Interaction between Capecitabine and Gemcitabine

Muhammad Wasif Saif, Nawal Wasif
Yale Cancer Center, Yale University School of Medicine. New Haven, CT, USA
Summary
Gemcitabine is the only chemotherapeutic
agent approved by the U.S. Food and Drug
Administration (FDA) for the treatment of
advanced pancreatic cancer. 5-fluorouracil or
its oral pro-drug, capecitabine is the second
most commonly used agent in this
malignancy. Capecitabine or 5-fluorouracil is
the second most common agent used either in
second-line or as a radiosensitizer.
Thromboembolism requiring anticoagulation
is a common paraneoplastic complication in
these patients. We report a patient with
pancreatic cancer, challenged with
maintaining the international normalized ratio
(INR)
with
gemcitabine-capecitabine
combination, and later with gemcitabine
monotherapy with concomitant warfarin, as
well as, a brief review of the literature.
Patients with pancreatic cancer who receive
warfarin and gemcitabine should be
monitored for any potential drug interactions.
Frequent prothrombin time and INR
evaluations are suggested for anticoagulated
patients receiving gemcitabine, especially
when combined with capecitabine.
Dear Sir:
Gemcitabine is the only chemotherapeutic
agent approved by the U.S. Food and Drug
Administration (FDA) for the treatment of
patients with pancreatic cancer [1]. It is also
indicated for use in non-small-cell lung
cancer, bladder cancer, and is commonly used
in other gastrointestinal malignancies.
Patients with cancer, specifically pancreatic
carcinoma, are at increased risk for
thrombosis requiring anticoagulation. In
addition, due to aging and common risk
factors, cardiac ailments such as atrial
fibrillation are also common in this group. In
such cases, warfarin is generally the agent of
choice.
In 1999, a potential interaction between
gemcitabine and warfarin was reported [2]. In
2002, the manufacturer of gemcitabine, Eli
Lilly, reported four similar cases, indicating
an incidence of 0.04% suspected drug
interaction between gemcitabine and an
anticoagulant [3]. They also reported that
overall 5.4% of patients undergoing
gemcitabine therapy received concomitant
anticoagulants [3] Moreover, the U.S. Food
and Drug Administration and Roche have
added a "Black Box" warning and
strengthened the "Precautions" section on the
label of capecitabine, which is indicated for
the treatment of colorectal and breast cancer
[4, 5]. We present the seventh case of a
patient with pancreatic cancer complicated by
an elevated INR following treatment with
concomitant
gemcitabine-capecitabine-
warfarin first and then gemcitabine-warfarin
later.
Case Report
A 70-year-old female with a past medical
history of atrial fibrillation who reports being

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740
in her usual state of health until May of 2006
when she presented with history of fatigue,
nausea, darkening of her urine, anorexia, and
occasional diarrhea. She subsequently
developed jaundice and underwent an
abdominal ultrasound which revealed stones
and sludge filling the gallbladder, dilated
intrahepatic ducts and a 15 mm dilated
common bile duct without evidence of stone.
The pancreatic duct was dilated to nearly 1
cm in diameter. A CT scan failed to reveal
any definite pancreatic mass, and MRI also
did not reveal a discreet mass although an
"abrupt truncation of the pancreatic and
common bile ducts" suggesting a mass. An
MRCP failed to identify any stones within the
dilated duct system. Finally, she underwent
endoscopic ultrasound which revealed a
20x17 mm intrapancreatic mass was seen
obstructing the distal bile duct and pancreatic
duct, abutting the portal vein and superior
mesenteric vein over a 12 mm length with the
loss of the echo plane. No liver masses were
noted and a fine needle aspirate was
performed with pathology revealing
malignant cells consistent with pancreatic
adenocarcinoma. Subsequently, she under-
went ERCP at which time a metallic stent was
deployed in the common bile duct.
Her medical history was notable for atrial
fibrillation for which she was taking warfarin
at a weekly dose of 7.5 mg and 5 mg. Her
international normalized ratio (INR) was
stable at 1.94.
She came to the Yale Cancer Center and was
started on GTX (gemcitabine, taxotere, and
xeloda) regimen. However, her treatment
required cessation of capecitabine related to
elevation of INR as shown in Table 1.
Gemcitabine and docetaxol were continued
but maintaining the INR in the required range
remained a challenge as shown in the Table 1.
Docetaxol was also discontinued after cycle 9
due to edema and fatigue. Gemcitabine was
continued every 2 weeks with close
monitoring of PT/INR suggesting an
interaction between the two agents. Patient
continued gemcitabine till February 2008
when CT scan showed progressive disease
evidenced by development of new ascites and
findings consistent with carcinomatosis. In
addition an implant on the gallbladder fundus
was also noticed. Patient was offered second-
line chemotherapy but was not administered
due to clinical deterioration.
Discussion
Gemcitabine is licensed for use in pancreatic
cancer, and is also used for other
gastrointestinal malignancies, as well as for
bladder cancer, breast cancer, and non-small-
cell lung cancer. Patients with cancer,
specifically pancreatic carcinoma, are more
prone to develop thrombosis. Such patients
have long periods of immobility, often poor
appetite, and experience nausea and vomiting
with a subsequent decrease in vitamin K
while receiving chemotherapy. As a
consequence, the prothrombin time increases
Table 1. Association between capecitabine and
gemcitabine with increase in PT/INR.
Date
Regimen PT (sec)
/INR
ALT/AST
(U/L)
September 11th, 2006 GTX 23.2/2.5
33/18
October 1st, 2006
GTX 52.1/6.0
27/19
November 1st, 2006
GT
19.9/2.1
22/16
December 7th, 2006
GT
19.9/2.1
23/16
December 27th, 2006
GT
25.6/2.8
27/13
January 10th, 2007
GT
25.1/2.7
38/20
January 30th, 2007
GT
13.7/1.4
24/15
February 20th, 2007
GT
25.9/2.8
34/14
March 7th, 2007
GT
54.8/6.3
26/23
April 6th, 2007
G
28.8/3.2
28/12
April 21st, 2007
G
32.4/3.6
27/16
May 6th, 2007
G
28.0/3.1
20/15
June 3rd, 2007
G
25.4/2.8
21/11
July 2nd, 2007
G
19.0/2.0
19/12
July 30th, 2007
G
15.6/1.4 22/414
August 3rd, 2007
G
23.0/2.5
21/16
September 17th, 2007
G
24.5/2.7
25/14
October 15th, 2007
G
34.4/1.5
26/23
November 9th, 2007
G
18.0/1.8
22/12
November 27th, 2007
G
26.0/2.7
53/26
December 7th, 2007
G
26.2/4.8
21/13
January 7th, 2008
G
38.6/4.1
21/9
February 4th, 2008
G
20.8/3.0
22/12
February 12th, 2008
G
18.9/2.5
20/8
Reference ranges: PT, 0-14.0 sec; INR, 0.9-1.4; ALT,
0-37 U/L; AST, 0-37 U/L
Standard desired range of INR for patients with atrial
fibrillation: 2.0-3.0
GTX: gemcitabine + taxotere + capecitabine
GT: gemcitabine + taxotere
G: gemcitabine

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741
and the effect of warfarin increases. Despite
these factors, the suspected interaction has
been rarely reported.
In this patient, an interaction between
warfarin and gemcitabine-capecitabine and
then with gemcitabine monotherapy resulted
in an elevated INR and a drop in hematocrit
requiring upper and lower endoscopy.
However, no evidence of gastrointestinal
bleeding was found.
After the publication of the first case report in
1999 [2], the Eli Lilly safety database was
searched for any information reported up to
December 31
st
, 2000, regarding interactions
between gemcitabine and anticoagulants. This
search included published literature,
spontaneous reports, and serious reports from
clinical trials involving gemcitabine. The
results used to determine if the safety concern
was justified. Six cases of a suspected
interaction between gemcitabine and
anticoagulants were found. Four cases
reported a suspected interaction with warfarin,
one with phenprocoumon, and one with
heparin [3]. The latter patient experienced
palpitations but no bleeding. The Eli Lilly
safety database showed a total of 13,496
reported adverse events for gemcitabine
during that period among an estimated
426,000 patients treated with the drug since
its initial licensing. Seven hundred twenty-
four patients taking gemcitabine were
receiving concomitant anticoagulants as well,
showing a proportion of 5.4% (724/13,496).
The identified cases that reported a suspected
drug interaction accounted for an incidence of
0.8% (6/724) [3]. This proportion is much
higher than the number of patients in whom a
suspected drug interaction between
gemcitabine and an anticoagulant was
reported (0.04%; 6/13,496).
Warfarin is the most commonly used oral
anticoagulant for long-term anticoagulation
for a variety of conditions, including atrial
fibrillation, deep venous thrombosis, and
venous line patency. With rapid absorption by
the gastrointestinal tract, warfarin is
metabolized by the cytochrome P450 (CYP)
enzyme system in the liver [4]. It is
administered as a racemic mixture of both the
S and R enantiomers. The more potent S
enantiomer has a short half-life and is
metabolized mainly by CYP2C9. The R
enantiomer has a longer half life and is
metabolized by CYP1A2, CYP3A4, and other
isoenzymes. The drug is highly protein bound
(99%).
Pharmacokinetic and pharmacodynamic
factors influence maintenance of anti-
coagulation and occurrence of toxicity.
Gemcitabine is a deoxycytidine analog similar
to the pyrimidine antimetabolite cytarabine,
with activity against solid tumors [5]. The
pharmacokinetics of gemcitabine are different
from warfarin. Gemcitabine enters cells by
the facilitated nucleoside transport
mechanism and undergoes phosphorylation in
a stepwise fashion by the enzyme dC kinase,
first to the 5l-monophosphate form (dFdCMP)
by deoxycytidine kinase (dCK). The drug is
subsequently phosphorylated by nucleotide
monophosphate kinase and nucleotide
diphosphate kinase to the 5l-diphosphate
(dFdCDP) and 5l-triphosphate derivatives
(dFdCTP), respectively. dFdCDP is an
inhibitor of ribonucleotide reductase, resulting
in decreases in the four physiologic
deoxyribonucleotide triphosphates: dATP,
dCTP, dGTP, and dTTP. dFdCTP is
incorporated into DNA by DNA polymerase
and results in inhibition of DNA synthesis.
The cytotoxicity of this compound is related
to the di- and tri-phosphate forms [6]. When
administered as a 30-minute infusion, the
plasma half-life of gemcitabine ranges from
32 to 94 minutes. The intracellular half-life of
the tri-phosphate metabolite ranges from 1.7
to19.4 hours. Based on the above description,
a pharmacokinetic interaction between
warfarin and gemcitabine appears unlikely.
Our patient’s warfarin dose and INRs were
stable both before and after she received
gemcitabine. Neither changes in diet nor any
severe episodes of vomiting were observed in
this patient. She did not start or discontinue
any drugs during chemotherapy that could
have had an interaction with gemcitabine.
Gemcitabine can cause reversible elevations
in hepatic transaminases in more than 50% of
patients, as happened in our patient [7]. The

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JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 9, No. 6 - November 2008. [ISSN 1590-8577]
742
exact mechanism underlying liver dysfunction
is not known but is probably related to
cytotoxicity to hepatic cells. It is possible that
the decreased warfarin requirement during
gemcitabine therapy might be due to
gemcitabine either by:
1) decreasing the metabolic function of the
CYP enzymes, resulting in decreased
warfarin metabolism, or
2) decreased synthesis of clotting factors,
resulting in reduced warfarin requirements.
The exact mechanism of this interaction is
still not clear.
Fluoropyrimidines, including intravenous 5-
FU and capecitabine have been reported to
cause clinically significant increase in partial
thromboplastin time (PTT) and INR in
patients on concomitant use with
anticoagulants [8, 9]. These alterations in
coagulation parameters occurred within
several days and for as long several months
after initiation of capecitabine or 5-FU
therapy and, in a few cases, within a month
after stopping capecitabine or 5-FU therapy.
These events occurred in patients with and
without liver metastases. The inhibition of
hepatic metabolism of warfarin by 5-FU was
postulated to explain this drug interaction, but
the true mechanism and how to monitor it
remain under investigation [8, 9]. The U.S.
Food and Drug Administration and Roche
have added a "Black Box" warning and
strengthened the "Precautions" section on the
label of capecitabine, which is indicated for
the treatment of colorectal and breast cancer
[8, 9]. Patients should have their
anticoagulant response (INR or PTT)
monitored frequently in order to adjust the
anticoagulant dose accordingly.
However, despite the lack of data supporting
the interaction between anticoagulants and
gemcitabine, we still believe that it is
important to be aware of the possible
interaction between warfarin and gemcitabine
that could manifest as a rise in INR. Such an
interaction may require a weekly monitoring
of INR and a reduction in warfarin dose
accordingly.
This issue gains more significance when a
combination chemotherapy regimen, such as
GTX is administered in a patient already
anticoagulated with warfarin, akin to our
patient. Fine et al. retrospectively studied 35
patients who received GTX and showed grade
3-4 leukopenia in 14%, thrombocytopenia in
14%, and anemia in 9% [10]. However, no
data regarding interaction with anticoagulants
were given, probably due to the small sample
size.
Interestingly, some investigators evaluated the
effects of low-dose warfarin and regional
chemotherapy on survival in patients with
pancreatic carcinoma [11]. A retrospective
analysis was performed on 180 patients with
pancreatic carcinoma. Patients received one
of seven regimens of chemotherapy.
Unrelated to the type of chemotherapy, some
patients received 1.25 mg warfarin daily. The
primary end-point was median survival. The
results showed that treatment with warfarin
resulted in improved median survival from
the start of regional therapy (warfarin versus
no warfarin: 5.0 versus 2.3 months; 111
versus 69 patients; P<0.0001). This effect was
not dependent on the type of chemotherapy
used. Among the seven regimens examined,
the one consisting of regional gemcitabine
and mitomycin-C with systemic gemcitabine
was associated with the longest median
survival of 5.1 months from the start of
regional therapy (P=0.006) and 12.7 months
from diagnosis. This regimen combined with
warfarin was associated with improved
median survival (7.1 months; 32 patients).
However, no such data exist based on a
prospective randomized study.
It is also important to bear in mind that
acetaminophen is an underrecognized cause
of overanticoagulation in the outpatient
setting [12]. Increased monitoring of INR
values when such risk factors are present or
modification of the risk factors themselves
should reduce the frequency of dangerously
high levels of anticoagulation.
Conclusion
In oncology clinics, INR is typically
measured every 1 to 3 months in patients on
chronic
anticoagulation
receiving
chemotherapy, reducing the likelihood of

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743
identifying a drug interaction before an
adverse event. In addition, more frequent
monitoring of liver function is advised, as it
may identify interactions earlier and help
decrease the likelihood of adverse reactions
associated with an elevated INR. This is an
important issue as gemcitabine is indicated
for pancreatic and breast cancers, the risk of
which increased with age. Moreover, atrial
fibrillation is also associated with increased
age. As the average age of the population
continues to increase, we expect to see more
concomitant use of gemcitabine and warfarin
in the future.
Received July 25
th
, 2008 - Accepted
September 24
th
, 2008
Keywords
capecitabine; gemcitabine;
Hemorrhage; Pancreatic Neoplasms; Warfarin
Abbreviations CYP: cytochrome P450; G:
gemcitabine; GT: gemcitabine + taxotere;
GTX: gemcitabine + taxotere + capecitabine;
INR: international normalized ratio
Conflict of interest The authors have no
potential conflict of interest
Correspondence
Muhammad Wasif Saif
Division of Medical Oncology
333 Cedar Street, FMP 116
New Haven, CT 06520
USA
 
References
1. Burris HA 3rd, Moore MJ, Andersen J, Green MR,
Rothenberg ML, Modiano MR, et al. Improvements in
survival and clinical benefit with gemcitabine as first-
line therapy for patients with advanced pancreas
cancer: a randomized trial. J Clin Oncol 1997;
15:2403-13. [PMID 9196156]
2. Kinikar SA, Kolesar JM. Identification of a
gemcitabine-warfarin interaction. Pharmacotherapy
1999; 9:1331-3. [PMID 10555940]
3. Kilgour-Christie J, Czarnecki A. Gemcitabine and
the interaction with anticoagulants. Lancet Oncol 2002;
3:460. [PMID 12147431]
4. Holford NHG. Clinical pharmacokinetics and
pharmacodynamics of warfarin. Understanding the
dose-effect relationship. Clin Pharmacokinet 1986;
11:483-504. [PMID 3542339]
5. Hui YF, Reitz J. Gemcitabine: a cytidine analogue
active against solid tumors. Am J Health Syst Pharm
1997; 54:162-70. [PMID 9117804]
6. Gandhi V, Plunkett W, Du M, Ayres M, Estey EH.
Prolonged infusion of gemcitabine: clinical and
pharmacodynamic studies during a phase I trial in
relapsed acute myelogenous leukemia. J Clin Oncol
2002; 20:665-73. [PMID 11821446]
7. Sessa C, Aamdal S, Wolff I, Eppelbaum R, Smyth
JF, Sulkes A, et al. Gemcitabine in patients with
advancedmalignant melanoma or gastric cancer: Phase
II studies of the EORTC EarlyClinical Trials group.
Ann Oncol 1994; 5:471-2. [PMID 8075055]
8. Shah HR, Ledbetter L, Diasio R, Saif MW. A
retrospective study of coagulation abnormalities in
patients receiving concomitant capecitabine and
warfarin. Clin Colorectal Cancer 2006; 5:354-8.
[PMID 16512995]
9. Saif MW. An adverse interaction between warfarin
and fluoropyrimidines revisited. Clin Colorectal
Cancer 2005; 5:175-80. [PMID 16197620]
10. Fine RL, Fogelman DR, Schreibman SM, Desai M,
Sherman W, Strauss J, et al. The gemcitabine,
docetaxel, and capecitabine (GTX) regimen for
metastatic pancreatic cancer: a retrospective analysis.
Cancer Chemother Pharmacol 2008; 61:167-75. [PMID
17440727]
11. Nakchbandi W, Müller H, Singer MV, Löhr M,
Nakchbandi IA. Effects of low-dose warfarin and
regional chemotherapy on survival in patients with
pancreatic carcinoma. Scand J Gastroenterol 2006;
41:1095-104. [PMID 16938724]
12. Hylek EM, Heiman H, Skates SJ, Sheehan MA,
Singer DE. Acetaminophen and other risk factors for
excessive warfarin anticoagulation. JAMA 1998;
279:657-62. [PMID 949698

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