Effect of gefitinib on warfarin antithrombotic activity.
BACKGROUND
Despite the literature indicating adverse interactions between warfarin and cytotoxic agents, whether such an interaction occurs when warfarin and gefitinib are used concomitantly is unknown. We analyzed the prevalence of the concomitant use of warfarin and gefitinib, and the incidence of prothrombin time-international normalized ratio (PT-INR) alterations or adverse interactions in concomitant users of warfarin and gefitinib.


METHODS
We conducted a retrospective study of patients with non-small cell lung cancer treated at the Kitasato University Hospital who received concomitant warfarin and gefitinib between September 2002 and January 2007. Medical information, including the indication for warfarin use, warfarin dosing and dosing changes, and exposure to gefitinib were collected from computerized databases and medical records.


RESULTS
Twelve (4.1%) of 296 patients treated with gefitinib received warfarin. PT-INR elevation occurred in 6 patients (50.0%). Two (16.7%) of the 12 patients had liver metastases. Liver dysfunction was associated with PT-INR elevation (P = 0.0100).


CONCLUSIONS
As there is a possibility of PT-INR abnormalities occurring during the concomitant use of gefitinib and warfarin, clinicians should be aware of this interaction. Because of the potentially severe consequences of this interaction, close monitoring of PT-INR and warfarin dose adjustment are recommended for patients receiving warfarin and gefitinib, especially during the first 2 weeks in the beginning of warfarin therapy.
Arai
Susumu
S
Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, Japan.
Mitsufuji
Hisashi
H
Nishii
Yasuto
Y
Onoda
Sayaka
S
Ryuge
Shinichiro
S
Wada
Mayuko
M
Katono
Ken
K
Iwasaki
Maiko
M
Takakura
Akira
A
Otani
Sakiko
S
Yamamoto
Michiko
M
Yanaihara
Tomoko
T
Yokoba
Masanori
M
Kubota
Masaru
M
Katagiri
Masato
M
Fukui
Tomoya
T
Kobayashi
Hirosuke
H
Yanase
Nobuo
N
Hataishi
Ryuji
R
Masuda
Noriyuki
N
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001777:Blood Coagulation / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D004347:Drug Interactions; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019934:International Normalized Ratio; D008113:Liver Neoplasms / Q000097:blood / Q000556:secondary; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011517:Prothrombin Time; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D013997:Time Factors; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014859:Warfarin; D000077156:Gefitinib
Drugs. 1983 Jun;25(6):610-20
6347619
Cancer. 2006 Sep 15;107(6):1207-18
16909423
Ann Pharmacother. 1994 Apr;28(4):464-7
8038468
J Clin Oncol. 2003 Jun 15;21(12):2237-46
12748244
Invest New Drugs. 2006 Jul;24(4):291-7
16502356
Clin Cancer Res. 2004 Feb 15;10(4):1212-8
14977817
Thromb Haemost. 2002 Apr;87(4):575-9
12008937
Ann Pharmacother. 1997 Sep;31(9):1006-8
9296241
Pharmacotherapy. 1998 Jan-Feb;18(1):84-112
9469685
Postgrad Med J. 1990 Oct;66(780):860-1
2129174
Drugs Today (Barc). 2006 May;42(5):331-50
16801996
Jpn J Clin Oncol. 2005 Aug;35(8):478-82
16006576
JAMA. 2003 Oct 22;290(16):2149-58
14570950
Pharmacotherapy. 1997 Sep-Oct;17(5):917-28
9324181
Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37
16257339
J Clin Invest. 1963 Oct;42:1542-51
14074349
Chemotherapy. 1999 Sep-Oct;45(5):392-5
10473927