| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the 1Department of Obstetrics & Gynecology, Kelsey-Seybold Clinic, Houston, Texas.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Women on warfarin therapy for 6 months or more with no change in dose within 4 weeks of the study, and a prothrombin time (PT) with an International Normalized Ratio (INR) between 2 and 3 were invited to participate. Two consecutive baseline PTs were obtained (days –1 and 0), and women were given 150 mg of fluconazole. Prothrombin times were measured on days 2, 5, and 8 of the study. The change in PT was calculated from the difference between the baseline PT on day 0 and the PT during the study period. To detect a 10% difference in a PT (approximately 2.1 seconds) of a patient with an INR of 2.0, at P < .05 and a power of 90%, 5 subjects are required.
RESULTS: Six women participated. The mean (± standard deviation) PT for day 0 was 27.7 ± 4.1 seconds or INR 2.6 ± 0.4. The PT increased 11% at day 2, 34% at day 5, and 2% at day 8; these differences were not statistically significant. However, one half of the women had either a clinically relevant increase of the INR greater than 4, or bleeding that required their dosage of warfarin to be decreased.
CONCLUSION: A single 150-mg oral dose of fluconazole may increase the PT to a clinically relevant level in a woman on chronic warfarin therapy. Clinicians should monitor the PT carefully after a single dose of fluconazole.
LEVEL OF EVIDENCE: II-2
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Eligible women who agreed to participate had baseline measurements of serum creatinine, alanine aminotransferase, and aspartate aminotransferase. Two consecutive baseline PTs were obtained (days –1 and 0). After measuring the subject’s PT, she was given a single 150-mg oral dose of fluconazole on day 0. Prothrombin times were measured after the administration of fluconazole on days 2, 5, and 8 of the study. The maximum change in PT was calculated from the difference between the mean baseline PT on day 0 and the mean PT during the study period (days 2, 5, and 8) after administration of the fluconazole.
Prothrombin time measurements were performed by LabCorp (Laboratory Corporation of America, Dallas, TX). LabCorp hematology division reports a mean PT for an INR of 2.0 equals 20.8 seconds. The standard deviation for the PT assay is 5% or less or 1.0 seconds. To detect a 10% difference in a PT (approximately 2.1 seconds) in a patient with an INR of 2.0, at P < .05 and a power of 90% would require a sample size of 5 subjects. Repeated measures analysis of variance was used to compare the mean PT before and after fluconazole administration. If an increase of a subject’s PT required modification of her dosage of warfarin, any subsequent measurements of the PT were not used for the statistical calculations. A P of .05 was considered significant. Analysis was performed using True Epistat 5.3 (Epistat Services, Richardson, TX).
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The means of the baseline PTs for days –1 and 0 were 27.5 ± 4.3 and 27.7 ± 4.1 seconds, respectively, or INR 2.6 ± 0.4. Compared with day 0, the mean PT increased 11% at day 2, 34% at day 5, and 2% at day 8 after administration of fluconazole; these differences were not statistically significant, P = .30 (Table 1). However, one half of the women (n = 3) had either a clinically relevant increase of the INR (INR > 4) or bleeding that required their dosage of warfarin to be decreased or held for 24 to 48 hours. Two participants (subjects 5 and 6) had their INR increase to 4.6 on day 2 and 5.2 on day 5 after fluconazole administration, respectively. One woman (subject 4) on day 6 developed a subconjunctival hemorrhage; her PT was 33.3 seconds and INR was 3.4. She denied any trauma or physical straining. No other subjects experienced any episodes of hemorrhage.
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The pharmacokinetics of a single 150-mg oral dose of fluconazole indicate that peak plasma concentrations occur 2 hours after ingestion, with the maximal plasma concentration reaching only one half the in vivo level reported to cause inhibition of liver cytochrome P450 enzymes involved in the degradation of warfarin.16,17 With the half-life of fluconazole being 30 hours, a single oral 150-mg dose theoretically should have no clinical effect on the prothrombin time of individuals taking warfarin.16 Based on the study cited by the manufacturer, one could infer that the careful monitoring advocated is for a multiple dose strategy.13 The manufacturer’s recommendations are derived from a study of 13 males. In this study, the dynamics of the anticoagulant response to a single dose of warfarin rather than the kinetics of the compound itself were evaluated.4 Male subjects were given 200 mg of fluconazole daily for 7 days and then received a single 15-mg dose of warfarin. Daily dosing with fluconazole was continued for 7 additional days while the prothrombin time was monitored. A 7% increase in the anticoagulant response of warfarin was noted in association with fluconazole.4,13 No studies are available to guide gynecologists faced with the more common clinical scenario that may lead to a warfarin-fluconazole interaction. That is, a woman previously stabilized on warfarin who develops vulvovaginal candidiasis requiring fluconazole therapy.
It is unknown whether the increase in the prothrombin times would have continued if the warfarin dose were unchanged in the 2 women with an INR greater than 4 on days 2 or 5, and whether these changes would have become statistically significant. The number of measurements (n = 3) remaining for day 8 had only a 70% power of detecting a 10% difference in the prothrombin times. From our study, the largest increase of the prothrombin time occurred 5 days after ingestion of the fluconazole. This was most likely due to an increase in the level of warfarin secondary to inhibition of the liver cytochrome P450 enzymes. In the study by Kunze et al,17 men receiving multiple daily doses of 400 mg fluconazole showed increases in the 40-hour half-life of warfarin. Because of indirect mechanisms of warfarin-induced anticoagulation, changes in the prothrombin time lag behind changes in warfarin levels, with the peak response of prothrombin times occurring at 3 to 5 days later.18 The lack of a clinically relevant response in 3 subjects in our study underscores the individual differences in warfarin pharmacodynamics observed. It also underscores that relatively minor changes in warfarin levels may lead to toxic effects, as noted in 1 woman who had a minor hemorrhagic episode with an INR of 3.4.
One limitation of the current study is the selection of women as their own controls. Each patient was stable on long-term warfarin therapy, with inclusion only if her prothrombin times were therapeutic and varied less than 10% on 2 consecutive days. Changes in the prothrombin times were then compared with each patient’s baseline values. If a comparison had been performed to a group of women on long-term warfarin therapy during a similar period who were not given fluconazole, the magnitude of the changes seen may have been significantly different.
The results of this study suggest that gynecologists prescribing oral fluconazole in this clinical scenario will need to advise their patients to monitor their prothrombin times on day 5 after a single-dose therapy. Given the narrow therapeutic index of warfarin and individual sensitivity demonstrated by a portion of the population, some alteration of the dose of warfarin may be necessary when patients are given even a single dose of fluconazole.
|
Footnotes |
|---|
Presented at the 53rd annual clinical meeting of the American College of Obstetricians and Gynecologists. San Francisco, California, May 7–11, 2005.
Corresponding author: Mark A. Turrentine, MD, 318 Crestwood Drive, Houston, TX 77007; e-mail: DrT318{at}aol.com.
doi:10.1097/01.AOG.0000196722.13403.33
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Watson MC, Grimshaw JM, Bond CM, Mollison J, Ludbrook A. Oral versus intra-vaginal imidazole and triazole anti-fungal agents for the treatment of uncomplicated vulvovaginal candidiasis (thrush): a systematic review. BJOG 2002;109:85–95.[Medline]
3. Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178:203–11.[Medline]
4. Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis 1990;12:S327–33.
5. Isalska BJ, Stanbridge TN. Fluconazole in the treatment of candidal prosthetic valve endocarditis. BMJ 1988;297:178–9.
6. Seaton TL, Celum CL, Black DJ. Possible potentiation of warfarin by fluconazole. DICP 1990;24:1177–8.[Abstract]
7. Kerr HD. Case report: potentiation of warfarin by fluconazole. Am J Med Sci 1993;305:164–5.[Medline]
8. Gericke KR. Possible interaction between warfarin and fluconazole. Pharmacotherapy 1993;13:508–9.[Medline]
9. Baciewicz AM, Menke JJ, Bokar JA, Baud EB. Fluconazole-warfarin interaction. Ann Pharmacother 1994;28:1111.[Medline]
10. Mootha VV, Schluter ML, Das A. Intraocular hemorrhages due to warfarin fluconazole drug interaction in a patient with presumed Candida endophthalmitis. Arch Ophthalmol 2002;120:94–5.
11. Allison EJ, McKinney TJ, Langenberg JN. Spinal epidural haematoma as a result of warfarin/fluconazole drug interaction. Eur J Emerg Med 2002;9:175–7.[Medline]
12. Crussell-Porter LL, Rindone JP, Ford MA, Jaskar DW. Low-dose fluconazole therapy potentiates the hypoprothrombinemic response of warfarin sodium. Arch Intern Med 1993;153:102–4.[Abstract]
13. Physicians’ desk reference. 59th ed. Montvale (NJ): Thomson PDR; 2005.
14. Giraldo P, Von Nowaskonski A, Gomes FA, Linhares I, Neves NA, Witkin SS. Vaginal colonization by Candida in asymptomatic women with and without a history of recurrent vulvovaginal candidiasis. Obstet Gynecol 2000;95:413–6.
15. U.S. pharmaceutical industry data 2004 from NDCHealth pharmaceutical audit suite, March 2005. Available at: http://www.ndchealth.com. Retrieved August 21, 2005.
16. Debruyne D, Ryckelynck JP. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet 1993;24:10–27.[Medline]
17. Kunze KL, Trager WF. Warfarin-fluconazole. III. A rational approach to management of a metabolically based drug interaction. Drug Metabol Dispos 1996;24:429–35.[Abstract]
18. Neal JM, Kunze KL, Levy RH, O’Reilly RA, Trager WF. Kiiv, an in vivo parameter for predicting the magnitude of a drug interaction arising from competitive enzyme inhibition. Drug Metabol Dispos 2003;31:1043–8.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
