Eur J Clin Pharmacol (1992) 42:227-229 Eurooea,ao.rnaiof C ~ i ~ ( ~

© Springer-Verlag 1992

Absence of interaction between tenoxicam and warfarin H.-G. Eichler 1, M. Jung 1, P. A. Kyrle 2, M. Rotter 1, and A. Korn 1 1 Division of Clinical Pharmacology, and 2 Hematology and Hemostasiology, Department of Medicine I, Vienna University Hospital, Vienna, Austria Received: January t0, 1991/Accepted in revised form: May 14, 1991

Summary. T h e influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has b e e n studied in healthy volunteers. T e n o x i c a m did not alter the plasma warfarin c o n c e n t r a t i o n versus time profile. Treatm e n t with it for 14 days had no effect on the average dose of warfarin required to maintain the p r o t h r o m b i n time within a specified range. T h e c o u m a r i n dose index, an indicator of warfarin sensitivity, r e m a i n e d u n c h a n g e d during t e n o x i c a m administration. The results d e m o n s t r a t e the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation. K e y words: Tenoxicam, Warfarin; drug interaction, pharmacokinetics, anticoagulation Tenoxicam (Tilcotil ®) is a n e w non-steroidal anti-inflamm a t o r y drug ( N S A I D ) belonging to the oxicam group [Wiseman and L o m b a r d i n o 1981]. It is effective in the s y m p t o m a t i c t r e a t m e n t of r h e u m a t i c and i n f l a m m a t o r y diseases and is well tolerated. The elimination half-life (70 h) allows once daily dosing; binding of tenoxicam to plasma protein is 99% [Gonzalez and T o d d 1987]; the reco m m e n d e d therapeutic dose is 20 m g p e r day. Clinically relevant interactions with coumarins have b e e n detected for s o m e [Lewis et al. 1974; K o c h - W e s e r and Sellers 1971 a, b] but not all [Penner and A b b r e c h t 1975; Rttst et al. 1975] N S A I D s . H e n c e , the potential to interact with c o u m a r i n - i n d u c e d anticoagulation requires investigation of each new N S A I D . T h e effect of tenoxicam on the anticoagulant effect of warfarin has n o w b e e n investigated. In addition, the influence of tenoxicam on the plasma c o n c e n t r a t i o n versus time profile of warfarin, and the effect of warfarin on steady state plasma concentrations of tenoxicam were also assessed.

Subjects and methods Subjects Sixteen healthy volunteers (15 m, 1 f; age 19-35y, mean (SD) 25 (4) y) with a body weight _+10% of ideal weight (Geigy Tables) participated in the study. They were in good health, as assessed by

physical examination, ECG and laboratory tests. The following coagulation tests were done before the study: bleeding time, as described by Lechner (1982), employing the Simplate I ®device (Organon, Teknika, Turuhout, Belgium), prothrombin time (PT), partial thromboplastin time, thrombin time, and the activity of Factors II, V, VII, IX and X. All subjects were non-smokers and were drug-free for a minimum of 14 days before and during the study. Results from coagulation tests were normal in all subjects. Written informed consent was obtained from each subject; the study protocol was approved by the institutional Ethics Committee.

Study design a) Single dose study. Eight volunteers received single oral doses of warfarin 0.75 mg.kg < on two separate occasions, 4weeks apart (open, randomized cross over design). On one occasion, the dose of warfarin was given without concomitant treatment, and on the other, the single dose of warfarin was preceded for two weeks by single oral daily doses of 20 mg tenoxicam (Tilcotil ® tablets, E Hoffmann-La Roche & Co AG, Basel, Switzerland); the tenoxicam treatment was continued for i week after the warfarin. The day of warfarin administration was designated Day 0, thus, tenoxicam was given from Day -13 until Day 7. All drugs were administered at 08.00 h, under close supervision. Venous blood samples for determination of PT and the measurement of warfarin in plasma were taken after both warfarin doses, at the times indicated in Fig. 1. Blood samples were obtained at 08.00 h. Plasma warfarin concentrations were also measured 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 h after the administration of warfarin (not shown in Fig. 1). Additional blood samples for the measurement of plasma tenoxicam were taken on Days 4 to 7 of the treatment with tenoxicam, immediately before the daily dose (Fig. 1). b) Steady-state study: Initially, the effect of repeat-dose tenoxicam on blood coagulation was studied. Eight subjects received 20 mg tenoxicam once daily for 14 days. The following coagulation tests were done on Day 0 (before tenoxicam) and on Days 7 and 14: bleeding time, P1, partial thromboplastin time, thrombin time, activity of Factors II, V, VII, IX and X. After a three week wash out period, warfarin administration was commenced using daily doses adjusted to maintain the PT at a level between 1.47 and 1.81 International Normalized Ratios (INR) (corresponding to Thrombotest ®levels between 20 and 30%). The appropriate dose was assessed and adjusted daily or every other day throughout this period to keep the PT within the specified range. After a 2 week equilibration period (run-in phase), oral tenoxicam

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All subjects completed the study according to the protocol. There were no drug-induced adverse effects or haemorrhagic complications.

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The cumulative warfarin dosage during the preceding 72 hours was used [Koch-Weser and Sellers 1971 a]. CDI was calculated for every study day. One-way or two-way analysis of variance (ANOVA) for repeated measures, as appropriate, was used for data analysis. For statistical analysis of the steady state study, results were split into 2week periods: Period I of Weeks3-4, i.e. during tenoxicam treatment, Period II was Weeks 5-6, and Period III was Weeks 7-8. A N O V A for repeated measures was used to compare the CDI, daily warfarin dose and prothrombin time results from the three periods. P < 0.05 was considered significant.

Results from the single warfarin dose study are shown in Fig. 1. There was a slight, but non-significant rise in plasma tenoxicam levels on the day after warfarin administration.

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Fig. 1. Trough plasma tenoxicam concentrations, prothrombin time, and plasma warfarin after single doses of warfarin with (o---o) or without (o---o) tenoxicam. Vertical bar represents SD. Warfarin was given on Day 0 (vertical line); on one occasion oral tenoxicam 20 mg/d was administered from D a y - 1 3 to Day 7. INR, international normalized ratio (number of subjects = 8)

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3.020 mg daily was added for a further 2 weeks. Tenoxicam was then stopped and warfarin administration was continued for a further 4 weeks (run-out phase); the total duration of warfarin administration was 8 weeks. PT was determined daily or on alternate days (Fig.2).

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Analytical methods Total drug concentrations in plasma were assayed by HPLC, as described by Pickup et al. (1981) for tenoxicam (internal standard piroxicam), and by De Vries et al. (1982) for warfarin (internal standardphenprocoumon).Thesensitivitylimitwas15 ng.ml lforboth assays. PT was measured using a commercial kit (Thrombotest TM) from Nycomed AS, Oslo, Norway. Test results are expressed in International Normalized Ratios (INR). All other coagulation tests were done by routine methods and equipment, as described by Lechner (1982).

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Data evaluation For evaluation of the results of the steady state study, the eoumarin dose index (CDI) was calculated as: CDI =

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Time (days) Fig.2. Warfarin dose, prothrombin time (PT) and coumarin dose index (CDI) during a steady state tenoxicam-warfarin interaction study. Daily doses of warfarin were adjusted to maintain PT at levels between 1.47 and 1.81 international normalized ratios (INR). After a 2 week equilibration period, oral tenoxicam 20 mg/d was added for 2 weeks. Number of subjects = 8; vertical bar represents i SD

229 For clarity, the total plasma warfarin levels measured between 0.25 and 6 h after warfarin administration (Day 0) have been omitted from the figure. The peak plasma warfarin concentrations (Cmax) with or without tenoxicam treatment were 3.05 (0.91)gg-ml 1 (mean (SD); range 1.72-4.55 gg-ml 1) and 3.02 (0.75) ~tg-m1-1 (1.874.05 gg-ml-1), respectively. The time of the peak plasma level (tmax) with or without tenoxicam treatment was 1.69 (0.65) h (range 1-3 h) and 3.00 (2.19) h (1.5-8 h) after warfarin administration, respectively (NS between treatment cycles). The late tmaxobserved during the treatment cycle without tenoxicam was due to one outlying value (8 h); this value was included in the statistical analysis. There was no significant difference in the plasma warfarin-time profile, or in PT results between treatment cycles (ANOVA: P > 0.05).

b) Steady-state study Administration of tenoxicam 20 mg/day over 14 days had no effect on blood coagulation tests or on bleeding time (data not shown). The mean daily warfarin dose, mean daily PT value, and mean daily CDI are shown in Fig. 2. Mean (SD) warfarin doses over the individual treatment periods (see Methods) were: 4.4 (1.2) mg per day (Period I), 4.8 (1.4) mg per day (Period II), and 5.0 (1.3) mg per day (Period III), respectively. Mean PT results were 1.57 (0.14) INR (CDI 0.14 (0.05)) for Period I, 1.54 (0.08) INR (CDI 0.12 (0.01)) for Period II, and 1.60 (0.13) INR (CDI 0.11 (0.02)) for Period III, respectively. There was no significant difference between the treatment periods (ANOVA: P > 0.05).

Discussion Pretreatment over 14 days with a therapeutic dose of tenoxicam had no influence on the plasma concentrationtime profile of a single dose of warfarin (Fig. 1). This indicates that tenoxicam had no detectable effect on the absorption and overall elimination of warfarin. Only total warfarin concentrations were measured, so an action of tenoxicam on the free/protein-bound warfarin ratio could have remained undetected. However, the lack of effect on prothrombin time or on sensitivity to warfarin (indicated by CDI) makes a relevant influence of tenoxicam on warfarin protein binding appear unlikely [Koch-Weser and Sellers 1971 a]. The effect of a single dose of warfarin on steady state plasma tenoxicam levels was also investigated. There was a slight increase in the trough level on the day after warfarin administration (Fig. 1). It was not significant, but a small effect of warfarin on plasma tenoxicam cannot be excluded. To detect a potential drug interaction with delayed onset, separate experiments were done at steady state levels both of warfarin and tenoxicam. There was no alteration in the average warfarin dose required after the cessation of tenoxicam (Fig.2). Use of the coumarin dose

index will reveal any change in sensitivity to warfarin, even when the dose of warfarin is not constant, as here [Koch-Weser and Sellers 1971 a]. There was a slight trend towards lower average CDI values over the study period, but the differences between the treatment periods were not significant. In particular, there was no significant difference in CDI between Period I (Weeks 3-4, during tenoxicam administration) and Period III (Weeks 7-8), a time when potential tenoxicam-induced effects may be expected to have subsided. Previous experience has shown that, in general, the results of drug interaction studies with warfarin are also applicable to phenprocoumon, another coumarin drug in clinical use [Gugler 1979]. This appears valid for tenoxicam; case studies from a small number of patients and preliminary results from healthy volunteer studies have not revealed a significant effect of tenoxicam on phenprocoumon-induced anticoagulation [data on file, E HoffmannLa Roche & Co. AG, Basel, Switzerland].

Acknowledgements.The study was supported by EHoffmann-La Roche & Co. AG, Basel, Switzerland.

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Dr. H.-G. Eichler I. Medizinische Universit~tsklinik Lazarettgasse 14 A-1090 Wien Austria