Dosisjustering af warfarin kan blive nødvendig afhængig af INR. Hyppig kontrol af INR ved indledning og ophør af kombinationsbehandlingen
Der er lokaliseret tre kasuistisker omhanlende øget virkning af warfarin ved samtidig brug af norfloxacin. I eet kontrolleret studium på patienter i warfarin behandling, men uden infektioner eller andre intercurrente sygdomme ,findes ingen signifikante interaktioner, hverken kinetisk eller dynamisk.
Ciprofloxacin og warfarin
To studier (Israel DS, Stotka J et al, 1996a; Bianco TM, Bussey HI et al, 1992) viser hos ialt 48 raske forsøgspersoner ingen statistisk signifikant interaktion mellem warfarin og ciprofloxacin ud fra et farmakokinetisk og farmakodynamisk synspunkt bedømt ved måling af serum warfarin koncentrationer og protrombintider (PT).
Et andet prospektivt studie (Rindone JP, Kelley CL et al, 1991) omhandlende 9 relevante patienter i kombinationsbehandling med warfarin og ciprofloxacin finder ingen statistisk signifikante ændringer i patienternes prothrombintid. Dog ses for 2 af patienterne stigninger i prothrombintid på henholdsvis 13 og 22%.
En anden retrospektiv undersøgelse med 64 patienter fandt, at ciprofloxacin i kombination med warfarin gav signifikant INR stigning. Stigningen i INR førte ikke til klinisk signifikante blødninger eller hospitalsindlæggelser Ghaswalla PK, Harpe SE et al, 2012.
Derudover er der i litteraturen fundet 6 case-reports (ialt 7 patienter) med rapporterede blødningsepisoder ved samtidig behandling med warfarin og ciprofloxacin (Ellis RJ, Mayo MS et al, 2000a; Mott FE, Murphy S et al, 1989; Renzi R og Finkbeiner S, 1991b; Kamada AK, 1990; Dugoni-Kramer BM, 1991; Byrd DC, Gaskins SE et al, 1999b).
Ifølge litteraturen kan den forøgede antikoagulantiske virkning af warfarin dog også skyldes andre parametre, f.eks. er det kendt, at feber og infektionstilstande kan øge den antikoagulatoriske effekt af warfarin. I et studie (Ellis RJ, Mayo MS et al, 2000a) er inkluderet 64 tilfælde som er anmeldt til FDA p. gr. a. mistanke om interaktion mellem warfarin og ciprofloxacin, i 25 af tilfældene optrådte blødninger og i 1 tilfælde død.
Supplerende litteratur: Lane MA, Zeringue A et al, 2014
Ofloxacin/Norfloxacin og warfarin
Et studie (Rocci ML, Vlasses PH et al, 1990) finder hos 10 raske forsøgspersoner ingen statistisk signifikant interaktion mellem warfarin og norfloxacin ud fra et farmakokinetisk og farmakodynamisk synspunkt.
Der er yderligere fundet to case-reports omhandlende mulig interaktion mellem warfarin og norfloxacin (Linville T og Matanin D, 1989; Jolson HM, Tanner LA et al, 1991) og to case-reports omhandlende mulig interaktion mellem ofloxacin og warfarin Leor J og Matetzki S, 1988; Baciewicz AM, Ashar BH et al, 1993).
Observationen var her ligeledes som for ciprofloxacin, at patienterne oplevede blødninger under samtidig behandling med warfarin og norfloxacin/ofloxacin.
Ofloxacin og phenprocoumon
Ved samtidig indgift af flerdosis phenprocoumon og ofloxacin hos 7 raske forsøgspersoner (Verho M, Malerczyk V et al, 1987) er der ud fra et farmakodynamisk synspunkt ikke fundet interaktion.
Moxifloxacin og warfarin
En retrospektiv undersøgelse med 54 patienter fandt at moxifloxacin i kombination med warfarin gav signifikant INR stigning. Stigningen i INR førte ikke til klinisk signifikante blødninger eller hospitalsindlæggelser Ghaswalla PK, Harpe SE et al, 2012.
Ialt 3 patienter (O'Connor KA og O'Mahony D, 2003) i kombinationsbehandling med warfarin og moxifloxacin viser kraftige stigninger i patienternes peak INR. På trods af seponering af warfarin behandlingen forbliver INR forhøjet 1-2 uger efter. Der rapporteres ikke om nogle blødningstilfælde.
To kasuistikker (Elbe DHT og Chang SW, 2005; Arnold LM, Nissen LR et al, 2005) omhandlende ialt 8 patienter viser at patienterne ved kombinationsbehandling med warfarin og moxifloxacin får forhøjede INR værdier.
Produktresumeet (SPC) for moxifloxacin angiver, at der ved ved samtidig indgift af en enkelt dosis warfarin (25 mg) og 400 mg moxifloxacin daglig hos 24 raske forsøgspersoner ikke observeres statistisk signifikante ændringer i forsøgspersonernes INR værdier.
Endnu en kasuistik (Yildiz F, Kurtaran B et al, 2008) omhandlede en 74-årig mand, der indlægges med infektiøs endocarditis og behandles med penicillin. 3 uger senere ses ingen forbedring og hjertesvigt udvikles. Patienten får indsat ny mitralklap og behandles med warfarin (5 mg/dag) efter 72 timer. Moxifloxacin (400 mg/dag) behandling opstartes pga. lungebetændelse 8 dage efter operationen. Herefter stiger INR, warfarin-behandling stoppes og INR måles 12 dage efter operationen til 12,0. Patienten får plasma og INR falder til 2,8 og warfarin-behandling opstartes igen. 3 dage senere måles INR til 13,0 og warfarin- og moxifloxacin-behandlingen stoppes. Herefter gives plasma og når INR er faldet gives warfarin igen. INR forbliver nu på 2,5-3,5.
I yderligere to kasuistikker, omhandlende en hhv. 67-årig kvinde og en 62-årig kvinde i samtidig behandling med warfarin (hhv. 2,5 mg/dag og 1,5mg/dag) og moxifloxacin (400 mg/dag), beskrives en klinisk relevant stigning i INR. Den 67-årige kvinde udviklede blødning i det peritoneale hulrum. Chao C, Lin S et al, 2013, Yew KL og Lee WC, 2012a.
Levofloxacin og warfarin
En prospektiv undersøgelse (Liao S, Palmer M et al, 1996) omhandlende ialt 16 raske forsøgspersoner viste ingen statistisk signifikante ændringer i warfarins kinetik og dynamik efter indgift af en enkelt dosis warfarin og 1000 g levofloxacin daglig. Et andet studie (Yamreudeewong W, Lower DL et al, 2003) viser, at ved samtidig indgift af warfarin og levofloxacin gennemsnitlig ikke ses statistisk signifikante ændringer i INR før og efter kombinationsbehandling. Under forsøget var det dog nødvendigt at ændre warfarin dosis for 7 patienter pga. forhøjede INR værdier, og deraf risiko for forekomst af blødninger.
En retrospektiv undersøgelse med 28 patienter fandt at levofloxacin i kombination med warfarin gav signifikant INR stigning. Stigningen i INR førte ikke til klinisk signifikante blødninger eller hospitalsindlæggelser Ghaswalla PK, Harpe SE et al, 2012.
Tre kasuistikker (Jones CB og Fugate SE, 2002; Ravnan SL og Locke C, 2001: Gheno G og Cinetto L, 2001) omhandlende ialt 8 patienter viste forhøjede INR-værdier ved kombinationsbehandling med warfarin og levofloxacin. Kun en enkelt patient havde forekomst af mindre blødninger, hvor patientens dosis af warfarin blev reduceret med ca. 20% (Jones CB og Fugate SE, 2002).
Et studie (Vadlamudi RS, Smalligan RD et al, 2007) gennemgår tre kasuistikker, hvor tre patienter i behandling med warfarin fik forhøjede INR-værdier samt blødninger efter kombination med levofloxacin. Den ene patient døde, mens de to andre fik seponeret warfarin.
Endnu en kasuistik (Howard-Thompson A, Hurdle AC et al, 2008) omhandler en 78-årig kvinde, som har været i stabil warfarin-behandling (7 mg dagligt med INR 2,5) i tre måneder, da hun får en infektion, der behandles med metronidazol (250 mg 3 gange dagligt i 5 dage) og levofloxacin (500 mg po. QD i 6 dage). 6 dage efter behandlingsstart bliver patienten indlagt med INR 9, næseblod samt intraparenchymal blødning. Blødningen formodes dog at skyldes interaktion mellem warfarin og metronidazol.
I en retrospektiv evaluering af patienter, som var i samtidig behandling med levofloxacin og warfarin, Mercadal OG, Gracia GB et al, 2009 måltes INR før, under og efter kombinationsbehandlingen. De 21 patienter, der inkluderedes fik co-administration af de 2 stoffer i 7 ± 4,4 dage. Hos 3 patienter opstod blødning som følge af INR ændringer. Hos yderligere 2 patienter sås INR ændringer, som krævede reduktion af warfarindosis. Hos en tredje patient var administration af vitamin K nødvendigt.
Den gennemsnitlige INR steg signifikant fra 1,85 til 2,64 ved addition af levofloxacin til patienter i warfarin-behandling. Glasheen JJ, Fugit RV et al, 2005
Supplerende litteratur: Lane MA, Zeringue A et al, 2014, Nemoto C, Ikegami Y et al, 2012a
NB! I Danmark er kun øjendråber indeholde levofloxacin markedsført.
Yildiz F;Kurtaran B;Cayli M;Candevir A;Sumbul Z, Heart and Vessels, 2008, 23:286-288; A significant interaction between moxifloxacin and warfarin in a patient with a mitral bioprosthetic valve
Moxifloxacin is an advanced-generation fluoroquinolone with a broad spectrum of antimicrobial activity that is not metabolized by cytochrome P450 system. Therefore, the drug interaction of moxifloxacin is rarely seen. It has been reported that moxifloxacin is safe and well tolerable. We aimed to report a drug interaction between moxifloxacin and warfarin in a 74-year-old patient with a prosthetic mitral valve. copyright Springer Japan 2008
Chao C;Lin S;Lai C, Tomt indhold, 2013, 61:August; Abdominal wall hematoma and hemoperitoneum in an individual with concomitant use of warfarin and moxifloxacin
Liao S;Palmer M;Fowler C;Nayak RK, J Clin Pharmacol, 1996, 36:1072-1077; Absence of an effect of levofloxacin on warfarin pharmacokinetics and anticoagulation in male volunteers
Some fluoroquinolone drug-drug interactions involving inhibition of the hepatic metabolism of agents such as theophylline and caffeine have been identified. This study was designed to investigate the potential interaction of the fluoroquinolone levofloxacin in a standard multiple-dose regimen with the oral anticoagulant warfarin. Sixteen healthy male volunteers were given a single oral dose of 30 mg warfarin sodium during a multiple-dose regimen of placebo or levofloxacin 500 mg twice daily, in a placebo-controlled, randomized, double-blind, two-way crossover design. Plasma R(+) and S(-) warfarin concentrations and prothrombin times were measured for 6 days after administration of each warfarin dose. The pharmacokinetic parameters of both enantiomers of warfarin were comparable in the absence and presence of levofloxacin, with no significant differences noted in warfarin peak plasma concentration, time to peak plasma concentration, apparent total body clearance, and terminal disposition half-life. Levofloxacin also had no significant effect on warfarin pharmacodynamics, as assessed by baseline-corrected maximum prothrombin time, time to maximum prothrombin time, and area under the prothrombin time-versus-time curve. The lack of pharmacokinetic or pharmacodynamic interaction observed in this study suggests that a clinically important effect of levofloxacin on warfarin is unlikely to occur during concurrent therapy
Verho M;Malerczyk V;Rosenkranz B;Grotsch H, Curr Med Res Opin, 1987, 10:474-479; Absence of interaction between ofloxacin and phenprocoumon
The effect of ofloxacin on steady-state phenprocoumon pharmacodynamics was investigated in 7 healthy male volunteers taking daily sub-therapeutic doses of phenprocoumon. Ofloxacin 200 mg once daily for 7 days did not alter the anti-coagulant response (Quick values) to phenprocoumon after a stabilization phase of 2 weeks. Mean Quick values during the steady-state phase before and during ofloxacin administration were 54% and 52%, respectively. In vitro studies with concentrations of 0 to 100 mg ofloxacin/1 added to plasma also failed to show any interaction. The results indicate, therefore, that ofloxacin does not interfere with vitamin K-dependent coagulation cascade, as seen after other antibiotics
Nemoto C;Ikegami Y;Shimada J;Tsukada Y;Abe Y;Tase C, J Anesth, 2012, a, 26:943-944; Acute renal failure caused by severe coagulopathy induced by the interaction between warfarin potassium and levofloxacin: a case report
Mott FE;Murphy S;Hunt V, Ann Intern Med, 1989, 111:542-543; Ciprofloxacin and warfarin
Kasuistik omhandlende en 72-årig mandlig patient der sættes i behandling med 750 mg ciprofloxacin 2 gange daglig i 2 uger på grund af en cyste på venstre nyre.1 uge efter at patienten bliver færdig med ciprofloxacin behandlingen indlægges denne med en PT på 42 s. PT før behandling med ciprofloxacin er ikke angivet i artiklen.Patienten behandles med warfarin (4 mg/daglig) og frossen plasma, og PT falder til 16-18 s.Efter 2 uger observeres igen hæmaturia og patienten sættes i behandling med 500 mg ciprofloxacin 2 gange daglig. I 6 dage forebliver PT konstant (18-19 s). Da ciprofloxacinbehandlingen ophører (ikke angivet hvornår) falder PT til 12,8 s i løbet af 2 dage.
Linville D;Emory C;Graves L, Am J Med, 1991, 90:765; Ciprofloxacin and warfarin interaction
A recent letter by Mott et al. reported a possible interaction between ciprofloxacin and warfarin increasing the prothrombin time (PT). We report a similar case in which the administration of ciprofloxacin to a patient receiving a stable warfarin dose resulted in a prolongation of the PT and hemorrhage.
Renzi R;Finkbeiner S, Am J Emerg Med, 1991, b, 9:551-552; Ciprofloxacin interaction with sodium warfarin: a potentially dangerous side effect
Ciprofloxacin, a quinolone antibiotic which exhibits minimal side effects and has broad antimicrobial spectrum, is being used frequently to treat various infections. A patient is reported who had previously maintained a stable prothrombin time on Coumadin for 5 years, and who exhibited a marked prolongation of prothrombin time when placed on ciprofloxacin for gastroenteritis
Washington C;Hou SY;Hughes NC;Campanella C;Berner B, J Clin Pharmacol, 2007, c, 47:1320-1326; Ciprofloxacin prolonged-release tablets do not affect warfarin pharmacokinetics and pharmacodynamics
The purpose of this study was to determine whether the pharmacokinetics of warfarin and ciprofloxacin PR (a prolonged-release formulation of ciprofloxacin) were altered after coadministration. Eighteen healthy male volunteers were given a single oral 7.5-mg dose of warfarin, a single oral 500-mg dose of ciprofloxacin PR, or both drugs administered together in a randomized, open-label, 3-way crossover study. Ciprofloxacin concentrations, warfarin (R)- and (S)-enantiomer concentrations, prothrombin time, and activated partial thromboplastin time were measured over 120 hours following study drug administration. There were no significant differences in pharmacokinetic or pharmacodynamic parameters among treatments. A slightly greater value of half-life for (R)-warfarin was observed when coadministered with ciprofloxacin PR compared with warfarin administered alone (52.6 vs 50.1 hours, P = .029). This difference is not considered clinically relevant, because the values remain similar. These results show that warfarin pharmacokinetics and pharmacodynamics are not altered with concomitant administration of ciprofloxacin PR
Ellis RJ;Mayo MS;Bodensteiner DM, Am J Hematol, 2000, a, 63:28-31; Ciprofloxacin-warfarin coagulopathy: a case series
Ciprofloxacin, when given to patients previously anticoagulated with warfarin, can occasionally cause an exaggerated hypoprothombinemic response and bleeding diatheses. Two such cases encountered at our institution are presented and data is combined with 64 cases reported to the Food and Drug Administration's (FDA) Spontaneous Reporting System (SRS) database, which included all cases reported from 1987 through 1997. Of 66 total cases the median age was 72 (range 36-94). The mean time to detection of the coagulopathy following the ciprofloxacin challenge was 5.5 days (n = 50). Hospitalization was reported in 15 cases, bleeding in 25 cases, and death in one case. The median prothrombin time (PT) and International Normalized Ratio (INR) was 38.0 (n = 13) and 10.0 (n = 23), respectively. The mean number of medications taken was 6.5 (n = 45). The mean time to correction was significantly shorter between the treated (2.5 days) and the untreated (4.0 days) groups (P < 0. 008). The ciprofloxacin-warfarin coagulopathy occurred most commonly in patients in their seventh decade and in those who require polypharmacy. Active treatment of the coagulopathy results in more rapid resolution than observation alone. Clinicians should be aware of the potential bleeding complications that can occur with the ciprofloxacin-warfarin drug-drug interaction
Dugoni-Kramer BM, DICP, 1991, 25:1397; Ciprofloxacin-warfarin interaction
Kasuistik omhandlende en 70-Õrig mandlig patient sµttes 7 mÕneder efter en bypass operation pÕ langtidsbehandling med 1,25 mg warfarin daglig. Patientens PT blev mÕlt til 18,3 sekunder. Desuden er patienten ogsÕ i behandling med furosemid, digoxin, isosorbid dinitrat, ranitidin, insulin og et Kalium supplement.4 dage efter start med ciprofloxacin behandling mÕles patientens PT til 29,1 sekund. Warfarin behandlingen stoppes, og der fortsµttes med ciprofloxacin. I l°bet af de nµste 3 dage stiger PT dog til 33,0 sekunder.Efter stop med ciprofloxacin behandling fortsµttes med warfarin behandling (1,0 mg/daglig), men PT forbliver ukontrollabel. 10 dage efter oph°r med ciprofloxacin behandling stabiliseres patientens PT pÕ 1,5 mg warfarin /daglig.
Israel DS;Stotka J;Rock W;Sintek CD;Kamada AK;Klein C;Swaim WR;Pluhar RE;Toscano JP;Lettieri JT;Heller AH;Polk RE, Clin Infect Dis, 1996, a, 22:251-256; Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin
To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin
Yamreudeewong W;Lower DL;Kilpatrick DM;Enlow AM;Burrows MM;Greenwood MC, Pharmacotherapy, 2003, 23:333-338; Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy
STUDY OBJECTIVE: To evaluate the effect of levofloxacin coadministration on the international normalized ratio (INR) in patients receiving warfarin therapy. DESIGN: Prospective analysis. SETTING: Outpatient clinic at a Veterans Affairs medical center. PATIENTS: Eighteen adult patients receiving warfarin. INTERVENTION: On the basis of clinical diagnosis and judgment, levofloxacin was prescribed to the 18 patients for treatment of various types of infection. The INR was measured before and at 2-8-day intervals after the coadministration of levofloxacin therapy, and once after completing therapy. Warfarin dosages were adjusted when necessary. MEASUREMENTS AND MAIN RESULTS: Warfarin dosages were changed in seven patients as a result of the first nontherapeutic INR values obtained after start of levofloxacin therapy. Owing to a concern regarding noncompliance and the adverse effect of bleeding, warfarin dosage was adjusted in one patient even though his first INR value was in the high end of the therapeutic range (2.98, therapeutic range 2-3). One patient withdrew from the study after the first INR measurement after levofloxacin coadministration. Because of a concern about the possible bleeding complication, warfarin dosage was also adjusted in this patient after obtaining his first INR value. Therefore, only the INR values obtained before and the first INR values obtained after levofloxacin administration were compared to evaluate the effect of levofloxacin on INR determination of warfarin therapy. The INR values obtained before levofloxacin administration did not differ significantly from the first INR values obtained after levofloxacin coadministration (mean +/- SD 2.61 +/- 0.44 vs 2.74 +/- 0.83, 95% confidence interval -0.449-0.196, p=0.419). CONCLUSION: The INR values measured before and after concomitant levofloxacin therapy were not significantly different. However, the ability to detect a significant difference may be affected by the small number of patients studied. Further studies with a larger sample are required to better determine the effect of levofloxacin coadministration on INR monitoring during warfarin therapy
Glasheen JJ;Fugit RV;Prochazka AV, Pharmacotherapy, 2003, 23:1079-1080; Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy--a comment
Comments on study by Dr. Yamreudeewong and her colleagues.
Fischer HD;Juurlink DN;Mamdani MM;Kopp A;Laupacis A, Arch Intern Med, 2010, 170:617-621; Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study
BACKGROUND: Some antibiotic agents, including cotrimoxazole, inhibit the metabolism of warfarin sodium and possibly increase the risk of hemorrhage. We examined the risk of upper gastrointestinal (UGI) tract hemorrhage in older patients receiving warfarin in combination with antibiotics commonly used to treat urinary tract infection, with a focus on cotrimoxazole. METHODS: This population-based, nested case-control study using health care databases in Ontario, Canada, between April 1, 1997, and March 31, 2007, identified residents 66 years or older who were continuously treated with warfarin. Cases were hospitalized with UGI tract hemorrhage. For each case, we selected up to 10 age- and sex-matched control subjects. We calculated adjusted odds ratios (aORs) for exposure to cotrimoxazole, amoxicillin trihydrate, ampicillin trihydrate, ciprofloxacin hydrochloride, nitrofurantoin, and norfloxacin within 14 days before the UGI tract hemorrhage. RESULTS: We identified 134 637 patients receiving warfarin, of whom 2151 cases were hospitalized for UGI tract hemorrhage. Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33). Treatment with ciprofloxacin was also associated with increased risk (aOR, 1.94; 95% CI, 1.28-2.95), but no significant association was observed with amoxicillin or ampicillin (1.37; 0.92-2.05), nitrofurantoin (1.40; 0.71-2.75), or norfloxacin (0.38; 0.12-1.26). Compared with amoxicillin or ampicillin, cotrimoxazole prescription was associated with an almost 3-fold risk (ratio of ORs, 2.80; 95% CI, 1.48-5.32). CONCLUSIONS: Among older patients receiving warfarin, cotrimoxazole is associated with a significantly higher risk of UGI tract hemorrhage than other commonly used antibiotics. Whenever possible, clinicians should prescribe alternative antibiotics in patients receiving warfarin
Rindone JP;Kelley CL;Jones WN;Garewal HS;Keuey CL, Clin Pharm, 1991, 10:136-138; Hypoprothrombinemic effect of warfarin not influenced by ciprofloxacin
Recent case reports have suggested that some fluorquinolone antimicrobials may inhibit drug metabolism. For example, enoxacin and ciprofloxacine have been reported to decrease the clearance of theophylline, and norfloxacin and ciprofloxacin have been associated with enhancing the hypoprothrombinemic response to warfarin. To date, researchers have not specifically examined the effect of ciprofloxacin on the pharmacodynamics of warfarin. The purpose of this study was to evaluate the effect of ciprofloxacin on the hypoprothrombinemic effect of long-term, low-intensity warfarin therapy.
Ahmed A;Stephens JC;Kaus CA;Fay WP, J Thromb Thrombolysis, 2008, 26:44-48; Impact of preemptive warfarin dose reduction on anticoagulation after initiation of trimethoprim-sulfamethoxazole or levofloxacin
BACKGROUND: Antibiotics can potentiate warfarin anticoagulation. While preemptive warfarin dose reduction (DR) upon initiation of antibiotics has been advocated by experts, there are no published data regarding the efficacy of this strategy vs. the conventional strategy of not changing warfarin dose and carefully following international normalized ratio (INR) results. METHODS AND RESULTS: We compared the efficacy of preemptive 10-20% DR vs. no change in warfarin dosing in 40 chronically anticoagulated patients initiating trimethoprim-sulfamethoxazole (TMP-SMX) or levofloxacin. Eighteen patients received preemptive warfarin DR and 22 control patients underwent no change in warfarin dosing. There was no difference between the DR and control groups in the mean INR before beginning antibiotic therapy (2.53 +/- 0.12 vs. 2.52 +/- 0.11; P > 0.9). Mean interval between initiation of antibiotic and next INR was 5.1 +/- 0.4 vs. 4.7 +/- 0.5 days for DR vs. control patients, respectively (P > 0.5). For both TMP-SMX and levofloxacin, patients managed with a preemptive warfarin DR strategy did not exhibit a statistically significant change in the INR after initiating antibiotic therapy. In contrast, for each antibiotic, control group patients exhibited a significant increase in mean post-antibiotic INR compared to mean pre-antibiotic INR, though the effect was more pronounced in patients treated with TMP-SMX than with levofloxacin. Of DR group patients who were treated with TMP-SMX, none (0/8) developed a subtherapeutic INR, while 40% (4/10) of levofloxacin-treated patients developed a sub-therapeutic INR. Supra-therapeutic INR results led to transient interruption of warfarin dosing in 2 patients (11%) in the DR group vs. 12 patients (55%) in the control group (P = 0.007). CONCLUSIONS: Prophylactic warfarin DR of 10-20% is effective in maintaining therapeutic anticoagulation in patients initiating TMP-SMX. An expectant strategy consisting of no change in warfarin dosing with short-term INR follow-up appears reasonable in patients treated with levofloxacin
Vadlamudi RS;Smalligan RD;Ismail HM, South Med J, 2007, 100:720-724; Interaction between warfarin and levofloxacin: case series
Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin
Baciewicz AM;Ashar BH;Locke TW, Ann Intern Med, 1993, 119:1223; Interaction of ofloxacin and warfarin
Kasuistik omhandlende en 73-årig kvindelig patient der er i langtidsbehandling med warfarin ( 5 mg 6 gange ugentlig). Derudover er kvinden også i behandling med verapamil, enalapril, hydrochlorothiazide-trimterene og amitryptilin. Kvinden lider af gentagne urinvejsinfektioner og behandles med 400 mg ofloxacin 2 gange daglig. Før behandling med ofloxacin har kvindens PT svinget mellem 15 og 21 sec, og hæmatocrit-værdi på 38,1%. Efter 5 dages behandling med ofloxacin indlægges kvinden på hospital med hæmaturi og PT = 77,7 sec. Hæmatokritværdi= 28%.
Howard-Thompson A;Hurdle AC;Arnold LB;Finch CK;Sands C;Self TH, Am J Geriatr Pharmacother , 2008, 6:33-36; Intracerebral hemorrhage secondary to a warfarin-metronidazole interaction
Background: It has been >25 years since the interaction between warfarin and metronidazole was last reported in the literature. The current case report represents the first documentation of this interaction associated with intracerebral hemorrhage. Case summary: We present a case of a 78-year-old white woman started on metronidazole (250 mg every 8 hours for 5 days) and levofloxacin (500 mg QD for 6 days) for an upper respiratory tract infection after visiting a walk-in clinic. The patient did not notify any of the health care professionals involved that she was on concomitant warfarin therapy, which had been stable over the last 3 months. Her warfarin dose was 7 mg daily, and her most recent international normalized ratio (INR) reading was 2.5. Nine days after her clinic visit, the patient was admitted to the hospital for a profuse nosebleed with an INR of 8.0 and was found to have an intraparenchymal hemorrhage of the left occipital lobe. The Naranjo adverse drug reaction probability scale indicated that the association with metronidazole was probable and the association with levofloxacin was possible (scores of 7 and 4, respectively). After a 1-week hospital stay, she was discharged. Conclusions: This adverse event is highly suggestive of a drug interaction caused primarily by metronidazole, which produces an increase in S-warfarin concentrations. Treatment provided by health care providers who were not familiar with the patient and the use of a different pharmacy (where the pharmacist was unaware of her current medications) likely contributed to the event. copyright 2008 Excerpta Medica Inc
Ravnan SL;Locke C, Pharmacotherapy, 2001, 21:884-885; Levofloxacin and warfarin interaction
Numerous case reports have documented an enhanced hypoprothrombinemic effect caused by an interaction between fluoroquinolones (most notably, ciprofloxacin) and warfarin sodium. Conflicting data exist regarding the clinical significance of this interaction. Two patients who had elevated international normalized ratios after receiving concurrent levofloxacin and warfarin sodium are described
Jones CB;Fugate SE, Ann Pharmacother, 2002, 36:1554-1557; Levofloxacin and warfarin interaction
OBJECTIVE: To report 4 cases of hypoprothrombotic response resulting from addition of levofloxacin therapy to chronic warfarin therapy and to review related literature to support or refute a warfarin-levofloxacin interaction. CASE SUMMARY: Four patients, 34-81 years old, were prescribed levofloxacin concomitantly with stable warfarin therapy. Three patients had a target international normalized ratio (INR) range of 2.0-3.0 and experienced an increase in INR to 3.5, 8.12, and 11.5 on days 11, 5, and 4 of a 10-day course of levofloxacin, respectively. The fourth patient experienced minor bleeding, with a slightly elevated INR on the second day of levofloxacin therapy that required up to a 19% warfarin dose reduction during levofloxacin treatment. DISCUSSION: An initial premarketing clinical trial concluded that levofloxacin had no effect on warfarin's pharmacokinetics and pharmacodynamic response. Two case reports have since documented an increase in INR in patients taking long-term warfarin on completion of levofloxacin therapy. Our case reports provide further evidence of a significant increase in INR observed during concomitant levofloxacin therapy. The proposed mechanism of this interaction is displacement of warfarin from protein binding sites, reduction in gut flora producing vitamin K, and decreased warfarin metabolism. CONCLUSIONS: Prolonged prothrombin response in patients undergoing chronic warfarin therapy has been well documented with many antibiotics, including fluoroquinolones. Recognition of newer antibiotics' effects on warfarin therapy is important to guide safe use and monitoring of anticoagulation therapy. Our case studies demonstrate significant elevations in INR values during and up to 1 day after levofloxacin therapy in patients undergoing stable warfarin therapy
Gheno G;Cinetto L, Eur J Clin Pharmacol, 2001, 57:427; Levofloxacin-warfarin interaction
Recently, we observed two patients on warfarin treatment for whom a short course of levofloxacin was associated with significant prolongation of the international normalized ratio (INR).
Arnold LM;Nissen LR;Ng TMH, Pharmacotherapy, 2005, 25(6): 904-907-907; Moxifloxacin and warfarin: Additional evidence for a clinically relevant interaction
Several case reports have been published regarding an interaction between fluoroquinolones and warfarin; however, the exact mechanism of the interaction has yet to be established. We describe three patients who were receiving warfarin and experienced increases in international normalized ratio (INR) when moxifloxacin was added. Two of the patients had stable anticoagulation regimens and then experienced persistent elevations in their INRs shortly after therapy with moxifloxacin was started. The third patient experienced a dramatic rise in INR after the first dose of moxifloxacin was administered. These cases strengthen the evidence that an interaction does exist despite manufacturer-generated statements to the contrary. Increased awareness of this potential interaction is necessary to ensure appropriate monitoring and improve therapeutic decision making
Yew KL;Lee WC, Tomt indhold, 2012, a, 67:August; Moxifloxacin-warfarin Interaction
Elbe DHT;Chang SW, Ann Pharmacother, 2005, 39:361-364; Moxifloxacin-Warfarin interaction: A series of five case reports
OBJECTIVE: To report 5 cases of a moxifloxacin-warfarin drug interaction, all resulting in elevated international normalized ratios (INRs) and clinically significant hemorrhage in one case. CASE SUMMARIES: Between January 2002 and January 2004, 4 men and 1 woman (age range 63-92 y) were retrospectively identified as having significantly elevated INR results shortly after being prescribed moxifloxacin with concomitant warfarin therapy. DISCUSSION: This is the second series of case reports describing an interaction between warfarin and moxifloxacin. The current moxifloxacin product monograph indicates this drug has no significant effect on the pharmacokinetics of R- or S-warfarin or the prothrombin time (INR). A moxifloxacin-warfarin interaction probably led to prolonged hospitalization in 2 cases and significant gastrointestinal hemorrhage in one case. In 3 of the 5 cases, a moxifloxacin-warfarin interaction was assessed as probable, and in the remaining 2 cases, a moxifloxacin-warfarin interaction was assessed as possible by use of the Naranjo probability scale. CONCLUSIONS: Healthcare professionals should consider moxifloxacin for the potential to interact with warfarin. Routine, frequent INR monitoring for patients previously stabilized on warfarin during initiation and discontinuation of moxifloxacin may help detect this potential interaction
Linville T;Matanin D, Ann Intern Med, 1989, 110:751-752; Norfloxacin and warfarin
Kasustik omhandlende en 91-årig kvindelig patient hvis sygehistorie er følgende: mild demens, periodisk artriel fibrillering, hypertension, hyperparathyroidisme og degenerative ´joint disease´. Før behandling med norfloxacin måles patientens PT til 21,6 sekunder. 5 dage efter start behandling med norfloxacin opdages en 4,5 cm stor blodsamling i hjernen og PT måles til 36,5 sekunder. Patienten behandles med vitamin K og plasma for at sænke PT, men patienten dør 3 dage efter.
Leor J;Matetzki S, Ann Intern Med, 1988, 109:761; Ofloxacin and warfarin
Visser LE;Penning-van Bees FJ;Kasbergen AA;de Smet PA;Vulto AG;Hofman A;Stricker BH, Thromb Haemost, 2002, 88:705-710; Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants
BACKGROUND: Several case reports associated combined use of coumarins and antibacterial drugs with overanticoagulation. Despite the fact that these drugs are frequently prescribed concurrently, there is little quantitative information on the risks of such complications. OBJECTIVE: To study which antibacterial drugs are associated with overanticoagulation during therapy with coumarins. Design: Population-based cohort study in a sample of the Rotterdam Study. SUBJECTS: All patients who were treated with acenocoumarol or phenprocoumon in the study period from April 1, 1991 through December 31, 1998 and for whom INR data were available. METHODS: Patients were followed until an INR >/= 6.0, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of an INR >/= 6.0 in relation to concomitant use of an oral anticoagulant and antibacterial drugs after adjustment for several potentially confounding factors such as age, gender, hepatic dysfunction, malignancies, and heart failure. RESULTS: Of the 1,124 patients in the cohort, 351 developed an INR >/= 6.0. The incidence rate was 6.9 per 10,000 treatment days. Sulfamethoxazole combined with trimethoprim most strongly increased the risk of overanticoagulation with an adjusted relative risk of 20.1 (95% CI: 10.7-37.9). Stratification showed that the induction period of overanticoagulation varied between different antibacterial drugs. CONCLUSION: In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, several antibacterial drugs strongly increased the risk of overanticoagulation. Awareness of these drug interactions and more frequent monitoring of INR values during the initial stages of antibacterial drug therapy are warranted to minimize the risk of bleeding complications
Kamada AK, DICP, 1990, 24:27-28; Possible interaction between ciprofloxacin and warfarin
A 72-year-old man had been taking warfarin for a pulmonary embolus and recurrent deep-vein thromboses. His prothrombin times (PTs) were maintained between 15 and 18 sec (PT ratio 1.25-1.5 x control) for several months on a dose of warfarin 2.5 mg/d. Six weeks prior to starting ciprofloxacin 500 mg bid, the patient´s PT was 15.5 sec (Pt ratio 1.29 x control). After one week of ciprofloxacin, his PT had increased to 22 sec (PT ratio 1.83 x control). No other causes for the increase were apparent. It is recommended that patients receiving both medications have their prothrombin times carefully monitored and warfarin doses adjusted only as necessary
Bianco TM;Bussey HI;Farnett LE;Linn WD;Roush MK;Wong YW, Pharmacotherapy, 1992, 12:435-439; Potential warfarin-ciprofloxacin interaction in patients receiving long- term anticoagulation
This study prospectively evaluated the potential interaction between the oral anticoagulant warfarin and the quinolone antimicrobial agent ciprofloxacin. After a 10-day placebo lead-in phase, 16 patients stabilized with long-term warfarin therapy were randomized to receive ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized ratios (INRs) measured by both standard laboratory analysis and by Coumatrak (finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a significant increase in INR. No patient experienced a bleeding event. These data support the fact that a warfarin-ciprofloxacin interaction does not routinely occur at this dosage and duration of ciprofloxacin therapy
Mercadal OG;Gracia GB;Leiva BE;Perayre BM;Reynaldo MC;Jodar MR, Pharm World Sci, 2009, 31:224-229; Retrospective assessment of potential interaction between levofloxacin and warfarin
Objective There is currently a controversy regarding interactions between levofloxacin and warfarin. The aim of this study was to determine the clinical relevance of this interaction in our setting. Setting A university hospital in Barcelona, Spain. Methods We carried out a retrospective evaluation of all patients hospitalized in our hospital during the period 2000-2005, selecting all those concomitantly treated with levofloxacin and warfarin for the study. The following data were compiled: demographic information, concomitant medication, comorbid conditions, and relevant analytical parameters, particularly the international normalized ratio (INR), including values taken before, during, and after concomitant administration of the two study drugs. Patients for whom INR values during concomitant administration were not available were excluded. Differences in INR before and during the potential interaction, and before and after the interaction were analyzed with the Wilcoxon t test using SPSS (V12.0). In addition, patients were stratified according to presence or not of toxic habits (smoking/alcohol consumption) to investigate the possible impact of these factors on the interaction under study. Results Among the 30 patients identified, 9 were excluded because INR data during concomitant administration of warfarin and levofloxacin were not available. Statistical analysis demonstrated significant increase in INR (P = 0.001) following addition of levofloxacin to warfarin therapy. Conclusions. The results of this study reaffirm the hypothesis that concomitant administration of levofloxacin and warfarin leads to INR increase; hence close monitoring of INR is advisable when patients are prescribed this combination of drugs. copyright 2008 Springer Science+Business Media B.V
McCall KL;Scott JC;Anderson-Jr HG, Pharmacotherapy, 2005; Retrospective evaluation of a possible interaction between warfarin and levofloxacin
Study Objectives. In order to clarify the clinical significance of a suspected drug interaction, we sought to determine if the international normalized ratio (INR) is affected when levofloxacin is administered in patients receiving long-term warfarin therapy Design. Retrospective cohort study using pharmacy and medical records. Setting. Outpatient clinic. Patients. Forty-three patients receiving long-term warfarin therapy who subsequently were prescribed either levofloxacin (22 patients) or felodipine (21 controls); felodipine was chosen as it has been shown not to interact with warfarin. Patients in both groups were required to have a documented INR before the start of levofloxacin or felodipine (pre-INR) and either during levofloxacin or felodipine therapy or within 15 days after the drug had been started (post-INR). Measurements and Main Results. Patient demographics were similar between the two treatment groups. The mean ± SD age of the patients in the levofloxacin and control groups was 59.5 ± 8.7 and 65.3 ± 11.5 years, respectively (p=0.07). The mean change between the pre- and post-INR (primary outcome measure) was 0.31 ± 0.82 (pre-INR 2.46, post-INR 2.76) and 0.21 ± 0.54 (pre-INR 2.46, post-INR 2.67) in the levofloxacin and felodipine groups, respectively (p=0.65). A post hoc power analysis, based on a sample-derived, weighted standard deviation of 0.68, revealed that the study had 66% power to detect a change of 0.5 in the INR value. The percentage of patients who required a warfarin dosage adjustment based on the post-INR (secondary outcome measure) was 41% (9 of 22 patients) in the levofloxacin group and 33% (7 of 21 patients) in the felodipine group. Conclusion. Although our primary analysis did not detect a warfarin-levofloxacin interaction, the potential for such an interaction, especially in idiosyncratic cases, cannot be ruled out. Clinicians should closely monitor INR values when levofloxacin is administered jointly with warfarin
Lane MA;Zeringue A;McDonald JR, Tomt indhold, 2014, 127:July; Serious bleeding events due to warfarin and antibiotic co-prescription in a cohort of veterans
Background Antibiotics may interact with warfarin, increasing the risk for significant bleeding events. Methods This is a retrospective cohort study of veterans who were prescribed warfarin for 30 days without interruption through the US Department of Veterans Affairs between October 1, 2002 and September 1, 2008. Antibiotics considered to be high risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin. Low-risk antibiotics include clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions, and receipt of other medications interacting with warfarin. Results A total of 22,272 patients met inclusion criteria, with 14,078 and 8194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (hazard ratio [HR] 1.48; 95% confidence interval [CI], 1.00-2.19) and azithromycin (HR 1.93; 95% CI, 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.50), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. International normalized ratio (INR) alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed within 3-14 days of co-prescription were at a decreased risk of serious bleeding (HR 0.61; 95% CI, 0.42-0.88). Conclusions Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk. 2014 Elsevier Inc. All rights reserved
O'Connor KA;O'Mahony D, Eur J Intern Med, 2003, 14:255-257; The interaction of moxifloxacin and warfarin in three elderly patients
Moxifloxacin is an oral 8-methoxyquinolone with a broad spectrum of anti-microbial activity. Clinical trials indicate that moxifloxacin is a safe and well-tolerated antibiotic. We describe a potentially serious interaction between moxifloxacin and warfarin in three frail, elderly patients. The healthy volunteers studied for the moxifloxacin-warfarin interaction differ from these patients
Glasheen JJ;Fugit RV;Prochazka AV, J Gen Intern Med , 2005, 20:653-656; The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens
BACKGROUND: Medication interactions account for a significant proportion of overanticoagulation in warfarin users. However, little is known about the incidence or degree of interaction with commonly used oral antibiotics. OBJECTIVE: To investigate the incidence and degree of overanticoagulation associated with commonly used oral antibiotics. DESIGN: Retrospective cohort study of patients using warfarin who initiated an antibiotic (azithromycin, levofloxacin, or trimethoprim/sulfamethoxazole (TMP/SMX)) or terazosin for clinical indications between January 1998 and December 2002. The incidence of international normalized ratio (INR) elevation and the degree of change and bleeding events after institution of either medication type was recorded. SUBJECTS: Patients at a university-affiliated Veteran's Affairs Medical Center. RESULTS: The mean change in INR was -0.15 for terazosin, 0.51 for azithromycin, 0.85 for levofloxacin, and 1.76 for TMP/SMX. These mean INR changes in the antibiotic groups were all statistically different from the terazosin group. The incidence of supratherapeutic INR was 5% for terazosin, 31% for azithromycin, 33% for levofloxacin, and 69% for TMP/SMX. The incidence of absolute INR >4.0 was 0% for terazosin, 16% for azithromycin, 19% for levofloxacin, and 44% for TMP/SMX. CONCLUSIONS: Among acutely ill outpatients, oral antibiotics (azithromycin, levofloxacin, and TMP/SMX) increase the incidence and degree of overanticoagulation
Stroud LF;Mamdami MM;Kopp A;Bell CM, Am J Med, 2005, 118:1417; The safety of levofloxacin in elderly patients on warfarin
Byrd DC;Gaskins SE;Parrish AM;Freeman LB, J Am Board Fam Pract, 1999, b, 12:486-488; Warfarin and ciprofloxacin interaction: case report and controversy
Ghaswalla PK;Harpe SE;Tassone D;Slattum PW, Am J Geriatr Pharmacother , 2012, 10:352-360; Warfarin-antibiotic interactions in older adults of an outpatient anticoagulation clinic
BACKGROUND: Several classes of drugs, such as antibiotics, may interact with warfarin to cause an increase in warfarins anticoagulant activity and the clinical relevance of warfarin-antibiotic interactions in older adults is not clear. OBJECTIVE: The aim of this study was to determine the effect of oral antibiotics, such as amoxicillin, azithromycin, cephalexin, ciprofloxacin, levofloxacin, and moxifloxacin, on the international normalized ratio (INR) in patients >/=65 years on stable warfarin therapy. The secondary objective was to compare the effect of warfarin-antibiotic interactions on outcomes of overanticoagulation. METHODS: Data for this retrospective cohort study were collected through a medical record review of patients in an outpatient anticoagulation clinic of a Veterans Affairs medical center. Patients aged >/=65 years on stable warfarin therapy and with at least 1 prescription of an oral antibiotic of interest during the period from January 1, 2003 to March 1, 2011 were included. A mixed-effects repeated-measures ANOVA model was used to determine the effect of antibiotics on the mean change in patients' INR. The Fisher exact test was used to determine the association between the antibiotics and secondary outcomes of overanticoagulation, using cephalexin as the control. Statistical significance was defined as a P value <0.05. RESULTS: A total of 205 patients had 364 prescriptions for warfarin and antibiotics concomitantly, and there was a significant interaction between antibiotic and time (F(15, 358) = 1.9; P = 0.0221). Antibiotics with a significant increase in INR were amoxicillin (P = 0.0019), azithromycin (P < 0.0001), ciprofloxacin (P = 0.002), levofloxacin (P < 0.0001) and moxifloxacin (P < 0.0001). There was a significant association between type of antibiotic and secondary outcomes of overanticoagulation. CONCLUSIONS: In older patients on stable warfarin therapy, antibiotics may lead to an increase in INR. However, this may not result in clinically significant outcomes of bleeding or hospitalization, suggesting that antibiotics may be prescribed for older adults taking warfarin as long as their INR is being routinely monitored