Kombination af NSAID og coumariner bør undgås såfremt behandling med simple analgetika som paracetamol er en mulighed. Såfremt kombinationen er nødvendig bør forebyggende behandling med en protonpumpehæmmer iværksættes og INR bør monitoreres ved indledning og ophør af kombinationen.
Lornoxicam kan øge plasma warfarinkoncentrationen med ca. 30% og INR med ca. 20%. NSAID påvirker reversibelt trombocytaggregeringen og øger risikoen for blødning. Ved kombination med NSAID er risikoen for gastrointestinal blødning 2-4 gange forøget i forhold til behandling med warfarin alene.
Coumariner og NSAID/COX-2 hæmmer som gruppe
Fra store epidemiologiske studier er der god evidens for, at samtidig behandling med warfarin og NSAID som en gruppe øger risikoen for blødning. Risikoen for gastrointestinal blødning er 2-4 gange øget i forhold til behandling med warfarin alene, Cheetham TC, Levy G et al, 2009; Delaney JA, Opatrny L et al, 2007; Battistella M, Mamdami MM et al, 2005.
Epidemiologiske studier, som omfatter behandling med phenprocoumon og andre coumariner, har ligeledes fundet en øget risiko for blødningkomplikationer (Knijff-Dutmer EA, Schut GA et al, 2003) og gastrointesinal blødning ved samtidig behandling med NSAID, Shorr RI, Ray WA et al, 1993; Schalekamp T, Klungel OH et al, 2008.
For Cox-hæmmere er billedet mindre klart, idet to epidemiologiske undersøgelser tilsvarende COX-1 hæmmer har vist en 2-3 gange øget risiko for gastrointestinal blødning ved samtidig behandling med warfarin (Delaney JA, Opatrny L et al, 2007; Battistella M, Mamdami MM et al, 2005), mens et studie ikke fandt en signifikant øgning, Cheetham TC, Levy G et al, 2009.
Warfarin og phenylbutazon
Ved undersøgelse af en mulig interaktion mellem warfarin og phenylbutazon, er der i litteraturen fundet flere prospektive undersøgelser (O'Reilly RA, Trager WF et al, 1980; Chierichetti S, Bianchi G et al, 1975; Aggeler PM, O'Reilly RA et al, 1967a; Banfield C, O'Reilly R et al, 1983; Lewis RJ, Trager WF et al, 1974a), hvor det ses, at phenylbutazon interagerer med warfarin ud fra såvel et farmakokinetisk som et farmakodynamisk synspunkt. Der observeres betydelige stigninger i koagulationsfaktorerne (INR) eller forlængelse af protrombintiderne, samt øgning af plasma warfarin-koncentrationen på grund af phenylbutazons hæmning af CYP2C9, som omsætter S-warfarins i leveren.
Warfarin og lornoxicam
Protrombintiden faldt i gennemsnit fra 23,6 s til 19,6 s og INR fra 1,48 til 1,23 hos 12 frivillige, efter at lornoxicam behandling blev stoppet efter en periode med samtidig behandling med lornoxicam 8 mg/d og warfarin. Plasma warfarin-koncentrationen faldt ca. 25%, Ravic M, Johnston A et al, 1990.
Mulig mekanisme: Lornoxicam øger serumkoncentrationen af warfarin samt protrombintid højst sandsynlig ved, at lornoxicam hæmmer den hepatiske clearance af warfarin.
Warfarin og ibuprofen
Ved undersøgelse af en mulig interaktion mellem warfarin og ibuprofen (Penner JA og Abbrecht PH, 1975; Schulman S og Henriksson K, 1989) findes ingen ændringer i INR under kombinationsbehandlingen, og der er derfor ingen tegn på, at ibuprofen interagerer med warfarin. I modsætning hertil beskriver flere kasuistikker en mulig warfarin-ibuprofen interaktion med stigning i INR og blødning, Pullar T, 1989, Gabb GM, 1996, Juel J, Pedersen TB et al, 2013a.
Warfarin og ketoprofen
Ved undersøgelse af en mulig interaktion mellem warfarin og ketoprofen (Mieszczak C og Winther K, 1993a) findes ingen ændringer i INR under kombinationsbehandlingen. I modsætning hertil beskriver en kasuistik om stigning i prothrombintid og blødning hos en patient i warfarinbehandling 7 dage efter, at ketoprofenbehandling blev indledt, Flessner MF og Knight H, 1988.
Warfarin og indomethacin
Ved undersøgelse af en mulig interaktion mellem warfarin og indomethacin (Vesell ES, Passananti GT et al, 1975; Odegaard AE, 1974) findes ingen ændringer i INR under kombinationsbehandlingen. I modsætning hertil beskriver enkelte kasuistikker om stigning i INR og blødning ved samtidig behandling med warfarin og indometacin, Chan TY, 1997; Chan TY, Lui SF et al, 1994.
Warfarin og piroxicam
En kasuistik beskriver en patient i warfarinbehandling, hvor der blev observeret henholdsvis markant fald og stigning i prothrombintid, når piroxicambehandling ophørte og blev genoptaget, (Rhodes RS, Rhodes PJ et al, 1985). En anden kasuistik beskriver stigninger i INR hos to patienter i warfarinbehandling, efter at henholdsvis piroxicam 20 mg og behandling med piroxicam-gel blev påbegyndt, Chan TY, 1998.
Warfarin og sulindac
Ved undersøgelse af en mulig interaktion mellem warfarin og sulindac i raske frivillige (Loftin JP og Vesell ES, 1979) findes ingen ændringer i INR under kombinationsbehandlingen. I modsætning hertil beskriver flere kasuistikker om stigning i prothrombintid efter kombination med sulindac, Ross JR og Beeley L, 1979; Carter SA, 1979b; Loftin JP og Vesell ES, 1979.
Warfarin og tolmetin
En kasuistik beskriver en patient i warfarinbehandling. Patienten får efter 3 gange 400 mg tolmetin næseblod og en stigning i prothrombintiden fra 15 s til 70 s, Koren JF, Cochran DL et al, 1987.
Warfarin og tenoxicam
Ved undersøgelse af en mulig interaktion mellem warfarin og tenoxicam (Eichler HG, Jung M et al, 1992) findes ingen ændringer i INR eller plasma warfarinkoncentrationen under kombinationsbehandlingen.
Warfarin og naproxen
Ved undersøgelse af en mulig interaktion mellem warfarin og naproxen (Jain A, McMahon FG et al, 1979; Slattery JT, Levy G et al, 1979) findes ingen ændringer i INR under kombinationsbehandlingen, og der er derfor ingen tegn på, at naproxen interagerer med warfarin.
Warfarin og etodolac
Ved undersøgelse af en mulig interaktion mellem warfarin og etodolac (Ermer JC, Hicks DR et al, 1994) findes ingen ændringer i prothombintiden samt kun minimale ændringer i warfarin plasmakoncentration og clearence under kombinationsbehandlingen.
Warfarin og nabumeton
To studier finder ved undersøgelse af en mulig interaktion mellem warfarin og nabumenton ingen ændringer i INR under kombinationsbehandlingen, Hilleman DE, Mohiuddin SM et al, 1993. I modsætning hertil beskriver en kasuistik stigning i INR og hemathrose efter kombination med nabumeton, Dennis VC, Thomas BK et al, 2000. En anden kasuistik beskriver gastrointestinal blødning hos en 71-årig mand 28 dage, efter at nabumeton blev adderet til warfarinbehandling. INR lå inden for det terapeutiske interval, Voss GD og Schweitzer P, 1994.
Warfarin og meloxicam
Ved undersøgelse af en mulig interaktion mellem warfarin og meloxicam i raske frivillige (Turck D, Su CA et al, 1997) findes ingen ændringer i INR eller warfarin plasmakoncentrationen. Et studie i 98 patienter i kombinationsbehandling med NSAID og warfarin blev kombineret fandt, at meloxicam var en risikofaktor for stigning i INR>15%, odds ratio 4,88 (95% 1,23-19,45). 13 patienter fik meloxicam, hvoraf 8 havde stigninger i INR på mere end 15%. Resultatet var baseret på få patienter og skal tolkes med forsigtighed, Choi KH, Kim AJ et al, 2010.
Warfarin og ketorolac
I et placebo-kontrolleret studie i 10 raske frivillige sås efter behandling med ketorolac oralt i 12 dage ingen ændring i protrombintid eller farmkokinetiske data for warfarin enkeltdosis 25 mg indgivet på 6.-dagen. Blødningstiden var dog signifikant forlænget hos ketorolacgruppen sammenlignet med placebogruppen, Toon S, Holt BL et al, 1990.
Warfarin og diclofenac
En kasuistik beskriver stigning i INR hos en patient i warfarinbehandling, efter at behandling med diclofenac-gel blev påbegyndt, Chan TY, 1998.
Warfarin og celecoxib (COX-2 hæmmer)
Ved undersøgelse af en mulig interaktion mellem warfarin og COX-2 hæmmeren, celecoxib, er der i litteraturen lokaliseret to prospektive undersøgelser (Karim A, Tolbert D et al, 2000; Dentali F, Douketis JD et al, 2006a) på raske forsøgspersoner og patienter, og der ses i disse undersøgelser ingen interaktion mellem warfarin og celecoxib ud fra et farmakodynamisk- og farmakokinetisk synspunkt.
I modsætning hertil fandt en undersøgelse, at hos patienter i stabil warfarinbehandling blev INR øget med henholdsvis 13%, 6% og 5% efter henholdsvis 1,2 og 3 uger med behandling af celecoxib 200 mg daglig. Kun ændringen efter 1 uge var signifikant, Schaefer MG, Plowman BK et al, 2003a.
I en retrospektiv analyse af forekomsten af blødning hos patienter i behandling med warfarin og celecoxib (n=123) og patienter, som kun tog warfarin (n=1022), var risikoen for blødning ikke signifikant øget ved samtidig celecoxib behandling, Chung L, Chakravarty EF et al, 2005.
Herudover er der en del kasuistikker omhandlende patienter i kombinationsbehandling med warfarin og celecoxib, hvor der ses stigninger i patienternes INR og blødningskomplikationer, Haase KK, Rojas-Fernandez CH et al, 2000; McMorran M og Morawiecka I, 2000; Mersfelder TL og Stewart LR, 2000; Stading JA, Skrabal MZ et al, 2001; Stoner SC, Lea JW et al, 2003; Brown A, Bagley C et al, 2003; Malhi H, Atac B et al, 2004; Linder JD, Monkemuller KE et al, 2000.
Warfarin og etoricoxib (COX-2 hæmmer)
I et placebo-kontrolleret cross-over studie fik 14 raske personer warfarin i 28 dage for at opnå steady-state INR mellem 1,4 og 1,7, Schwartz JI, Agrawal NG et al, 2007. Derefter blev personerne randomiseret til 120 mg etoricoxib dagligt eller placebo i 21 dage, hvorefter de skiftede til den anden behandling. Der var ingen wash-out periode mellem de to forsøgsperioder. Etoricoxib forøgede INR med 13% (90% konfidensinterval: 8%, 19%; P
Phenprocoumon og phenylbutazon
I et studie med seks raske behandlet med phenylbutazon i 14 dage blev protrombintiden efter en enkelt dosis phenprocoumon indgivet på 4.-dagen fordoblet og plasma phenprocoumon-koncentrationen steg, O'Reilly RA, 1982.
Phenprocoumon og lornoxicam
I et cross-over studie med 6 raske personer forekom et beskedent fald i clearence af phenprocoumon efter 17 dage med lornoxicam 8 mg daglig. Til trods herfor sås en nedsat faktor II og VII aktivitet, Masche UP, Rentsch KM et al, 1999.
Phenprocoumon og ibuprofen
3 studier med patienter i stabil phenprocoumon behandling viste ingen ændringer i den antikoagulerende effekt ved samtidig behandling med ibuprofen 600 mg til 2,4 g daglig i 7-14 dage, Thilo 1974, Duckert F 1975, Boekhout 1974.
Phenprocoumon og indometacin
Ved undersøgelse af en mulig interaktion mellem phenprocoumon og indometacin (Muller KH og Herrmann K, 1966, Muller G og Zollinger W, 1966) findes ingen ændringer i den antikoagulerende effekt under kombinationsbehandling.
Phenprocoumon og sulindac
I en undersøgelse af en mulig interaktion mellem phenprocoumon og sulindac i 20 patienter i behandling med phenprocoumon sås ingen ændringer i prothrombintid, Schenk H, Klein G et al, 1980.
Phenprocoumon og tolmetin
Ved undersøgelse af en mulig interaktion mellem phenprocoumon og tolmetin (Rust O, Biland L et al, 1975) findes efter 10 dages behandling med tolmetin ingen ændringer i den antikoagulerende effekt af phenprocoumon.
Phenprocoumon og naproxen
Ved undersøgelse af en mulig interaktion mellem phenprocoumon og naproxen 250 mg to gange daglig (Angelkort B, 1978) sås en lille, men ikke klinisk relevant, effekt på blødningstiden og en kortvarig effekt på protrombintiden.
Phenprocoumon og flurbiprofen
I en undersøgelse af en mulig interaktion med flurbiprofen i 19 patienter i behandling med phenprocoumon sås ingen ændringer i prothrombintid eller plasma phenprocoumon-koncentrationen under 2 ugers behandling med flurbiprofen, Marbet GA, Duckert F et al, 1977.
Phenprocoumon og tiaprofensyre
I en undersøgelse af en mulig interaktion mellem phenprocoumon og tiaprofensyre i 6 raske frivillige sås efter 2 dages kombinationsbehandling med tiaprofensyre ingen ændringer i phenprocoumons farmakokinetik eller i den antikoagulerende effekt, Durr J, Pfeiffer MH et al, 1981.
Supplerende litteratur: Bull J og Mackinnon J, 1975; Cronberg S, Wallmark E et al, 1984; Harder S og Thurmann P, 1996; Schafer AI, 1995.
Schenk H;Klein G;Haralambus I;Goebel R, Z Rheumatol, 1980, 39:102-108; [Coumarin therapy during antirheumatism therapy with sulindac]
Possible interactions between the new non-steroidal antirheumatic drug Sulindac and a coumarin derivative have been investigated. 20 subjects, who required anticoagulation therapy for a variety of medical conditions, were treated for 4 consecutive weeks with Sulindac at varying dosages (200-400 mg per day). Prothrombin time, Thrombotest and bleeding time were not significantly affected by the concurrent administration of Sulindac. It can be concluded that there is no clinically important interaction between phenprocoumon and the doses of sulindac that are considered effective in rheumatic disorders. There were some moderate side effects, only one drop out was registered because of gastro-intestinal bleeding (melaena)
Muller G;Zollinger W, Praxis , 1966, 55:1462-1467; [Effect of indomethacin on blood coagulation with special reference to the interference with anticoagulants]
Angelkort B, Fortschr Med, 1978, 96:1249-1252; [Effect of naproxen on the thrombocyte bleeding time and on the anticoagulant treatment with phenprocoumon]
With a dose of 250 mg b.i.d. naproxen causes a slight, apparently clinically not relevant alteration of the primary bleeding pattern. Against phenprocoumon, naproxen has a transient hypoprothrombinemic effect which is followed by a short phase of increased tolerance. A further influence on anticoagulant therapy is not shown
Odegaard AE, Tidsskr Nor Laegeforen, 1974, 94:2313-2314; [Interaction between anticoagulants and indomethacin]
Prospektivt studie omhandlende kombinationsbehandling med warfarin og indomethacin hos 14 patienter.Der observeres potentisering af warfarins effekt.
Muller KH;Herrmann K, Med Welt, 1966, 29:1553-1554; [Is a simultaneous therapy with anticoagulants and indomethacin compatible?]
Durr J;Pfeiffer MH;Penth B;Wetzelsberger K;Lucker PW, Arzneimittelforschung, 1981, 31:2163-2167; [Study on possible interactions between tiaprofenic acid and phenprocoumon (author's transl)]
The study deals with the clinical and pharmacokinetic interaction of tiaprofenic acid (Surgam) and phenprocoumon. 6 healthy volunteers received phenprocoumon p.o. with a view to decreasing Quick's value. After the first administration a pharmacokinetic profile of phenprocoumon was taken. As Quick's value dropped to 37% at the 4th day of the study, the subjects received tiaprofenic acid additionally. Afterwards the pharmacokinetic profiles of phenprocoumon and tiaprofenic acid were taken again. The study led to the following results: 1. The clotting parameters are not changed on synchronous administration of tiaprofenic acid and phenprocoumon. 2. The pharmacokinetic profile of tiaprofenic acid is not changed by pretreatment with phenprocoumon. 3. The parmacokinetic profile of phenprocoumon is not changed by tiaprofenic acid
Rust O;Biland L;Thilo D;Nyman D;Duckert F, Schweiz Med Wochenschr, 1975, 105:752-753; [Testing of the antirheumatic agent tolmetin for its interactions with oral anticoagulants]
In 15 patients on long-term oral anticoagulation the new antirheumatic drug tolmetin (Tolectin) was administered over a period of 10 days. Based on 11 parameters of coagulation, no interaction between the drug and phenprocoumon was found. A significant though clinically irrelevant prolongation of bleeding time was observed
Ravic M;Johnston A;Turner P;Ferber HP, Hum Exp Toxicol, 1990, 9:413-414; A study of the interaction between lornoxicam and warfarin in healthy volunteers
Prospektiv undersøgelse omhandlende 12 raske forsøgspersoner i kombinationsbehandling med warfarin og lornoxicam. Lornoxicam øgede serum koncentrationen af warfarin og forlænger PT.
Rhodes RS;Rhodes PJ;Klein C;Sintek CD, Drug Intell Clin Pharm, 1985, 19:556-558; A warfarin-piroxicam drug interaction
A piroxicam-warfarin interaction is presented with a discussion of the possible mechanism of action. A 60-year-old white male on warfarin therapy for recurrent pulmonary embolism and deep venous thrombophlebitis showed a decrease in his previously therapeutic and stable prothrombin time when piroxicam was discontinued from his drug regimen. On two rechallenges over a ten-month period, his prothrombin times showed consistent and clinically significant fluctuations as piroxicam was added and deleted from his drug regimen
Eichler HG;Jung M;Kyrle PA;Rotter M;Korn A, Eur J Clin Pharmacol, 1992, 42:227-229; Absence of interaction between tenoxicam and warfarin
The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has been studied in healthy volunteers. Tenoxicam did not alter the plasma warfarin concentration versus time profile. Treatment with it for 14 days had no effect on the average dose of warfarin required to maintain the prothrombin time within a specified range. The coumarin dose index, an indicator of warfarin sensitivity, remained unchanged during tenoxicam administration. The results demonstrate the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation
Juel J;Pedersen TB;Langfrits CS;Jensen SE, Eur J Clin Pharmacol, 2013, a, 69:February; Administration of tramadol or ibuprofen increases the INR level in patients on warfarin
Chan TY;Lui SF;Chung SY;Luk S;Critchley JA, Drug Saf, 1994, 10:267-269; Adverse interaction between warfarin and indomethacin
A 57-year-old man developed spontaneous skin bruising and haematuria during combined therapy with warfarin and indomethacin. Due to the potential effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the anticoagulant action of warfarin and platelet function, patients receiving both warfarin and NSAIDs should have their prothrombin time monitored very closely. Also, the risk of gastrointestinal haemorrhage with any NSAIDs must always be remembered
Brown A;Bagley C;Smith D;Caton V, Pharm J, 2003, 271-782; An interaction between warfarin and COX-2 inhibitors: Two case studies
Chung L;Chakravarty EF;Kearns P;Wang C;Bush TM, J Clin Pharm Ther, 2005, 30:471-477; Bleeding complications in patients on celecoxib and warfarin
PURPOSE: Non-selective non-steroidal anti-inflammatory drugs (nNSAIDs) used in combination with warfarin are associated with an approximately 3-fold increased risk of upper gastrointestinal bleeding (UGIB) compared with warfarin alone. Celecoxib, a selective inhibitor of cyclo-oxygenase 2 (COX-2), is associated with less gastric mucosal injury and platelet dysregulation than nNSAIDs. We compared rates of bleeding complications in patients taking celecoxib and warfarin with those taking warfarin alone. SUBJECTS AND METHODS: We performed a retrospective analysis using data from our Protime Clinic and pharmacy databases from January 2001 to April 2004. We identified 123 patients who took celecoxib and warfarin concurrently (overlap group). We compared rates of bleeding complications in this group with 1022 control patients who were taking warfarin alone. Bleeding complications were defined as major if they resulted in hospitalization, blood transfusion or death. RESULTS: During approximately 1063 months of exposure to both celecoxib and warfarin, 10 bleeding complications were identified, only one of which was considered major. No patients had UGIB. In the control group, 116 bleeding complications were identified over approximately 16 520 months of exposure to warfarin alone, with 101 minor and 15 major events, including six episodes of UGIB. The relative risk of all bleeding complications was 1.34 (95% CI: 0.70-2.57) in the overlap vs. control groups, and for major bleeds was 1.04 (95% CI: 0.14-7.85). CONCLUSIONS: There is a mild but non-significant increase in bleeding complications in patients taking celecoxib and warfarin compared with those taking warfarin alone
Karim A;Tolbert D;Piergies A;Hubbard RC;Harper K;Wallemark CB;Slater M;Geis GS, J Clin Pharmacol, 2000, 40:655-663; Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects
The objective of this study was to determine the effects of celecoxib, an anti-inflammatory/analgesic agent that primarily inhibits COX-2 and not COX-1 at therapeutic doses, on the steady-state pharmacokinetic profile and hypoprothrombinemic effect of racemic warfarin in healthy volunteers. Twenty-four healthy adult volunteers on maintenance doses of racemic warfarin (2-5 mg daily), stabilized to prothrombin times (PT) 1.2 to 1.7 times pretreatment PT values for 3 consecutive days, were randomized to receive concomitant celecoxib (200 mg bid) or placebo for 7 days in an open-label, multiple-dose, randomized, placebo- controlled, parallel-group study of warfarin pharmacokinetics and PT. Steady-state exposure of S- and R-warfarin (area under the curve [AUC]) and maximum plasma concentration (Cmax) in subjects receiving celecoxib were within 2% to 8% of the warfarin AUC and Cmax in subjects receiving placebo during the concomitant treatment period. In addition, PT values were not significantly different in subjects receiving warfarin and celecoxib concomitantly compared with subjects receiving warfarin and placebo. In conclusion, concomitant administration of celecoxib has no significant effect on PT or steady-state pharmacokinetics of S- or R- warfarin in healthy volunteers
Chierichetti S;Bianchi G;Cerri B, Curr Ther Res Clin Exp, 1975, 18:568-572; Comparison of feprazone and phenylbutazone interaction with warfarin in man
The potentiation of the anti-coagulant activity of warfarin by phenylbutazone 300 mg daily was compared with feprazone 400 mg daily. Fourteen patients receiving long-term treatment with Warfarin were divided into 3 groups: 5 received feprazone, 5 received phenylbutazone, and 4 received placebo for 5 days. Daily prothrombin times were measured for 2 weeks before and 9 days after treatment commenced. The results showed that the potentiation of warfarin activity was significantly lower in the feprazone group (P< 0,05) and less prolonged (P< 0,025) in comparison with the phenylbutazone group.
Ermer JC;Hicks DR;Wheeler SC;Kraml M;Jusko WJ, Clin Pharmacol Ther, 1994, 55:305-316; Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin
Potential interactions between the nonsteroidal anti-inflammatory etodolac and the anticoagulant warfarin were studied in 18 healthy subjects by use of a randomized, three-period crossover design. Each treatment lasted 2 1/2 days and consisted of warfarin, etodolac, or both drugs. Prothrombin time was determined daily during each warfarin period to measure pharmacologic effect. Total serum concentration and unbound fraction of both drugs were determined over the dose interval after the last dose of the study drug(s). Concomitant etodolac did not affect the prothrombin time response or the unbound clearance of warfarin. During concomitant etodolac administration, the median peak concentration of total warfarin was significantly decreased by 19% (p = 0.005), median total clearance was significantly increased by 13% (p = 0.0123), and the unbound fraction tended to increase (median unbound fraction of warfarin, 1.245% with etodolac and 1.045% without etodolac; p = 0.0979; not statistically significant). These observations suggest a small displacement of warfarin from serum protein by etodolac or a metabolite of etodolac. No etodolac pharmacokinetic parameter was significantly affected by concomitant warfarin administration. Thus etodolac does not appear to alter the unbound clearance of warfarin or augment its pharmacologic effect. Nevertheless, it is prudent that clinical monitoring be done for individuals taking these two compounds concomitantly
Linder JD;Monkemuller KE;Davis JV;Wilcox CM, South Med J, 2000, 93:930-932; Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombinemia
Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia occurred
Dentali F;Douketis JD;Woods K;Thabane L;Foster G;Holbrook A;Crowther M, Ann Pharmacother, 2006, a, 40(7-8): 1241-1247-8; Does celecoxib potentiate the anticoagulant effect of warfarin? A randomized, double-blind, controlled trial
BACKGROUND: The management of patients who are receiving warfarin therapy and have musculoskeletal problems that require treatment with a nonsteroidal antiinflammatory drug (NSAID) is problematic because NSAID use may increase the risk for bleeding. Cyclooxygenase-2 selective NSAIDs such as celecoxib may be less likely to promote gastrointestinal bleeding; however, there are concerns that they could potentiate the anticoagulation effect of warfarin. OBJECTIVE: To determine whether celecoxib potentiates the anticoagulant effect of warfarin, as measured by the international normalized ratio (INR). METHODS: We performed a randomized, controlled, crossover trial to assess the effect on INR of celecoxib versus codeine (control treatment) in 15 patients who were receiving warfarin therapy and required analgesic treatment for osteoarthritis. During Phase 1 of the study, patients were randomly allocated to receive celecoxib 200 mg/day or codeine phosphate 7-15 mg 3-4 times daily for 5 weeks. During Phase 2 of the study, patients stopped the first study medication and started the other study medication; there was no drug-free interval between phases. Weekly INR testing was performed during the 10 week study period. Adopting the intent-to-treat principle, we used generalized estimating equations to analyze the data. RESULTS: There was no significant difference in the mean INR values during each 5 week treatment period when patients received either celecoxib or codeine. There was, therefore, insufficient evidence to reject the hypothesis that these 2 treatments had an equal effect on the INR (mean difference [95% CI] 0.10 [-0.04 to 0.24]; p = 0.16) based on mean imputation. This finding was confirmed after we repeated the analysis with multiple imputations (mean difference [95% CI] 0.093 [-0.16 to 0.35]; p = 0.47). CONCLUSIONS: Our results suggest that treatment with celecoxib does not potentiate the INR when taken with warfarin. Larger randomized trials are warranted to address the effects of coadministered warfarin and celecoxib on clinical outcomes
Chan TY, Int J Clin Pharmacol Ther, 1998, 36:403-405; Drug interactions as a cause of overanticoagulation and bleedings in Chinese patients receiving warfarin
Little is known about the incidence and consequences of drug interactions in patients receiving warfarin. Hence, drug interactions as a cause of overanticoagulation and bleedings were determined in Chinese patients admitted to our medical unit during a 9-month period in 1994/95. Only patients with an admission international normalized ratio (INR) of > 3.0 (target range 2.0-2.5) were included since the drug interactions, if present, were more likely to be of clinical significance. Of 35 patients reviewed, 7 had a predisposing condition such as peptic ulcer and 19 received drugs or folk medicines that can interact with warfarin. Based on the temporal relationship between the initiation of the interacting agent(s) and the rise in INR/onset of bleedings, drug-warfarin interactions were definitely (n = 6) or possibly (n = 1) responsible in 7 patients (drugs for common cold 2, piroxicam plus piroxicam gel 2, medicated oil (15% methyl salicylate) plus Salvia miltiorrhiza Bge 1, 'analgesic balm' (50% methyl salicylate) 1, diclofenac gel 1). These agents were prescribed by their physicians (n = 1), family doctors (n = 1) and other specialists (n = 1) or bought over-the-counter (n = 2). One other patient used the drugs from previous consultations. Five of the 7 patients developed bleedings. Drug interactions accounted for 20% of all patients with an INR of > 3.0 and 5 (36%) of 14 patients with bleedings. Patients receiving warfarin should be warned about the danger of self-medication. When prescribing warfarin, physicians should be aware of other medications that their patients are taking
Slattery JT;Levy G;Jain A;McMahon FG, Clin Pharmacol Ther, 1979, 25:51-60; Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin
The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin
Jain A;McMahon FG;Slattery JT;Levy G, Clin Pharmacol Ther, 1979, 25:61-66; Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin
The purpose of this investigation was to determine whether the anti- inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen
Vesell ES;Passananti GT;Johnson AO, J Clin Pharmacol, 1975, 15:486-495; Failure of indomethacin and warfarin to interact in normal human volunteers
In young, normal, male Caucasian volunteers, two different double- blind, placebo-controlled, randomized studies were performed to determine whether indomethacin interacts in a clinically significant fashion with warfarin. In the first study, stabilized hypoprothrombinemia was achieved by daily oral warfarin administration for at least 11 days; then indomethacin was administered concurrently with warfarin for five more days. During this five-day period failure of indomethacin to alter the degree of hypoprothhrombinemia induced by warfarin indicated that indomethacin does not interact with warfarin in vivo in a clinically significant fashion. A similar conclusion was drawn from results of the second experiment, in which plasma warfarin concentrations and prothrombin times were measured after a single oral dose of warfarin administered both before and after ten consecutive days of oral indomethacin administration. Thus, these studies suggest that warfarin may be given to patients receiving indomethacin and indomethacin may be administered to patients on warfarin without intensification or diminution of the normally expected hypoprothrombinemie effects of the dose of warfarin in that individual
Gabb GM, Med J Aust, 1996, 164:700-701; Fatal outcome of interaction between warfarin and a non-steroidal anti- inflammatory drug
Kauistik omhandlende en patient i kombinationsbehandling med warfarin og ibuprofen.
Voss GD;Schweitzer P, Am J Hosp Pharm, 1994, 51:2506, 2508; GI bleeding associated with nabumetone
Loftin JP;Vesell ES, J Clin Pharmacol, 1979, 19:733-742; Interaction between sulindac and warfarin: different results in normal subjects and in an unusual patient with a potassium-losing renal tubular defect
While sulindac failed to affect significantly warfarin-induced hypoprothrombinemia in normal male volunteers, it markedly prolonged prothrombin time in a patient with a renal tubular defect who had been anticoagulated with warfarin. This difference in individual response with respect to a drug interaction illustrates the need to adjust information on drug interactions to the particular clinical circumstances and conditions under which drugs are coadministered
Pullar T, Br J Rheumatol, 1989, 28:265-266; Interaction of ibuprofen and warfarin on primary haemostasis
Schulman S;Henriksson K, Br J Rheumatol, 1989, 28:46-49; Interaction of ibuprofen and warfarin on primary haemostasis
It has been stated that ibuprofen can be safely prescribed with concomitant warfarin. The effect of ibuprofen on primary haemostasis was investigated in 20 patients on warfarin for venous thromboembolism. Ibuprofen, 600 mg orally t.i.d., was added for 1 week. Bleeding time, prothrombin time, platelet count and urinalysis for haemoglobin were performed before and 90 minutes after the first dose and after 1 week. The bleeding time was significantly prolonged after 90 minutes (p less than 0.01) and after 1 week (p less than 0.05) and in four cases it was prolonged above the normal range. No clinical side-effects were observed apart from microscopic haematuria and haematoma. Thus, ibuprofen may cause clinical problems in some patients treated with warfarin, particularly in the elderly on complex drug regimens. It is advisable to check the bleeding time a few days after treatment with ibuprofen has been started in patients already on oral anticoagulation, and discontinue the former if the bleeding time is prolonged above the normal range
Schaefer MG;Plowman BK;Morreale AP;Egan M, Am J Health Syst Pharm, 2003, a, 60:1319-1323; Interaction of rofecoxib and celecoxib with warfarin
The interaction of celecoxib and rofecoxib with warfarin was studied. Patients stable on warfarin therapy and concurrently taking a cyclooxygenase-2 (COX-2) inhibitor comparator (traditional nonsteroidal antiinflammatory medications, salsalate, or acetaminophen) randomly received celecoxib 200 mg/day or rofecoxib 25 mg/day for three weeks. After a one-week washout period, the patients were crossed over to treatment with the opposite COX-2 inhibitor for three more weeks. The International Normalized Ratio (INR) was measured at baseline and at weeks 1, 2, and 3 of therapy with each COX-2 inhibitor by testing blood samples obtained by finger stick. Data for 16 patients were analyzed. The INR increased by 13%, 6%, and 5% on average in patients taking celecoxib at weeks 1, 2, and 3, respectively, and by 5%, 9%, and 5% in patients taking rofecoxib. Changes in the INR were statistically significant at week 1 for celecoxib and at week 2 for rofecoxib. Of the 12 subjects who had a clinically significant > or = 15% change in the INR while receiving either COX-2 inhibitor, 4 showed this change for both agents. Adverse drug reactions were similar for each COX-2 inhibitor, but the rate of edema requiring medical intervention was higher in the rofecoxib group. Significant increases in the INR were observed in patients who were stable on warfarin therapy after the addition of therapy with rofecoxib or celecoxib
Marbet GA;Duckert F;Walter M;Six P;Airenne H, Curr Med Res Opin, 1977, 5:26-31; Interaction study between phenprocoumon and flurbiprofen
The effects of flurbiprofen on various coagulation and haemostasis parameters were studied in 19 patients adequately anticoagulated on a fixed dose of phenprocoumon. Laboratory controls were performed 5 times at weekly intervals. Flurbiprofen 50 mg 3-times daily was given for 2 weeks after an initial control period of 2 weeks. The last control followed 1 week after cessation of flurbiprofen. All changes observed during the administration of flurbiprofen were quantitatively moderate; some reached statistical significance. The prothrombin time (%) Factor II and Factor X values fell; Factor II values remained unchanged. Factor IX values fell only in the first week on flurbiprofen and reached control values thereafter. Phenprocoumon concentration remained constant throughout. There was no change in spontaneous platelet aggregation. Although there was a slight, statistically significant increase in the Ivy bleeding time, it remained within the normal range. These findings suggest that the interference of flurbiprofen with oral anticoagulation is minimal and probably of no clinical relevance
Toon S;Holt BL;Mullins FG;Bullingham R;Aarons L;Rowland M, Br J Clin Pharmacol, 1990, 30:743-750; Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin
1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring
Penner JA;Abbrecht PH, Curr Ther Res Clin Exp, 1975, 18:862-871; Lack of interaction between ibuprofen and warfarin
In 36 normal male volunteers a placebo controlled, double-blind, randomised factorial design study was carried out to determine whether ibuprofen (Motrin«) interacts with warfarin. Seven and one-half milligrams (7,5 mg) of warfarin were administred concurrently with the morning dose of 300 or 600 mg of ibuprofen for 14 consecutive days. The total daily dose of ibuprofen was 1200 or 2400 mg. (300 eller 600 mg 4 gange daglig). During this 14-day period of combined ibuprofen+warfarin administration, ibuprofen failed to alter the degree of hypoprothrombinemia caused by warfarin. The total plasma warfarin levels, the PT, PTT and Factors II, V;VII and IX results do not indicate the possibility of displacement of warfarin by ibuprofen
Turck D;Su CA;Heinzel G;Busch U;Bluhmki E;Hoffmann J, Eur J Clin Pharmacol, 1997, 51:421-425; Lack of interaction between meloxicam and warfarin in healthy volunteers
OBJECTIVE: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. RESULTS: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S- warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCss values for the more potent S-enantiomer were 5.07 mg.h.l-1 (27.5%) for warfarin alone and 5.64 mg.h.l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg.h.l-1 (43.8%) and 7.58 mg.h.l-1 (39.1%). CONCLUSION: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory
Mieszczak C;Winther K, Eur J Clin Pharmacol, 1993, a, 44:205-206; Lack of interaction of ketoprofen with warfarin
We gave ketoprofen (100 mg bid) for 7 days, on a placebo-controlled, double-blind basis, to 15 healthy male volunteers already stabilized on warfarin in dosages which lowered the prothrombin time by about 60%. Ketoprofen did not affect the prothrombin time, there was no change in coagulation cascade parameters, and there was no clinical evidence of bleeding. We conclude that ketoprofen in this dosage has no significance effect on the anticoagulant effect of warfarin
Hilleman DE;Mohiuddin SM;Lucas BD, Am J Med, 1993, 95:30S-34S; Nonsteroidal antiinflammatory drug use in patients receiving warfarin: emphasis on nabumetone
Phenylbutazone has been clearly demonstrated to interact pharmacokinetically and clinically with warfarin, although several other nonsteroidal antiinflammatory drugs (NSAIDs) also have the potential to interact with warfarin to cause alterations in prothrombin time. Aspirin is known to inhibit platelet aggregation irreversibly, whereas nonaspirin NSAIDs are thought to inhibit platelet aggregation reversibly. In contrast, nabumetone was not shown to cause significant inhibition of platelet aggregation, which may be related to the fact that nabumetone preferentially inhibits the prostaglandin synthase-2 isozyme instead of the prostaglandin synthase-1 isozyme. Furthermore, in studies in patients and normal volunteers stabilized on warfarin, nabumetone did not cause alterations in the prothrombin time or international normalized ratio. Based on data evaluating the concomitant use of nabumetone and warfarin, the relative lack of platelet inhibition, and the relatively lower risk of nabumetone- induced gastrointestinal mucosal damage as assessed by radiolabeled chromium-51 fecal blood loss studies and endoscopic evaluations, nabumetone may be preferred if concomitant therapy with warfarin is indicated
Masche UP;Rentsch KM;von Felten A;Meier PJ;Fattinger KE, Eur J Clin Pharmacol, 1999, 54:857-864; Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics
OBJECTIVE: To investigate the effect of co-administration of the non-steroidal anti-inflammatory drug (NSAID) lornoxicam on the pharmacokinetics of (R)- and (S)-phenprocoumon and their effect on factor II and VII activities. METHODS: Six healthy male volunteers completed an open crossover study. Plasma concentrations of (R)- and (S)-phenprocoumon and activities of coagulation factors II and VII were measured after a single oral dose of 9 mg phenprocoumon racemate. In the second session, lornoxicam administration was started 3 days before phenprocoumon administration and continued twice daily until the last blood sample was drawn. RESULTS: Lornoxicam co-administration resulted in a statistically significant increase of the area under the concentration-time curve (AUC) of the more potent (S)-isomer of phenprocoumon from a median value of 100 (range 68-146) mg x h x 1(-1) to 124 (92-239) mg x h x 1(-1). For the (R)-isomer, the AUC increase from 96 (70-142) mg x h x 1(-1) in the absence to 108 (75-155) mg x h x 1(-1) in the presence of lornoxicam was not statistically significant. In a model-based analysis, an increase of (S)-phenprocoumon and (R)-phenprocoumon bioavailability of 14% [95% CI (9%, 19%)] and 6% (2%, 10%) and a decrease of their clearances by 15% (8%, 21%) and 6% (0%, 13%) was obtained. Lornoxicam co-administration did not influence the free fractions of (R)- or (S)-phenprocoumon. Contrary to what was expected from the changes in pharmacokinetics, a statistically significant decrease in the effect of phenprocoumon on factor II and VII activity was observed for the sessions with lornoxicam co-administration. For factor VII, lornoxicam was found to increase the concentration causing half-maximal effect (C50) of phenprocoumon by 70% [95% CI (38%, 111%)]. CONCLUSION: Co-administration of lornoxicam at the upper limit of recommended doses mainly altered the pharmacokinetics of the more potent (S)-isomer and to a lesser degree those of (R)-phenprocoumon. Despite these changes in pharmacokinetics, a decrease of the effect on factor II and VII activity was observed. These results suggest that in the case of lornoxicam co-administration in a patient treated with phenprocoumon the prothrombin time should be monitored closely
Bull J;Mackinnon J, Practitioner, 1975, 215:767-769; Phenylbutazone and anticoagulant control
Three patients in whom serious haemorrhagic complications occurred as a result of interaction of phenylbutazone with warfarin are described. A suggestion as to how this could be avoided is put forward
O'Reilly RA, Arch Intern Med, 1982, 142:1634-1637; Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon
To compare the marked hypoprothrombinemic augmentation in man of racemic warfarin sodium by the pyrazolons phenylbutazone and sulfinpyrazone with that of the coumarin anticoagulant phenprocoumon, these interactions were studied prospectively in six normal subjects. Large single doses of racemic phenprocoumon, 0.6 mg/kg orally, were administered with and without daily phenylbutazone, 300 mg, or sulfinpyrazone, 400 mg, beginning three days before phenprocoumon and continuing for 14 days. Daily blood samples were drawn for phenprocoumon content and one-stage prothrombin time. Phenylbutazone markedly increased both the phenprocoumon concentrations and prothrombin times, whereas sulfinpyrazone did not
Banfield C;O'Reilly R;Chan E;Rowland M, Br J Clin Pharmacol, 1983, 16:669-675; Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations
The pharmacokinetics and urinary metabolic profile of R and S-warfarin, following administration of a 1.5 mg/kg oral dose of racemic warfarin, alone and 4 days into an oral regimen of 100 mg phenylbutazone three times a day, was investigated in three volunteers using a stereospecific h.p.l.c. fluorescent assay. The mean elimination half- life of S-warfarin was increased from 25 to 46 h during phenylbutazone administration, whilst that of the R-isomer was decreased from 37 to 25 h. The peak unbound concentrations of both warfarin enantiomers were higher during phenylbutazone administration, due to displacement. Displacement was not stereoselective. The unbound clearance of more potent S-warfarin is decreased by four-fold during phenylbutazone administration, due to substantial inhibition of both 6- and 7- hydroxylation, significant pathways of elimination of S-warfarin in the absence of phenylbutazone. The unbound clearance of R-warfarin is almost unchanged during phenylbutazone administration, due to the marginal effect of phenylbutazone on 6- and 7-hydroxylation, themselves minor pathways of elimination of this enantiomer in the absence of phenylbutazone. The stereoselective reduction of S- and R-warfarin, to their respective SS and RS-alcohols, is also substantially inhibited during phenylbutazone administration. Collectively the data point to the complex effect of phenylbutazone administration on warfarin´s pharmacokinetics
Stoner SC;Lea JW;Dubisar BM;Farrar C, J Am Geriatr Soc, 2003, 51:728-729; Possible international normalized ratio elevation associated with celecoxib and warfarin in an elderly psychiatric patient
The development of the nonsteroidal antiinflammatory cyclooxygenase- 2 (COX-2) selective inhibitors (celecoxib, rofecoxib) revolutionized the treatment of osteoarthritis and rheumatid arthritis. Ideally, by selectively inhibiting COX-2, antiinflammatory action can be achieved with fewer gastrointestinal adverse events and drug interactions.
Carter SA, Lancet, 1979, b, 2:698-699; Potential effect of sulindac on response of prothrombin-time to oral anticoagulants
Kasuistik omhandlende en mandlig patient i kombinationsbehandling med warfarin og sulindac. Efter 3 ugers kombinationsbehandling stiger PT kraftigt.
Aggeler PM;O'Reilly RA;Leong L;Kowitz PE, N Engl J Med, 1967, a, 276:496-501; Potentiation of anticoagulant effect of warfarin by phenylbutazone
Prospektiv undersøgelse omhandlende 5 både patienter og raske forsøgspatienter i kombinationsbehandling med warfarin og phenylbutazon.
Dennis VC;Thomas BK;Hanlon JE, Pharmacotherapy, 2000, 20:234-239; Potentiation of oral anticoagulation and hemarthrosis associated with nabumetone
Concomitant therapy with warfarin and nonsteroidal antiinflammatory drugs (NSAIDs) is of concern due to the potential for increased bleeding. Nonsteroidal antiinflammatory drugs may alter patient response to warfarin by pharmacodynamic or pharmacokinetic interactions. A man receiving long-term, stable warfarin therapy experienced a significant increase in international normalized ratio 1 week after nabumetone was added to his regimen. Despite prompt reduction of the warfarin dosage, he experienced hemarthrosis of his right knee. Previous reports suggested lack of interaction between nabumetone and warfarin. Caution and close monitoring are advisable when the two agents are administered concomitantly
Flessner MF;Knight H, JAMA, 1988, 259:353; Prolongation of prothrombin time and severe gastrointestinal bleeding associated with combined use of warfarin and ketoprofen
Chan TY, Br J Clin Pract, 1997, 51:177-178; Prolongation of prothrombin time with the use of indomethacin and warfarin
A patient with a greatly prolonged international normalised ratio (INR) during the combined use of warfarin and indomethacin is described. In patients on warfarin, non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided as far as possible. If NSAIDs are absolutely necessary, patients should be closely monitored for prolongation of INR and bleeding
Choi KH;Kim AJ;Son IJ;Kim KH;Kim KB;Ahn H;Lee EB, J Korean Med Sci , 2010, 25:337-341; Risk factors of drug interaction between warfarin and nonsteroidal anti-inflammatory drugs in practical setting
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. In this study, we evaluated the risk factors for international normalized ratio (INR) increase, which is a surrogate marker of bleeding, after addition of an NSAID in a total of 98 patients who used warfarin. Patient age, sex, body mass index, maintenance warfarin dose, baseline INR, coadministered medications, underlying diseases, and liver and kidney functions were evaluated for possible risk factors with INR increase > or =15.0% as the primary end-point. Of the 98 patients, 39 (39.8%) showed an INR elevation of > or =15.0% after adding a NSAID to warfarin therapy. Multivariate analysis showed that high maintenance dose (>40 mg/week) of warfarin (P=0.001), the presence of coadministered medications (P=0.024), the use of meloxicam (P=0.025) and low baseline INR value (P=0.03) were the risk factors for INR increase in respect to NSAID-warfarin interaction. In conclusion, special caution is required when an NSAID is administered to warfarin users if patients are taking warfarin >40 mg/week and other medications interacting with warfarin
O'Reilly RA;Trager WF;Motley CH;Howald W, J Clin Invest, 1980, 65:746-753; Stereoselective interaction of phenylbutazone with [12C/13C]warfarin pseudoracemates in man
Prospektiv unders°gelse omhandlende 8 raske fors°gspersoner i kombinationsbehandling med warfarin og phenylbutazon.
Ross JR;Beeley L, Lancet, 1979, 2:1075; Sulindac, prothrombin time, and anticoagulants
Kauistik omhandlende 2 patienter i kombinationsbehandling med warfarin og sulindac.
Schwartz JI;Agrawal NG;Hartford AH;Cote J;Hunt TL;Verbesselt R;Eckols DR;Gottesdiener KM, J Clin Pharmacol, 2007, 47:620-627; The effect of etoricoxib on the pharmacodynamics and pharmacokinetics of warfarin
The effects of etoricoxib on pharmacodynamic and pharmacokinetic parameters of warfarin were determined in healthy men and women. Subjects titrated with warfarin to an international normalized ratio for prothrombin time of 1.4 to 1.7 during a 28-day prestudy period were randomly assigned in crossover fashion to be coadministered etoricoxib (120 mg) or matching placebo over two 21-day continuous periods. On day 21, a 24-hour pharmacokinetic profile of both S(-) and R(+) warfarin, as well as international normalized ratio values, were determined. Etoricoxib increased the international normalized ratio by 13% (90% confidence interval: 8%, 19%; P </= .001). Etoricoxib had no effect on the pharmacokinetics of S(-) warfarin but led to a modest increase in the AUC(24 h) ( approximately 10%) of R(+) warfarin. This increase in the international normalized ratio is not likely to be clinically important in most patients; however, the international normalized ratio of patients coadministered oral anticoagulants and etoricoxib should be closely monitored, particularly during initiation of therapy
Koren JF;Cochran DL;Janes RL, Am J Med, 1987, 82:1278-1280; Tolmetin-warfarin interaction
Kasuistik omhandlende en mandlig patient i kombinationsbehandling med warfarin og tolmetin. Efter indtag af tre doser tolmetin klager patienten over nµsebl°dninger og PT er steget fra 15 til 70,2 sekunder.
Mersfelder TL;Stewart LR, Ann Pharmacother, 2000, 34:325-327; Warfarin and celecoxib interaction
OBJECTIVE: To report a case of increased international normalized ratio (INR) in a patient receiving warfarin and celecoxib. CASE SUMMARY: A 73- year-old white woman with hypothyroidism and heart failure was admitted to the hospital with increased orthopnea, dyspnea on exertion, and hemoptysis. On laboratory evaluation, she was noted to have an increased INR. The only reported change in her medications was the addition of celecoxib approximately five weeks before admission. Her INR had previously been stable. After discontinuation of warfarin and celecoxib, fresh frozen plasma and vitamin K were administered to normalize INR. The patient was not rechallenged. DISCUSSION: Warfarin is an oral anticoagulant with numerous reports of drug interactions. It is possible that other drug therapies or disease states may have contributed to the elevation in INR; however, the observed increase in INR occurred five weeks after beginning celecoxib therapy. The Food and Drug Administration has issued a notice about the possibility of interactions between these two medications. CONCLUSIONS: Celecoxib may potentiate the anticoagulant effects of warfarin. Patients receiving warfarin should be carefully monitored when adding, changing, or removing celecoxib from their medication regimen
Malhi H;Atac B;Daly AK;Gupta S, Postgrad Med J, 2004, 80:107-109; Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication
Drug metabolism may be perturbed by genetically determined differences in the metabolic activity of cytochrome P450 enzymes. The authors encountered extensive bleeding in a patient receiving warfarin for anticoagulation after the introduction of celecoxib, an anti-inflammatory drug. As the CYP2C9 enzyme metabolises these drugs, it was determined whether variant alleles were responsible for altering warfarin handling. Genetic analysis established that the patient was a compound heterozygote with CYP2C9*2 and *3 variant alleles, which exhibit lower drug metabolising capacity and enhance susceptibility to drug toxicity
Lewis RJ;Trager WF;Chan KK;Breckenridge A;Orme M;Roland M;Schary W, J Clin Invest, 1974, a, 53:1607-1617; Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone
An examination of the metabolic fate of the R and S isomers of warfarin revealed that the two isomers were metabolised by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin.These observations suggested that interactions between warfarin and other drugs might be manifest stereospecifically, i.e. have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearence of S warfarin was slowed from 3,1 to 1,1 % per h in one subject and from 2,3 to 1,6% per h in another. In contrast, the clearence of R-warfarin was increased from 1,5 to 3,0 % per h and from 0,9 to 1,6 % per h in two subjects after phenylbutazone. The rate of clearence of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearence of the S isomer masked the stimulation of the clearence of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.