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Absence of a Pharmacokinetic Interaction between Etanercept and Warfarin

From the Clinical Pharmacology Department, Wyeth Research, Collegeville, Pennsylvania (Dr. Zhou, Ms. Buckwalter, Dr. Korth-Bradley); Clinical Pharmacology Department, Wyeth Research, Paris, France (Dr. Patat, Ms. Parks); and Forenap-Pharma, Rouffach, France (Dr. Metzger).

Address for reprints: Honghui Zhou, PhD, FCP, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426.

	ABSTRACT

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Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr) fusion protein, is effective and well tolerated in the treatment of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between a single dose of R- and S-enantiomers of warfarin and multiple doses of etanercept after administration of warfarin and etanercept alone and together. In a nonrandomized, three-period study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg subcutaneous doses of etanercept for seven doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Serial blood samples for plasma warfarin concentration measurement and international normalized ratio (INR) assessment were collected before and up to 144 hours after dose administration. Serial blood samples for serum etanercept concentration measurement were collected before and up to 60 hours after the sixth dose and 264 hours after the seventh dose. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of maximum serum concentration (C_max) and area under the serum concentration versus time curve (AUC) for pharmacokinetics (R- and S-enantiomers of warfarin) and INR fell within the confidence interval of 0.8 to 1.25. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics of etanercept. In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.

Key Words: Drug interaction • etanercept • warfarin

Preclinical and clinical evidence implicates tumor necrosis factor (TNF) in the pathogenesis of RA, and inhibition of TNF activity has been shown to reduce or ameliorate arthritic symptoms and joint injury in animal models and in clinical trials. TNF is a naturally occurring cytokine that is thought to play a central role in the pathogenesis of RA.¹ Etanercept is a soluble, dimeric fusion protein consisting of two copies of the extracellular ligand-binding portion of the human TNF p75 receptor linked to the constant (Fc) portion of human IgG₁. Etanercept binds to TNF and lymphotoxin (LT) with high affinity and has proven highly efficacious in animal models of rheumatic disease.² The safety and efficacy profiles of etanercept have been extensively assessed in clinical trials sponsored by the Amgen Corporation and Wyeth Research. Enbrel (etanercept) has been commercially available since 1998 in the United States and has recently become more widely available in Europe.

Etanercept is slowly absorbed from the site of subcutaneous injection. The absolute bioavailability of etanercept was 58% in healthy subjects who received two doses of subcutaneous etanercept.³ It is also slowly cleared from the body, with a t_1/2 of 70 to 100 hours and a mean body clearance of 0.066 L/h in patients with RA.⁴ After binding to TNF, the etanercept-TNF complex is believed to be metabolized by proteolytic processes in the body. The by-products are either recycled or eliminated in the bile, urine, or both.

Warfarin is used to prevent thromboembolic complications in patients with prosthetic heart valves or atrial fibrillation, as well as pulmonary emboli in patients with a history of or recent deep vein thrombosis.

Warfarin is a racemic compound (i.e., a 1:1 mixture of R- and S-enantiomers). The S-enantiomer has five times greater anticoagulant activity than the R-enantiomer.⁵ The most common cause of interaction with warfarin is due to the inhibition of CYP2C9, which increases the S-enantiomer of warfarin concentration and subsequently increases anticoagulation and risk of hemorrhage.

The pharmacokinetic profiles of etanercept and warfarin are such that interactions between the drugs are not anticipated. Because patients treated with etanercept may sometimes receive concurrent treatment with warfarin, however, and because warfarin is a drug with a narrow therapeutic index, the possibility of an interaction between etanercept and warfarin therefore was investigated.

	METHODS

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Subjects
Twelve healthy male subjects with a mean age of 28 years (range: 21-36 years) and within 20% of their ideal body weight were enrolled in the study. The mean (range) body weight of these 12 subjects was 71.8 kg (61.0-97.0 kg). Two were black and 10 were white. Subjects were judged to be in general good health based on medical history, physical examination, routine laboratory test results, and 12-lead electrocardiograms (ECG). Subjects could not use prescribed or nonprescribed drugs 1 month before and during the study or consume excessive alcohol (> 50 g/day) or caffeine (> 300 mg/day [3 cups of coffee]). Heavy smokers (more than 10 cigarettes or equivalent daily) or smokers who could not abstain from smoking for the duration of hospitalization were also excluded from the study.

All 12 enrolled subjects completed the study, and data for all 12 were included in the pharmacokinetic and pharmacodynamic analyses and in the safety assessment.

The study was approved by the local institutional review board (Comite Consultatif de Protection des Personnes dan la Recherche Biomedicale, Strasbourg, France), and all subjects gave written informed consent before study participation. The study was conducted at Forenap Pharma, Centre Hospitalier (Rouffach, France).

Study Design
This was a nonrandomized three-period study. A single dose of 25 mg warfarin as 5 x 5-mg tablets (Goldshield, UK) was administered orally during periods 1 (day 1) and 3 (day 29); etanercept (Wyeth Research) 25 mg twice weekly was administered subcutaneously during periods 2 and 3 (days 8-29). Subjects received twice-weekly subcutaneous injections of etanercept 25 mg on days 8, 12, 15, 19, 22, 26, and 29. All subjects had the same sequence of periods. Foods and fluids were prohibited for at least 8 hours before and up to 2 hours after warfarin oral administration. Water, however, could be taken ad libitum except during the 1 hour before and 2 hours after dose administration.

Blood samples (5 mL) for warfarin analysis were collected in periods 1 and 3 before warfarin administration and at 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours after administration.

Blood samples (8 mL) for etanercept analysis were collected at steady state before dose administration (day 8, period 2); before administration of the sixth and seventh doses; at 12, 24, 36, 48, 60, and 72 hours (same as the predose sample for the seventh dose) after administration of the sixth dose (day 26, period 2); and at 12, 24, 36, 48, 60, 72, 96, 120, 144, 192, and 264 hours after administration of the seventh dose (day 29, period 3). Due to the nature of the twice-weekly dosing regimen for etanercept (3 and 4 days apart), the blood sampling for etanercept in period 2 was collected up to 72 hours after the sixth dose administration, and the terminal phase of the etanercept in this period could not be fully captured.

International normalized ratios (INRs) were monitored before oral administration of warfarin and at 12, 24, 36, 48, 60, 72, 96, 120, and 144 after administration in both periods 1 and 3.

In all three study periods, a brief physical examination, ECG, routine laboratory tests, urinalysis, and vital sign measurements (supine blood pressure, pulse rate, and oral temperature) were conducted.

Analytical Methods
Etanercept serum concentrations were measured with enzyme-linked immunosorbent assay (ELISA) methodology. It was based on an ELISA developed at Immunex Corporation (Seattle, WA) with minor modifications. Serum etanercept concentrations were determined by a validated ELISA with a limit of quantitation of 0.3 ng/mL based on 1:5 minimum sample dilution. Specificity of the ELISA was demonstrated against a panel of human cytokines and cytokine receptors, including IL-1, IL-1b, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, TNF, TNFß, IL-1R, and IL-4R. The antibodies used in the ELISA do not distinguish between recombinant and endogenous TNFr. Accuracy was within 12% of nominal in serum spiking experiments, and intermediate precision was within 13% of coefficient of variation (CV).

The analysis for warfarin R- and S-enantiomers was performed at Medeval Ltd. (Manchester, UK). The analytical procedure involved extraction of R- and S-enantiomers from human plasma by solid-phase extraction. The human plasma samples were then analyzed using a validated high-pressure liquid chromatography (HPLC) method with ultraviolet detection. The extraction procedure involved solid-phase extraction followed by derivatization of the enantiomers with carbobenzloxy-L-proline in the presence of dicyclohexylcarbodiimide and imidazole. A portion of the extract was injected onto the HPLC system. The limit of quantitation is 0.15 to 2.49 µg/mL for both enantiomers. The range of quantitation is 0.15 to 2.49 µg/mL for both enantiomers. The CV% of the quality control (QC) samples observed during validation was less than 10%. Mean accuracy for the QC samples observed during assay validation was < 5%.

Data Analysis
SAS (version 6.12, SAS Institute Inc., Cary, NC) was used for both pharmacokinetic and statistical analysis. Warfarin (R- and S-enantiomers) pharmacokinetic parameters, maximum plasma concentration (C_max), and time to C_max (t_max) were obtained directly from the observed data. The terminal elimination rate constant (_z) was estimated by a linear regression of the concentration-time points at the log-linear terminal portion. The terminal elimination t_1/2 was subsequently calculated as t_1/2 = 0.693/_z. The area under the concentration-time profile from time 0 to infinity (AUC_0-) was calculated using the following equation:

where AUC_T was the AUC from time 0 to the last quantifiable concentration (C_T) and was computed using the trapezoidal rule.

Etanercept pharmacokinetic parameters, C_max and t_max, were obtained directly from the observed data. The terminal elimination rate constant (_z) was only estimated for etanercept during period 3 by a linear regression of the concentration-time points at the log-linear terminal portion. The terminal elimination t_1/2 was subsequently calculated as t_1/2 = 0.693/_z. The etanercept area under the concentration-time curve over one dose interval (AUC_0-, = 72 h) was calculated using the trapezoidal rule.

The warfarin pharmacodynamic parameter, maximum response (R_max), was read directly from the observed data, and the area under the effect time curve (AUE), calculated by linear trapezoid approximation, was between 0 and 144 hours. An INR of 1 was used as the baseline when AUE values were computed.

Analysis of variance (ANOVA) was used to compare pharmacokinetic and pharmacodynamic results when the drugs were given alone versus when they were given concomitantly. Bioequivalence criteria were subsequently applied to C_max or R_max for warfarin, as well as AUC for each drug or AUE for warfarin.

	RESULTS

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Etanercept Pharmacokinetics
Coadministration of a single oral dose of warfarin did not alter the serum pharmacokinetics of etanercept (Table I). The individual and mean serum concentration profiles of etanercept were comparable during administration of etanercept alone (days 26-29) or in combination with warfarin (days 29 onward) (Figure 1).

View larger version (31K): [in this window] [in a new window]   Figure 1. Individual and mean serum concentration-time profiles of etanercept after administration of etanercept alone (day 26) and in combination with warfarin (day 29) in 12 healthy male subjects.

After administration of etanercept and warfarin combination therapy on day 29, the mean AUC_0- of etanercept was 160 µg•h/mL, which was 11.1% lower than that on day 26 after etanercept alone. Similarly, the maximum serum concentration on day 29 (mean: 3.2 µg/mL) was 8.6% lower than that on day 26 (mean: 3.5 µg/mL), as illustrated in Table I.

No significant change in etanercept pharmacokinetics was observed after etanercept and warfarin combination therapy. The prolongation of median t_max could be due to the sparse sample collection schedule of etanercept and/or to the relatively flat serum concentration-time profile. The 90% confidence interval of the geometric mean ratio for etanercept C_max was within the bioequivalence limits—that is, (0.8, 1.25)—while the 90% confidence interval of the geometric mean ratio for etanercept AUC_0- was just outside prespecified bounds, with the lower bound slightly below 0.8.

Warfarin Pharmacokinetics
Coadministration of multiple doses of etanercept (25-mg twice-weekly subcutaneous administration) did not affect the plasma pharmacokinetics of either R- or S-enantiomers of warfarin. The individual and mean serum concentration profiles of S-enantiomer of warfarin were comparable during warfarin alone (day 1) or in combination with warfarin (day 29), as depicted in Figure 2, respectively.

View larger version (25K): [in this window] [in a new window]   Figure 2. Individual and mean serum concentration-time profiles of the S-enantiomer of warfarin after administration of warfarin alone (day 1) and in combination with etanercept (day 29) in 12 healthy male subjects.

The coadministration of multiple doses of etanercept did not alter the pharmacokinetics of either R- or S-enantiomers of warfarin, as shown in Table II. The 90% confidence intervals of the geometric mean ratios for both R- and S-enantiomers of warfarin C_max and AUC_0- were all within the bioequivalence limits, that is, (0.8, 1.25).

Warfarin Pharmacodynamics
The individual and mean INR profiles of warfarin after administration of warfarin alone (day 1) or in combination with etanercept (day 29) are depicted in Figure 3. The summary of the pharmacodynamic parameters of warfarin after both treatments is shown in Table III. Both R_max and AUE were mildly decreased when warfarin was administered with etanercept as opposed to when warfarin was administered alone. A 13% decrease in R_max and a 10% decrease in AUE were observed. However, the geometric mean ratios of both R_max and AUE remained within the 0.80 and 1.25 confidence interval. The slight decrease in INR following coadministration of warfarin and etanercept was unlikely to be clinically relevant and did not justify any dosage adjustment.

View larger version (28K): [in this window] [in a new window]   Figure 3. Individual and mean international normalized ratio (INR)-time profiles after administration of warfarin alone (day 1) and in combination with etanercept (day 29) in 12 healthy male subjects.

Clinical Safety
All 12 subjects who entered and completed the study were included in the safety analysis. No serious adverse events and no withdrawal for adverse events were observed throughout the study. Treatment-emergent adverse events (TEAEs) were reported by 5 subjects who received warfarin only (period 1), 4 subjects who received etanercept only (period 2), and 11 subjects who received warfarin and etanercept concomitantly (period 3), as shown in Table IV. The only TEAEs that occurred in 3 or more subjects per period were somnolence (n = 3), epistaxis (n = 3), and subcutaneous hematoma at the blood sample collection puncture point, a local reaction to the procedure related to warfarin administration (n = 6). All events were mild or moderate and resolved either spontaneously or with countertherapy. Site reactions (redness) to etanercept injection, all of which resolved, were reported for 2 subjects. Treatment-emergent infections were reported for 5 subjects: 3 in the warfarin-alone period, 1 in the etanercept-alone period, and 1 in the etanercept combined with warfarin period. Therefore, no increase in infections was observed after etanercept administration.

No clinically relevant changes in routine laboratory tests related to either warfarin or etanercept intake were observed. An increase in alanine amino-transferase (ALT) between two and three times the upper limit was observed in 1 subject during the warfarin-alone period, associated with pharyngitis.

	DISCUSSION

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The etanercept pharmacokinetic results observed in this study are similar to those reported previously for single doses in healthy subjects.⁶ Similarly, the R- and S-enantiomers of warfarin pharmacokinetic results reported in this study are comparable to those reported previously after single doses of warfarin.⁷

Warfarin has three major unfavorable characteristics that make it prone to serious drug-drug interactions: CYP-dependent metabolism, high protein binding, and a narrow therapeutic range.⁸ The isomeric differences in the metabolism of warfarin form an important basis for stereoselective metabolic interaction at the CYP level, especially inhibition.⁹ A number of drugs, such as metronidazole¹⁰ and bucolome,¹¹ can stereoselectively inhibit the metabolism of the S-enantiomer of warfarin, a CYP2C9 substrate. Certain drugs, such as miconazole¹² and amiodarone,¹³ can inhibit the metabolism of both R- and S-enantiomers (to a greater extent), while some other drugs, such as ciprofloxacin¹⁴ and cimetidine,¹⁵ can stereoselectively inhibit the metabolism of the R-enantiomer but do not have a significant impact on the INR. In contrast, a host of drugs, such as aminoglutethimide,¹⁶ phenytoin,¹⁷ cabamazepine,¹⁸ rifampin,¹⁹ nafcillin,²⁰ and phenobarbital,²¹ can induce the metabolism of warfarin. Several drugs or food intake can affect the pharmacodynamics of warfarin by altering the bioavailability of vitamin K, such as antibiotics, mineral oils,²² or cholestyramine.²³ Other drugs, such as estrogens, diuretics, and clofibrate, may influence vitamin K-dependent clotting factor synthesis, and drugs that affect hemostasis (e.g., via platelet function) may enhance the anticoagulant effect of warfarin.⁹

Some drug-drug interactions have been documented between antirheumatic drugs and warfarin. It was reported that leflunomide could potentiate the anticoagulant effect of warfarin.²⁴ Celecoxib has demonstrated an interaction with warfarin, and thus increased clinical vigilance should be maintained accordingly.²⁵ A possible warfarin-sulfasalazine interaction could result in warfarin resistance.^26,27 Generally speaking, patients on warfarin treatment should avoid nonsteroidal anti-inflammatory drugs (NSAIDs) as much as possible.²⁸ Given the vastly different disposition profiles and pharmacologic effects between warfarin and etanercept, it was not anticipated that there would be interaction during coadministration of etanercept and warfarin. Nevertheless, because patients treated with etanercept could also receive concurrent treatment with warfarin, which is a drug with a narrow therapeutic range, an investigation of the possibility of an interaction between etanercept and warfarin was warranted. In this study, etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. Moreover, warfarin did not cause a clinically significant alteration in the pharmacokinetics of etanercept.

In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered, although continued monitoring of INR for warfarin activity is advised.

	FOOTNOTES

 
DOI: 10.1177/0091270004264164

This study was also presented at an American College of Clinical Pharmacy meeting in Savannah in April 2002.

Submitted for publication September 11, 2003; Revised version accepted February 8, 2004.

	REFERENCES

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1. Culy CR, Keating GM: Etanercept: an updated review of its use in rheumatoid arthritis, psoriatic arthritis and juvenile rheumatoid arthritis. Drugs 2002;62(17): 2495-2539.[CrossRef]

2. Wooley PH, Dutcher J, Widmer MB, Gillis S: The influence of a recombinant human soluble tumor necrosis factor receptor Fc fusion protein on type II collagen-induced arthritis in mice. J Immunol 1993;151: 6602-6607.[Abstract]

3. Lebsack ME, Hanna RK, Lange MA, et al: Absolute bioavailability of TNF receptor fusion protein following subcutaneous injection in healthy volunteers [abstract 233]. Pharmacotherapy 1997;17(5): 1118.

4. European Agency for Evaluation of Medicinal Products: Scientific discussion: Enbrel [online]. Accessed September 9, 2003, from www.emea.eu.int

5. Takahashi H, Echizen H: Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001;40(8): 587-603.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Korth-Bradley JM, Rubin AS, Hanna RK, Simcoe DK, Lebsack ME: The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother 2000;34: 161-164.[Abstract]

7. Toon S, Holt BL, Mullins FGP, Bullingham R, Aarons L, Rowland M: Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol 1990;30: 743-750.[Web of Science][Medline] [Order article via Infotrieve]

8. Harder S, Thurmann P: Clinically important drug interactions with anticoagulants: an update. Clin Pharmacokinet 1996;30(6): 416-444.[Web of Science][Medline] [Order article via Infotrieve]

9. Serlin MJ, Breckenridge AM: Drug interactions with warfarin. Drugs 1983;25(6): 610-620.[Web of Science][Medline] [Order article via Infotrieve]

10. O'Reilly RA: The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med 1976;295(7): 354-357.[Abstract]

11. Matsumoto K, Ishida S, Ueno K, Hashimoto H, Takada M, Tanaka K, et al: The stereoselective effects of bucolome on the pharmacokinetics and pharmacodynamics of racemic warfarin. J Clin Pharmacol 2001;41(4): 459-464.[Abstract]

12. O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi M, Eddy AC, et al: Mechanism of the stereoselective interaction between miconazole and racemic warfarin in human subjects. Clin Pharmacol Ther 1992;51(6): 656-667.[Web of Science][Medline] [Order article via Infotrieve]

13. Heimark LD, Wienkers L, Kunze K, Gibaldi M, Eddy AC, Trager WF, et al: The mechanism of the interaction between amiodarone and warfarin in humans. Clin Pharmacol Ther 1992;51(4): 398-407.[Web of Science][Medline] [Order article via Infotrieve]

14. Israel DS, Stotka J, Rock W, Sintek CD, Kamada AK, Klein C, et al: Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin. Clin Infect Dis 1996;22(2): 251-256.[Web of Science][Medline] [Order article via Infotrieve]

15. Niopas I, Toon S, Aarons L, Rowland M: The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans. Eur J Clin Pharmacol 1999;55(5): 399-404.[CrossRef][Medline] [Order article via Infotrieve]

16. Lonning PE, Ueland PM, Kvinnsland S: The influence of a graded dose schedule of aminoglutethimide on the disposition of the optical enantiomers of warfarin in patients with breast cancer. Cancer Chemother Pharmacol 1986;17(2): 177-181.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

17. Cropp JS, Bussey HI: A review of enzyme induction of warfarin metabolism with recommendations for patient management. Pharmacotherapy 1997;17(5): 917-928.[Web of Science][Medline] [Order article via Infotrieve]

18. Denbow CE, Fraser HS: Clinically significant hemorrhage due to warfarin-carbamazepine interaction. South Med J 1990;83(8): 981.[Medline] [Order article via Infotrieve]

19. Lee CR, Thrasher KA: Difficulties in anticoagulation management during coadministration of warfarin and rifampin. Pharmacotherapy 2001;21(10): 1240-1246.[Medline] [Order article via Infotrieve]

20. Qureshi GD, Reinders TP, Somori GJ, Evans HJ: Warfarin resistance with nafcillin therapy. Ann Intern Med 1984;100(4): 527-529.

21. Udall JA: Clinical implications of warfarin interactions with five sedatives. Am J Cardiol 1975;35(1): 67-71.[Medline] [Order article via Infotrieve]

22. Serlin MJ, Breckenridge AM: Drug interactions with warfarin. Drugs 1983;25(6): 610-620.

23. Shetty HG, Fennerty AG, Routledge PA: Clinical pharmacokinetic considerations in the control of oral anticoagulant therapy. Clin Pharmacokinet 1989;16(4): 238-253.[Web of Science][Medline] [Order article via Infotrieve]

24. Lim V, Pande I: Leflunomide can potentiate the anticoagulant effect of warfarin. Br Med J 2002;325(7376): 1333.[Free Full Text]

25. Davies NM, Gudde TW, de Leeuw MA: Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother 2001;2(1): 139-152.[CrossRef][Medline] [Order article via Infotrieve]

26. Teefy AM, Martin JE, Kovacs MJ: Warfarin resistance due to sulfasalazine. Ann Pharmacother 2000;34(11): 1265-1268.[Abstract]

27. Toon S, Low LK, Gibaldi M, Trager WF, O'Reilly RA, Motley CH, et al: The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther 1986;39: 15-24.[Web of Science][Medline] [Order article via Infotrieve]

28. Chan TY: Prolongation of prothrombin time with the use of indomethacin and warfarin. Br J Clin Pract 1997;51(3): 177-178.[Web of Science][Medline] [Order article via Infotrieve]
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