3 doses of warfarin and then to continue taking the same dose
(50 mg/weekly). Her INR was 1.3, 5 days later and her weekly
warfarin dose was slightly decreased to 47.5 mg. For the next
2 months, her INR results were therapeutic at 2.1 and 2.7,
respectively, using a weekly warfarin dose of 45 mg. Over the
next year, her INR levels ranged from 2 to 3 at a warfarin dose
of 47.5 mg weekly. It is unknown if the 2 homeopathic medi-
cines used by the patient in this case may have interacted with
warfarin. However, because she was reportedly taking them on
a daily basis and most of her INR levels during that time were
either slightly above or within therapeutic range, it is unlikely
that they had a major effect on the anticoagulant properties of
warfarin. Similar to the other 2 cases where the patients expe-
rienced subsequent increased INR results on more than one
occasion after consuming cranberry products, the DIPS rating
was found to be probable for this report (DIPS score ¼ 7
[þ1 þ 0 þ 0 þ 1 þ 1 þ 2 þ 0 þ 0 þ 1 þ 1]).
Clinical trials. In the first clinical trial to investigate the poten-
tial interaction between cranberry products and warfarin, Li
et al conducted a randomized, placebo-controlled, double-
blind, crossover study to evaluate the effects of cranberry
juice on the anticoagulant effect of warfarin.30 Seven patients
with atrial fibrillation, who had been stabilized on warfarin
565
therapy for at least 3 months, randomly consumed either
250 mL of cranberry juice or placebo daily for 1 week fol-
lowed by a 1-week washout period. After the washout period,
subjects then drank the other beverage for 1 week so that all
participants consumed either placebo or cranberry juice for a
total of 1 week each. During the study, patients were
instructed to continue their normal warfarin regimen and not
to change any of their dietary or exercise habits. INR values
did not differ between the 2 groups at baseline (2.28 þ 0.53
for the cranberry juice group and 2.16 þ 0.40 for the placebo
group), on day 7 (2.23 þ 0.53 for the cranberry juice group
and 2.16 þ 0.40 for the placebo group), or at any point dur-
ing the study. It was thereby concluded that the consumption
of 250 mL daily of cranberry juice does not adversely affect
INR levels in patients taking warfarin.
Next, in a randomized, crossover study, the effects of cran-
berry juice on the pharmacodynamics of warfarin and the phar-
macokinetics of racemic R-S warfarin, tizanidine, and
midazolam were examined.31 For 10 days, 10 healthy volun-
teers with a baseline INR of <1.3 ingested 200 mL of cranberry
juice (from concentrate) or water 3 times daily, except on day
5, when cranberry juice or water was ingested 4 times through-
out the day. Additionally, on day 5, a cocktail of 10 mg of race-
mic warfarin, 1 mg of tizanidine, and 0.5 mg of midazolam was
ingested simultaneously with the 200 mL of water or cranberry
juice. Results revealed that cranberry juice reduced the area
under the plasma concentration–time curve (AUC0-1) of
S-warfarin by 7% (P ¼ .051) and slightly shortened its elimina-
tion half-life (t½) from 40.3 hours (control phase) to 36.4 hours
(P < .05). It did not significantly increase the peak plasma con-
centration (Cmax), time to Cmax (tmax), AUC0-1, or t½ of R-S
warfarin, tizanidine, and midazolam. In addition, the INR did
not differ during the cranberry juice phase compared to the con-
trol phase. Based on these results, the authors determined that
cranberry juice does not significantly inhibit the in vivo activ-
ities of CYP2C9, CYP1A2, or CYP3A4 and does not alter the
pharmacodynamic effect of warfarin.
In another study, the impact of garlic and cranberry on the
pharmacokinetics and pharmacodynamics of warfarin was
assessed in an open-label, randomized, crossover clinical
trial.32 Twelve healthy males between the ages of 20 and
35 years were pretreated for 2 weeks with enteric-coated gar-
lic tablets (2000 mg of fresh garlic bulb), cranberry concen-
trate capsules (equal to 500 mg of cranberry juice concentrate
or 57 g of cranberry fruit equivalent), or nothing at all. After
the pretreatment phase, a single oral dose of 25-mg racemic
warfarin (5  5 mg Coumadin tablets) was administered to
each subject. Participants continued taking the cranberry cap-
sules and garlic tablets for 7 more days and then were subse-
quently crossed over to the other treatment group following a
2-week washout period. According to the results, there was
not a significant pharmacokinetic interaction, as the plasma
concentration and unbound fraction of R- and S-warfarin was
unaffected by the concomitant administration of cranberry
concentrate capsules. However, the cranberry capsules did
appear to enhance the pharmacodynamic effect of warfarin,
566
as the area under the INR–time curve ([AUCINR] before war-
farin administration versus INR maximum after warfarin
administration) increased by 30% when the capsules were
coadministered with warfarin when compared to warfarin
treatment alone. Garlic did not appear to have a significant
effect on the pharmacokinetics or pharmacodynamics of
warfarin.
This randomized, double-blind trial evaluated the effects
of cranberry juice on the pharmacokinetics and pharmacody-
namics of warfarin.33 Thirty patients who were already
receiving warfarin for various indications were randomly
assigned to receive either 8 oz of cranberry juice or a
matched placebo drink once daily for 2 weeks. Although
plasma concentrations for R-warfarin were found to be over-
all higher than those of S-warfarin, plasma levels of R- and
S-warfarin were not significantly different between the cran-
berry juice group and the placebo group at any point during
the study. Mean INR values were found to be similar
between the 2 study groups at all times during the study
except on treatment day 12, where the mean INR for the
cranberry juice group was found to be significantly higher
than placebo (t ¼ 2.79; P < .02). It should be noted that at
the next measurement point (24 hours later), the mean INR
levels for both groups were nearly the same. For unknown
reasons, 8 patients developed an INR >3.3 (4 in the cranberry
juice group and 4 in the placebo group) and 1 patient in the
cranberry juice group developed a minimally reduced INR.
The authors concluded that consuming 8 oz of cranberry
juice daily does not significantly affect the metabolism or
anticoagulant effect of warfarin.
In this prospective, open-labeled study, the effects of ‘‘high-
dose’’ cranberry juice on the pharmacodynamics of warfarin
were examined.34 Ten patients on chronic warfarin therapy
consumed 240 mL of cranberry juice twice daily for 7 days.
PTs and INR values were collected at baseline and on days
2, 6, and 8 of the study. The mean PTs from each study day
were then compared to the mean PT at baseline using repeated
measures analysis of variance. There was no statistical differ-
ence noticed between the mean PT at baseline or at any time
during the study, and it was concluded that a significant phar-
macodynamic interaction does not exist between high-dose
cranberry juice and warfarin.
In the most recent trial to date, a prospective, open-labeled,
in vitro/in vivo study was conducted to determine the potential
inhibitory effects of cranberry juice on the hepatic CYP2C9-
mediated metabolism of S-warfarin.35 Five different types of
cranberry juice, purchased from 5 different vendors located
in the United States, were first evaluated to determine their
inhibitory effects on CYP2C9 activity (S-warfarin 7-hydroxy-
lation) in human liver microsomes (HLM). Multiple bottles
of the cranberry juice found to be the most potent inhibitor
of CYP2C9 in HLM were then mixed together and converted
into a ‘‘double-strength’’ stock concentrate that was later used
in the clinical phase of the trial. During the clinical study, 16
healthy individuals (8 men and 8 nonpregnant women), aged
20 to 58 years, fasted overnight and then consumed 3 to
Journal of Pharmacy Practice 28(6)
240 mL glasses of water or double-strength cranberry juice in
15-minute intervals. A single dose of warfarin (Coumadin,
Bristol-Myers Squibb, Princeton, New Jersey) 10 mg was
administered with the third glass of cranberry juice. To prevent
1
over-anticoagulation, 10 mg of vitamin K (Mephyton ; Merck,
Whitehouse station, New Jersey) was administered concomi-
tantly with the dose of warfarin. According to the results, the
juice that inhibited warfarin’s metabolism in HLM had no
effect on the geometric mean AUC0-1 and terminal half-life
of S/R warfarin in healthy participants. It was thereby con-
cluded that cranberry juice does not significantly alter the
metabolism of warfarin in humans.
According to the clinical trials reviewed, there does not
appear to be a significant pharmacokinetic or pharma-
codynamic interaction between warfarin and cranberry juice.
Cranberry concentrate capsules, however, may increase antic-
oagulant effect of warfarin and cause a pharmacodynamic
interaction. Overall, the trials were limited by a relatively small
patient population. In the largest of these trials, 30 patients
were evaluated. In each of the other trials, less than 20 patients
were included. With such small sample sizes, it is difficult to
determine the significance of these studies. Another possible
limitation to the studies was the amount of cranberry juice uti-
lized. Larger quantities of cranberry juice, similar to those sus-
pected to interact with warfarin in the majority of documented
case reports, could have been used to determine whether this
potential drug–food interaction is dependent on the amount
of cranberry juice consumed. To better understand this poten-
tial interaction, clinical trials involving more subjects who con-
sume larger amounts of cranberry juice are needed.
Patient considerations. Although the majority of evidence from
clinical trial data suggests cranberry juice does not significantly
interact with warfarin, the possibility of an interaction still
needs to be taken into consideration. As discussed, most of the
published case reports involved patients drinking larger
amounts of cranberry juice than those used in clinical trials.
Therefore, it is possible that a warfarin–cranberry juice interac-
tion exists but is dependent upon the amount of fruit juice
ingested. For now, patients who take warfarin should be
advised to consume cranberry products in moderation. A prac-
tical approach may be to limit the quantity of cranberry juice to
less than 8 oz, no more than 2 times per day, which is consistent
with the amount of juice that failed to significantly alter the
antithrombotic effect of warfarin when studied. If abnormal
INR readings occur and are thought to be related to the inges-
tion of cranberry juice or a cranberry product, patients should
be instructed to reduce the amount they drink/eat or discontinue
consuming cranberry products altogether.
Grapefruit (Citrus paradisi)
Grapefruit juice has been reported to inhibit the metabolism
of several medications metabolized by the CYP pathway.36
It is speculated that the furanocoumarin, bergamottin, and the
Norwood et al
flavonoid, naringenin, are responsible for grapefruit’s CYP-
inhibiting properties. These 2 compounds usually demonstrate
a greater affinity for CYP isoforms located in the small intes-
tine as opposed to the liver and are believed to affect the
metabolism of several drugs that undergo first-pass metabo-
lism.37-39 Warfarin does not undergo significant first-pass
metabolism and is not thought to be affected by the actions
of bergamottin and naringenin under normal conditions. How-
ever, there is evidence to suggest that bergamottin and narin-
genin may inhibit both intestinal and hepatic CYP3A4 in an
exposure-dependent manner.40 Therefore, the metabolism of
warfarin could be potentially impaired by large amounts of
grapefruit juice.
Case reports. A male patient in his 60s was found to have an
INR of 6.29 after a year of being on warfarin therapy (50%
of his previous INR readings were within the target range of
2-3).41 According to the report, the patient had been drinking
nearly 50 oz (1479 mL) of grapefruit juice daily for 10 days
prior to the supratherapeutic INR result. The patient was
instructed to hold warfarin therapy for 2 days, discontinue
drinking grapefruit juice, and then resume his usual dose of
warfarin. The majority of his next 10 INR values were within
the target range of 2 to 3, with 3.24 reported as the highest INR
value during that time. No bleeding episodes were reported.
Because warfarin is metabolized by several CYP isoenzymes
and there is scientific evidence that grapefruit juice may impair
the CYP pathway, the likelihood of a drug–food interaction
was increased in this report. Based on the DIPS, it was prob-
able that a warfarin–grapefruit juice occurred in this patient.
(DIPS score ¼ 6 [þ0 þ 1 þ 1 þ 1 þ 1 þ 0 þ 0 þ 0 þ 1 þ 1]).
Clinical trials. To date, there has been only 1 clinical trial con-
ducted to evaluate the potential interaction between grapefruit
juice and warfarin.42 In this small open-label study, 9 men
between the ages of 55 and 75 years, stabilized on chronic war-
farin therapy, drank 8 oz (240 mL) of freshly prepared frozen
grapefruit juice (Smith’s Grapefruit Juice, Salt Lake City,
Utah) 3 times a day for 1 week to determine whether grapefruit
juice would affect their PTs. Compliance rates with drinking
the grapefruit juice ranged from 85.7% to 100%. There were
no significant changes in the PT or INR during the study and
it was concluded that the consumption of prepared, frozen
grapefruit juice did not change the PT in patients stabilized
on warfarin therapy.
Similar to most of the clinical trials that evaluated the effects
of cranberry juice on warfarin, this study was limited by the
small sample size and by the amount of fruit juice used. In the
case described by Bartle,41 the patient who experienced a
supratherapeutic INR due to a possible grapefruit juice–war-
farin interaction consumed a larger amount of juice over a lon-
ger period of time (50 oz daily for 10 days) compared to the
amount used in the study (24 oz daily for 1 week). Thus, it is
possible that a significant interaction between grapefruit juice
and warfarin may not occur when the fruit juice is consumed
in small to moderate amounts but can when ingested in excess.
567
In addition, the type of juice used could have also limited the
study. The investigators chose to use previously frozen grape-
fruit juice; it is unknown if the freezing process itself can affect
the stability of grapefruit juice’s CYP inhibiting compounds. It
is feasible that previously frozen and freshly prepared grape-
fruit juice can have differing effects on drug metabolism.
Patient considerations. As discussed, grapefruit juice is most
likely to affect those medications that undergo first-pass
metabolism. Drugs, such as warfarin, that have a relatively
high bioavailability and do not undergo significant first-
pass metabolism, are not expected to interact with grapefruit
juice. However, because increased amounts may potentially
affect warfarin’s metabolism, patients should be advised to
drink grapefruit juice in moderation. When studied by
Sullivan et al,42 8 oz of grapefruit juice ingested 3 times
daily was not shown to interact with warfarin, and patients
may want to limit their initial consumption to this amount.
If INR levels increase and a warfarin–grapefruit juice interac-
tion is suspected, then it may be necessary to reduce the
amount of grapefruit juice consumed and/or monitor the INR
more frequently. Patients should also be encouraged to con-
sistently drink the same brand of grapefruit juice, as the
amount and potency of furanocoumarins and flavonoids may
differ among brands and types of grapefruit juice.36
Mango (Mangifera indica)
A clear mechanistic explanation for the potential interaction
between warfarin and mango fruit has not yet been described;
however, it is speculated that vitamin A (retinol) may be
responsible. Mangos contain varying amounts of vitamin A
which may inhibit CYP2C19, an enzyme involved in the meta-
bolism of warfarin’s R-isomer.43,44 It has been suggested that
large doses of vitamin A can increase the anticoagulant effect
of warfarin.45
Case report. Thirteen male patients ranging from 56 to 85 years
of age experienced a 38% average increase in their INR from
baseline (P < .001) after eating approximately 1 to 6 mangos
daily, 2 days to 1 month prior to anticoagulation testing.46 Two
weeks after removing mango from their diet, there was a 17.7%
average decrease in their INR from the previous result. There
were no bleeding episodes reported, and each of the men
denied alcohol use or changes in their health, diet, or medica-
tion regimen. Two of the patients were rechallenged with the
same amount of mango that had previously consumed and their
INR levels subsequently increased. Two separate DIPS assess-
ments were completed for this case report. For the 2 patients
who were rechallenged with mango, it was determined that a
probable drug–food interaction occurred (DIPS score ¼ 6
[þ0 þ 0 þ 0 þ 1 þ 1 þ 2 þ 0 þ 0 þ 1 þ 1]). In the other
11 patients, use of the DIPS indicated a rating of possible
(DIPS score ¼ 4 [þ0 þ 0 þ 0 þ 1 þ 1 þ 0 þ 0 þ 0 þ 1 þ 1]).
568
Patient considerations. Unlike cranberry and grapefruit, mango
products have not yet been evaluated in clinical trials to
determine whether they interact with warfarin. Even so,
because several patients were documented as having an
increase in their INR results after eating mangos, including
2 patients who were rechallenged, clinicians may want to
inquire about mango consumption as part of the dietary his-
tory in areas where the fruit is popular and in those who
experience elevated INR results for unknown reasons. If a
mango–warfarin interaction is suspected, then the amount
of fruit consumed should be reduced.
Pomegranate (Punica granatum)
Pomegranate juice is one of the more recently purported fruit
products to interact with warfarin. Although the mechanism for
this potential interaction is unknown, it has been suggested that
pomegranate juice may interfere with the metabolism of war-
farin by inhibiting CYP3A4 and/or CYP2C9.47,48
Case reports. Since 2009, 2 cases of a pomegranate juice–war-
farin interaction have been published. In the first case, it is
speculated that a drug–food interaction occurred in a 64-
year-old woman previously stabilized on warfarin, whose INR
decreased from 2.2 to 1.7 after she stopped drinking pomegra-
nate juice.49 Although her INR values appeared to normalize
after her warfarin dose was increased, the author noted that
the patient continued to have subtherapeutic INR values,
despite the initial dose uptitration, and further dose adjustments
were required to maintain therapeutic INR levels. The possibil-
ity of a warfarin–pomegranate juice interaction was weakened
in this case due to the need of continued warfarin adjustments
after the patient stopped drinking the fruit juice. This suggests
other factors, besides the cessation of pomegranate juice, may
have been responsible for the original subtherapeutic INR.
According to the DIPS, it is doubtful that a drug–food interac-
tion occurred in this case (DIPS score ¼ 1 [þ0 þ 0 þ 0 þ 1 þ 1
þ 0  1 þ 0 þ 1  1]).
The second report described a 37-year-old female on
chronic warfarin therapy, who was hospitalized with a
supratherapeutic INR of 14 and large intramuscular hematoma
after drinking 3 L of pomegranate juice over the previous
week.50 She was advised to drink pomegranate juice in modera-
tion and her INR eventually stabilized. It should be noted that
14 months prior to this event, the same patient experienced a
similar occurrence (supratherapeutic INR of 14 and large intra-
muscular hematoma) after drinking cranberry juice. Using the
DIPS, it was determined that a possible interaction between
pomegranate juice and warfarin occurred in this patient (DIPS
score ¼ 3 [þ0 þ 0 þ 0 þ 1 þ 1 þ 0  1 þ 0 þ 1 þ 1]).
Patient considerations. Although 2 cases of a warfarin–pomegra-
nate juice interaction have been documented, other variables
were present in each of these reports that may have contributed
to the abnormal INR results. To properly assess this potential
interaction, the effect pomegranate juice may have on the
Journal of Pharmacy Practice 28(6)
pharmacokinetics and pharmacodynamics of warfarin must
be evaluated in a controlled clinical trial. For now, it does not
appear necessary to advise patients to limit their consumption
of pomegranate juice. However, because pomegranate juice
may contain flavonoids and some other CYP-inhibiting com-
pounds similar in nature to those found in grapefruits, providers
may want to ask about recent consumption in patients who
experience fluctuations in their INR without any other known
causes.51 Patients known to drink large quantities of pomegra-
nate juice should be encouraged to reduce their intake if a
drug–food interaction is suspected.
Papaya (Carica papaya)
The fruit of the papaya tree has not been reported to interact
with warfarin. However, there has been one published case of
a possible interaction between warfarin and papain, which is
a mixture of proteolytic enzymes found in the papaya fruit.
Case report. A male patient, stabilized on warfarin, was admit-
ted to the hospital prior to cardiac surgery and was found to
have a supratherapeutic INR of 7.4. He was reportedly using
papaya extract, which contained papain as a weight loss
agent.52 After temporarily holding warfarin and discontinuing
the papaya extract, the patient’s INR decreased to <2 and he
was able to undergo surgery. No further details were provided.
A lack of general information weakened the evidence in this
report. Based on the DIPS, it is doubtful that a drug–fruit inter-
action occurred in this case (DIPS score ¼ 1 [þ0 þ 0 þ 0 þ 0 þ
0 þ 0 þ 0 þ 0 þ 1 þ 0]).
Patient considerations. Although an interaction between papain
and warfarin has been documented, evidence of a warfarin–
papaya fruit interaction is nonexistent. Therefore, it is not
necessary to advise patients taking warfarin to limit their con-
sumption of papaya fruit. As a precaution, however, clinicians
may want to encourage patients taking warfarin to eat the fruit
when it is ripe. Unripe papaya may contain concentrated levels
of papain, which has been reported to lead to gastrointestinal
mucus membrane damage and bleeding.53,54
Avocado (Persea americana)
The consumption of avocado fruit has been reported to
decrease the INR in 2 patients. Although clinical trial evidence
is lacking, avocados are known to contain vitamin K and may
interact with warfarin by reducing its antithrombotic effect.
Avocados typically contain relatively small to moderate
amounts of vitamin K (21 mg of vitamin K per 100 g of avo-
cado) compared to other vitamin K enriched foods (eg, raw spi-
nach ¼ 482.9 mg of vitamin K per 100 g). However, eating
large quantities of the fruit could result in significant vitamin
K ingestion potentially resulting in decreased INR results.55,56
Case reports. The first report describes a 15-year-old female
with antiphospholipid syndrome who was receiving warfarin
Norwood et al
for a parietooccipital brain infarct.57 Her INR was well con-
trolled for the first 6 weeks of therapy but then suddenly
decreased from 2.5 to 1.7. The patient was taking the same dose
of warfarin and denied any medication changes or recent ill-
nesses. During this time, she admitted to eating almost 100 g
of avocado daily. She was advised to discontinue eating avo-
cado and her INR returned to 2.5. Three months later, despite
counseling, the patient again started eating avocado and her
INR dropped to 1.7. Afterward, she completely eliminated avo-
cado from her diet and her INR stabilized. It is well understood
that foods containing vitamin K may potentially decrease the
anticoagulant effect of warfarin. In addition, the likelihood of
an interaction was increased in this case because the patient’s
INR decreased in 2 separate occasions after eating avocado
fruit. Therefore, using the DIPS, it was determined that a prob-
able drug–food interaction occurred in this patient (DIPS
score ¼ 8 [þ0 þ 1 þ 1 þ 1 þ 1 þ 2 þ 0 þ 0 þ 1 þ 1]).
The second report involves a 30-year-old female in her 22nd
gestational week of her 6th pregnancy, who was anticoagulated
with heparin followed by warfarin due to a pulmonary embo-
lism.57 For 2 months, she was adequately anticoagulated with
an average INR of 2.7. After eating nearly 200 g of avocado
on 2 consecutive evenings, her INR decreased to 1.6. She later
eliminated avocado from her diet and was able to maintain
therapeutic INR levels. Similar to the other case involving avo-
cado, the consumption of a vitamin K-containing food strength-
ened the possibility of an interaction in this report. Based on the
DIPS, an interaction between avocado and warfarin was prob-
able in this case as well (DIPS score ¼ 6 [þ0 þ 1 þ 1 þ 1 þ 1
þ 0 þ 0 þ 0 þ 1 þ 1]).
Patient considerations. In general, patients taking warfarin should
be encouraged to eat vitamin K enriched foods in moderation
and to eat a consistent amount of these foods from week to
week to avoid changes in the intensity of their anticoagulation
therapy. Clinicians may want to ask about the recent consump-
tion of avocado when obtaining a dietary history or when asses-
sing reasons for subtherapeutic INR results. Also, patients
should be discouraged from eating large amounts of avocado-
based products, such as guacamole, as vitamin K ingestion can
be significantly higher with these foods.56
Limitations of the Literature
Interpreting the literature to determine which fruits may cause a
significant interaction with warfarin is a challenge. Individual
case reports currently makeup the bulk of evidence. Although
they can be helpful in informing clinicians of potential occur-
rences, case reports in general are subjective and usually do not
contain enough information to establish a causative relation-
ship between a proposed interaction and outcome. In addition,
they are often confounded by variables which, therefore, limit
their usefulness. This was found to be true as well for the cases
reviewed in this article. The majority of reports contained very
little patient-specific information leading up to the incidents
and were usually influenced by other factors (eg, concurrent
569
use of over the counter products and/or alternative medicines,
existing infections, and poor dietary habits) that may have been
partially, if not fully, responsible for the outcomes. In one case,
the patient even ingested an extra dose of warfarin prior to
being tested which would have obviously contributed to the
abnormal INR result. Understanding the literature is further
complicated by the paucity of adequate clinical trial data. Most
of the studies included a small patient population (participants
< 20) and used amounts of fruit juice that was less than that pur-
ported to interact with warfarin in case reports. In addition,
only 3 fruit products (cranberry juice, cranberry concentrate,
and grapefruit juice) have been studied with warfarin in a clin-
ical setting. Larger studies that use a variety of fruits, at varying
amounts, are needed to offer a clearer understanding of poten-
tial warfarin-fruit interactions.
Conclusion
In summary, there have been a number of case reports pub-
lished that suggest warfarin has the potential to interact with
several fruit products, including cranberry juice and sauce,
grapefruit juice, mangos, pomegranate juice, avocados, and
papain (an enzyme found in the papaya fruit). It is difficult to
determine the relevance of these reports, however, as scientific
evidence is scarce. Thus far, only cranberry juice, cranberry
concentrate, and grapefruit juice have been evaluated in a few
human clinical trials to determine if they interact with warfarin.
Unfortunately, the majority of these studies have been limited
by small patient populations and the quantity of fruit juice used,
which has been considerably less than that reported to interact
with warfarin in case reports. To better ascertain potential
warfarin-fruit interactions, more randomized controlled studies
involving a greater number of patients, a wider variety of fruits,
and larger amounts of fruit product are warranted. Until further
information is available, clinicians may want to encourage
patients to consume cranberry products and grapefruit juice
in small to moderate quantities and to inquire about the recent
consumption of mangos, pomegranate juice, and avocados
when taking a dietary history or when assessing possible causes
for INR instability.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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