Hyppig kontrol af warfarins antikoagulerende virkning (INR) ved indledning og ophør af kombinationsbehandlingen.
I enkelte kasuistikker blev der målt stigning i INR/PT-værdier og i et enkelt tilfælde alvorlig blødning. Interaktion mistænkes, men mekanismen er ukendt. Der findes ingen prospektive kontrollerede undersøgelser.
Warfarin og erythromycin
I en prospektiv studie med 8 patienter i warfarin behandling (Weibert RT, Lorentz SM et al, 1989) øgede erythromycin 1 gram daglig den totale plasmakoncentration af warfarin med 9,4 %. Øgning af koncentrationen af S-warfarin og R-warfarin var af samme størrelsesorden. Der observeres signifikante stigninger i prothrombintid (PT) under behandling idet den gennemsnitlige stigning i prothrombin-ratio var 10 % efter 7 dages behandling med erythromycin.
I en undersøgelse med 12 raske frivillige (Bachmann K, Schwartz JI et al, 1984) sås en gennemsnitlig 14 % (0-30 %) signifikant reduktion af warfarin clearence efter indgift af erythromycin 1 gram i 5 dage. I forsøget blev der ikke konstateret nogen signifikant ændring af PT i erythromycin gruppen.
I modsætning til de beskedne ændringer vist i kliniske studier er der adskillige kasuistiske meddelelser (Sato RI, Gray DR et al, 1984; Hassell D og Utt JK, 1985) om markante stigninger i INR/PT og blødninger hos patienter i behandling med warfarin og erythromycin. Infektion kan være en confounder, idet infektion kan nedsætte aktiviteten af cytochrom P450 enzymsystemet og dermed påvirke warfarins metabolisme.
En 41-årig mand i behandling med warfarin (aorta- og mitralklapperne udskiftet), får erythromycin (1,5 mg samt 500 mg 6 timer efter) profylaktisk før tandbehandling. Dagen efter er der forsat blødning fra såret. INR steg fra 2.3 til 4.3 og hæmoglobin målt til 7.8 g/dl. Warfarin behandlingen blev stoppet og INR normaliseres (Wood,G.D. og Deeble,T., 1993).
Phenprocoumon og erythromycin
Et populationbaseret retrospekiv studie med patienter, som fik et coumarin (acencoumarol eller phenprocoumon) viste ingen øget risiko for INR>6 ved samtidig behandling med erythromycin (78 patienter), Visser LE, Penning-van Bees FJ et al, 2002. Et andet retrospektiv kohorte studie fra den samme forskningsgruppe fandt heller ikke hos patienter i acencoumarol eller phenprocoumon en øget risiko for hospitalsindlæggelse som følge af blødning ved samtidig behandling med erythromycin, Penning-Van-Beest FJA, Koerselman J et al, 2008
Warfarin og clarithromycin
Fire kasuistikker (Recker MW og Kier KL, 1997; Oberg KC, 1998; Gooderham MJ, Bolli P et al, 1999b; Dandekar SS og Laidlaw DA, 2001) viser, som for erythromycin en stigning i patienternes INR/PT-værdier. I den sidstnævnte kasuistik forekom der samtidig blødning (suprachoriodal).
Supplerende litteratur: Lane MA, Zeringue A et al, 2014
Phenprocoumon og clarithromycin
Et populationbaseret retrospektiv studie med patienter, som fik et coumarin (acencoumarol eller phenprocoumon) viste, at samtidig behandling med clarithromycin øgede risikoen for INR>6 med en relativ risiko på 11,7 (95 % KI 3,6-37,8), Visser LE, Penning-van Bees FJ et al, 2002. Risikoen var størst i de 3 første behandlingsdage. I modsætning hertil var der i et andet retrospektiv kohorte studie (fra den samme forskningsgruppe) med patienter i acencoumarol eller phenprocoumon ingen øget risiko for hospitalsindlæggelse som følge af blødning ved samtidig behandling med clarithromycin, Penning-Van-Beest FJA, Koerselman J et al, 2008. Infektion er en mulig confounder i de 2 studier.
En kasuistik beskriver en 70-årig kvinde i phenprocoumon behandling, som ved behandling med clarithromycin får markant stigning i prothrombintid og med efterfølgende behov for K-vitamin behandling. Der var ikke blødningskomplikationer, Meyboom RH, Heere FJ et al, 1996.
Warfarin og azithromycin
Fem kasuistikker (Woldtvedt BR, Cahoon CL et al, 1998a; Lane G, 1996a; Foster DR og Milan NL, 1999; Rao KB, Pallaki M et al, 2004; Shrader SP, Fermo JD et al, 2004a) viser stigning i patienternes INR/PT -værdier samt forekomst af blødninger ved kombinationsbehandling med warfarin og azithromycin. Nylig ændringer i warfarindosis, feber, anden medicin og kompliceret sygdom kan i disse kasuistikker have været medvirkende årsag til INR-stigningerne.
Et retrospektivt studie (McCall KL, Anderson HG et al, 2004) omhandlende 17 patienter i stabil warfarinbehandling viste ingen statistisk signifkante ændringer i patienternes INR-værdier under kombinationsbehandling med warfarin og azithromycin. For 6 patienter (35 %) var det dog nødvendigt med en justering af warfarin dosis på baggrund af post-INR-målinger. Et andet retrospektiv studie viste tilsvarende ingen forskel i INR mellem patienter i warafarin+azithromycin behandling og patienter i warfarin+terazozin behandling, Beckey NP, Parra D et al, 2000a. I modsætning hertil viste et retrospektiv studie med 32 patienter i stabil warfarinbehandling en gennemsnitlig stigning i INR på 0,51 ved samtidig behandling med azithromycin. Hos 16 % af patienterne var INR>4, Glasheen JJ, Fugit RV et al, 2005.
En anden retrospektiv undersøgelse med 73 patienter fandt, at azithromycin i kombination med warfarin gav signifikante INR stigninger. Disse stigninger i INR førte ikke til klinisk signifikante blødninger eller hospitalsindlæggelser Ghaswalla PK, Harpe SE et al, 2012.
Supplerende litteratur: Lane MA, Zeringue A et al, 2014
Phenprocoumon og azithromycin
Et retrospektiv kohort studie fandt, at den relative risiko for hospitalsindlæggelse som følge af blødning hos patienter i acencoumarol eller phenprocoumon behandling var 4,1 (95 % KI 1.0 -16,2) ved samtidig behandling med azithromycin. Infektion er en mulig confounder i studiet, Penning-Van-Beest FJA, Koerselman J et al, 2008.
Warfarin og roxithromycin
I et randomiseret placebo-kontrolleret studie (Paulsen O, Nilsson LG et al, 1988) med 21 raske frivillige sås ingen signifikante ændringer i koncentrationen af S-warfarin eller i protombintid ved kombinationsbehandling med warfarin og roxithromycin 150 mg 2 gange daglig.
Fem cases fra et større observationelt studie omhandler fem ældre kvinder i behandling med warfarin og samtidig behandling med roxitromycin, som indlægges med forhøjet INR (10,1-14.5). Aldersbetinget nedsat nyrefunktion og infektion kan have været medvirkende til forhøjet INR. Der er ikke oplysninger om INR målinger før kombinationsbehandlingen. Rotella J og Taylor DM, 2015.
Phenprocoumon og roxitromycin
En kasuistik beskriver en 75-årig mand i phenprocoumonbehandling, som ved behandling med roxithromycin for en luftvejsinfektion får markant stigining i prothrombintiden og efterfølgende behov for K-vitamin behandling. Der var ikke blødningskomplikationer, Meyboom RH, Heere FJ et al, 1996.
Supplerende litteratur: Eschenauer G, Collins CD et al, 2005; Pai MP, Graci DM et al, 2000; Westphal JF, 2000
Meyboom RH;Heere FJ;Egberts AC;Lastdrager CJ, Ned Tijdschr Geneeskd, 1996, 140:375-377; [Possible potentiation of phenprocoumon by clarithromycin and roxithromycin]
Two patients, a women of 70 and a man of 75 years old, who were using phenprocoumon chronically, and were monitored by a regional thrombosis service, received a macrolide antibiotic, clarithromycin and roxithromycin respectively, for an airway infection. Both patients developed a serious increase in hypocoagulability, requiring administration of phytomenadione and temporary decreases in phenprocoumon dose. There were no bleeding complications. After the antibiotics were discontinued, the original dosage of phenprocoumon was needed again. It is suggested that in these patients the macrolide antibiotics may have potentiated the effect of phenprocoumon, perhaps as a result of inhibition of phenprocoumon transformation by liver enzymes. In patients receiving chronic treatment with phenprocoumon, coagulation parameters should be regularly checked if they are given a macrolide antibiotic such as clarithromycin, roxithromycin or erythromycin
Shrader SP;Fermo JD;Dzikowski AL, Pharmacotherapy, 2004, a, 24:945-949; Azithromycin and warfarin interaction
A 57-year-old Caucasian woman came to the clinic with symptoms of an upper respiratory tract infection. She was treated with a 5-day course of oral azithromycin 500 mg on day 1, then 250 mg/day for 4 days. During this period, the patient decreased her cigarette smoking from 1 pack/day to 1 pack every 3 days. No additional confounding variables were present. Two days after the completion of therapy, her international normalized ratio (INR) was 8.32. Six case reports documented in the literature have suggested an azithromycin-warfarin interaction with a resultant increase in INR. Many confounding variables existed in each of these cases, such as hepatic dysfunction, poor appetite, and concomitant drugs that resulted in an increased anticoagulant response. We report a case that involved only one potential confounding variable. Continued documentation of azithromycin-warfarin interactions is valuable considering no mention of this drug interaction exists in most tertiary references and in the package insert for azithromycin, the demonstration that no drug interaction occurred in a retrospective review of 52 cases, and the widespread use of azithromycin in the community. Clinicians should be mindful when prescribing azithromycin in combination with warfarin, and INR values should be monitored
Eschenauer G;Collins CD;Regal RE, Pharmacotherapy, 2005, 25:630-631; Azithromycin-warfarin interaction: Are we fishing with a red herring?
Gooderham MJ;Bolli P;Fernandez PG, Ann Pharmacother, 1999, b, 33:796-799; Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin
OBJECTIVE: To report a case of a clarithromycin-associated warfarin interaction and digoxin toxicity in a patient. CASE SUMMARY: A 72-year- old white woman with chronic atrial fibrillation receiving long- standing therapy with digoxin 0.25 mg/d and warfarin 22.5 mg/wk was prescribed clarithromycin 500 mg three times daily for eradication of Helicobacter pylori. The patient presented to the emergency department with gastrointestinal symptoms, weakness, dizziness, and visual changes 12 days after initiation of clarithromycin. Laboratory results revealed a serum digoxin concentration of 4.6 ng/mL (normal 1.0-2.6) and an international normalized ratio of 7.3 (2.0-3.0). Digoxin, warfarin, and clarithromycin were discontinued and the patient was admitted to the hospital for treatment to resolve the symptoms and to return laboratory values to a safe range. Reduced dosages of digoxin (0.125 mg/d) and warfarin (17.5 mg/wk) were restarted on day 7 of hospitalization. The patient was discharged on day 11 in good condition. DISCUSSION: Several reports of clarithromycin-induced drug interactions with digoxin and with warfarin have been published. Previously, case reports of macrolide-associated interactions mainly involved erythromycin, but more recently have implicated clarithromycin. The interaction between clarithromycin and warfarin is thought to occur from an inhibition of the cytochrome P450 drug metabolizing system. Clarithromycin is thought to cause digoxin toxicity by an alteration of the digoxin-metabolizing gut flora, thereby causing an increase in the digoxin concentration in susceptible individuals. Drug interactions can occur by different mechanisms in the same patient. CONCLUSIONS: Potential drug interactions can occur between commonly prescribed medications. It is important to monitor patients for symptoms and alterations in laboratory values to prevent not only serious complications, but also unnecessary hospitalizations
Rotella J;Taylor DM, J Pharm Pract Res, 2015, 45:01; Concomitant roxithromycin use among elderly patients taking warfarin resulting in significant over-anti-coagulation
Background: There is a paucity of literature regarding the potential association between roxithromycin and excessive anti-coagulation in patients taking warfarin. An interaction may have important health implications for these patients, particularly the elderly, who are at greater risk of bleeding events due to falls and consequent injuries, as well as major gastrointestinal haemorrhage. Aim: To report five cases of a possible roxithromycin-warfarin drug interaction, all resulting in extreme elevations of the international normalised ratio (INR) and requiring admission and intervention with vitamin K. Clinical details: A retrospective medical record review of patients presenting to the emergency department of a tertiary-level, universityaffiliated hospital was undertaken. Patients treated with warfarin and who had an excessively elevated international normalised ratio at presentation were identified. Of 102 525 cases screened, 72 cases were selected for further analysis. In five cases, elderly patients were taking roxithromycin for treatment of a lower respiratory tract infectionandhada recorded international normalised ratio in the range of 10.1-14.5. Three of these five patients had impaired renal function. Outcomes: No patient had bleeding complications but all required admission and treatment with vitamin K. One patient died during admission but the cause of death was not related to bleeding. In each case, a potential roxithromycin-warfarin interaction was rated as probable using a commonly employed scale. Conclusion: The elevation of the international normalised ratio observed with these patients was most likely to have been caused by a drug interaction. Each patient required admission and considerable clinical intervention in order to correct the over-anti-coagulation. Hence, the clinician needs to be aware of the potential consequences of this drug interaction
Oberg KC, Pharmacotherapy, 1998, 18:386-391; Delayed elevation of international normalized ratio with concurrent clarithromycin and warfarin therapy
Clarithromycin is rarely reported to cause disturbances in anticoagulation. Theoretically, clarithromycin administered concurrently with warfarin could result in enhanced anticoagulation, since many properties of clarithromycin are similar to those of erythromycin, which interacts with warfarin. A search of the National Library of Medicine produced no published reports of an interaction between the drugs. Erythromycin competitively inhibits hepatic metabolism of warfarin, specifically the R-warfarin enantiomer, by the cytochrome P450 3A3 and 3A4 pathways, resulting in increased prothrombin time and international normalized ratio (INR). Two men, age 61 and 70 years, who received stable warfarin regimens, experienced supratherapeutic elevations in prothrombin time (98.4 and 26.8 sec) and INR (90.3 and 5.6), respectively. While taking warfarin, both patients experienced dramatically increased anticoagulation effects 5 days after starting clarithromycin for atypical pneumonia. They were similarly managed for overanticoagulation by discontinuing clarithromycin, holding warfarin, and receiving intravenous phytonadione. Neither man suffered from medical complications related to anticoagulation. Until clear documentation of the exact mechanism and temporal relationship of this interaction is known, patients receiving warfarin who require the concurrent clarithromycin should have prothrombin time and INR closely monitored
McCall KL;Anderson HG;Jones AD, Pharmacotherapy, 2004, 24:188-194; Determination of the lack of a drug interaction between azithromycin and warfarin
STUDY OBJECTIVE: To determine the effect on the international normalized ratio (INR) of adding azithromycin to patients receiving stable dosages of warfarin. DESIGN: Retrospective chart review. SETTING: Outpatient clinic. PATIENTS: Ambulatory patients receiving warfarin and azithromycin concurrently who had a documented therapeutic INR value before the start of azithromycin therapy (pre-INR) and a documented INR value within 30 days after the start of azithromycin therapy (post-INR). MEASUREMENTS AND MAIN RESULTS: Patients given felodipine during long-term warfarin therapy formed a comparative control group. Patient demographics were similar in both treatment groups. Mean age of the azithromycin group (17 patients) was 59 +/- 13 years and of the control group (20 patients) 65 +/- 12 years. All 17 patients in the azithromycin group and 16 of the controls were women. Mean change from pre-INR to post-INR in the azithromycin and control groups, respectively, was 0.14 +/- 0.64 (pre-INR 2.46, post-INR 2.61) and 0.19 +/- 0.54 (pre-INR 2.46, post-INR 2.66) (p = 0.74). A post hoc power analysis based on a pooled standard deviation of 0.60 revealed that the study had 68% power to detect a 0.5 change in the INR value. CONCLUSION: No interaction between azithromycin and warfarin was observed in ambulatory patients with therapeutic baseline INR values
Weibert RT;Lorentz SM;Townsend RJ;Cook CE;Klauber MR;Jagger PI, Clin Pharm, 1989, 8:210-214; Effect of erythromycin in patients receiving long-term warfarin therapy
Prospektiv undersøgelse omfattende 8 patienter. Alle patienter har før forsøgsstart været i behandling med warfarin i tidsrummet varierende fra 75-780 dage. Udvælgelseskriteriet for patienterne var, at de kunne fremvise en stabil antikoagulation, der var defineret som en prothrombin time ratio (PTR) på 1,5-2,0 timer i 2 efterfølgende uger uden ændring i warfarin dosis.Forsøget viser stigning i PTR efter indgift af erythromycin i patienter. PTR befinder sig i hele forsøgsperioden inden for det terapeutiske PT interval (1,5-2,0) og der observeres ingen blødning hos patienterne (8 stk). Det anbefales dog patienter som er i profylaktisk behandling med warfarin og hvor det er nødvendigt at indtage erythromycin at blive dosistilpasset mht. warfarin.
Rao KB;Pallaki M;Tolbert SR;Hornick TR, Ann Pharmacother, 2004, 38:982-985; Enhanced hypoprothrombinemia with warfarin due to azithromycin
OBJECTIVE: To report a case of probable azithromycin-warfarin drug interaction with enhanced hypoprothrombinemic effect of warfarin. CASE SUMMARY: An 83-year-old African American man stabilized on warfarin therapy (10 mg on Wednesdays, 7.5 mg on other days) developed a prolonged prothrombin time one day after starting azithromycin 500 mg. The elevated prothrombin time normalized 3 days after azithromycin was discontinued. After the initial increase in the international normalized ratio, the absence of any significant confounding factors affecting the anticoagulant effect of warfarin in our patient and the numerous reports of such interactions indicate that an interaction between azithromycin and warfarin may have been responsible for the elevated prothrombin time seen in this patient. An objective causality assessment revealed that the adverse event was probably related to the combination of these drugs. DISCUSSION: Azithromycin, unlike erythromycin and clarithromycin, is not known to inhibit the cytochrome P450 enzyme system and is presumed to be the macrolide of choice in patients already on warfarin. However, previously reported cases of azithromycin-warfarin interactions support the possibility that azithromycin does interact with warfarin, although the exact mechanism is not understood. CONCLUSIONS: Azithromycin may interact with warfarin and enhance its hypoprothrombinemic effects. This effect may be delayed for 4-8 days after a course of azithromycin has been completed. Periodic monitoring of the prothrombin time is recommended when using azithromycin in patients taking warfarin
Lane G, Ann Pharmacother, 1996, a, 30:884-885; Increased hypoprothrombinemic effect of warfarin possibly induced by azithromycin
Kasuistik omhandlende en patient i kombinationsbehandling med warfarin og azithromycin.
Westphal JF, Br J Clin Pharmacol, 2000, 50:285-295; Macrolide - induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin
Pai MP;Graci DM;Amsden GW, Ann Pharmacother, 2000, 34:495-513; Macrolide drug interactions: an update
OBJECTIVE: To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions. DATA SOURCES: A MEDLINE search (1975-1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers. STUDY SELECTION: All available data were reviewed to provide an unbiased account of possible drug interactions. DATA EXTRACTION: Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. DATA SYNTHESIS: Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the classic drug interactions characteristic of the macrolides. CONCLUSIONS: Most of the available data regarding macrolide drug interactions are from studies in healthy volunteers and case reports. These data suggest that clarithromycin appears to have an interaction profile similar to that of erythromycin. Given this similarity, it is important to consider the interaction profile of clarithromycin when using erythromycin. This is especially necessary as funds for further studies of a medication available in generic form (e.g., erythromycin) are limited. Azithromycin has produced few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system. Although the available data are promising, the final test should come from studies conducted in patients who are taking potentially interacting compounds on a chronic basis
Paulsen O;Nilsson LG;Saint-Salvi B;Manuel C;Lunell E, Pharmacol Toxicol, 1988, 63:215-220; No effect of roxithromycin on pharmacokinetic or pharmacodynamic properties of warfarin and its enantiomers
The macrolide antibiotics are metabolized by cytochrome P-450 enzymes in the liver and interactions with similarly metabolized compounds have been described. Simultaneous treatment with erythromycin and warfarin is known to decrease warfarin clearance and prolong prothrombin time. Roxithromycin (RU 28965), a new erythromycin derivative with improved pharmacokinetic properties, might then, because of structure similarity, be expected to interact with warfarin. In 21 healthy volunteers, the effect of orally administered roxithromycin (150 mg b.i.d.) on warfarin steady-state kinetics, and the effects of warfarin on roxithromycin kinetics, were investigated in a double-blind, randomized study versus placebo. Since the warfarin enantiomers, R- and S-warfarin have both different potency and different metabolism, the ratio between the enantiomers with and without roxithromycin, was also determined. In this study, mean AUC for warfarin increased slightly from day 14 of warfarin treatment to day 28, but no difference was found between the roxithromycin group and the placebo group, and no change appeared in the ratio between the warfarin enantiomers. A moderate increase in dosage was needed to maintain hypocoagulability during warfarin medication, but there was no difference between the roxithromycin group and the placebo groups, respectively. In addition, roxithromycin kinetics appeared to be unaffected by warfarin treatment
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
Woldtvedt BR;Cahoon CL;Bradley LA;Miller SJ, Ann Pharmacother, 1998, a, 32:269-270; Possible increased anticoagulation effect of warfarin induced by azithromycin
Kaustik omhandlende en patient i kombinationsbehandling med warfarin og azithromycin. Efter 11 dages kombinationsbehandling observeres høje INR-værdier, og blodigt ekspektorant.
Foster DR;Milan NL, Pharmacotherapy, 1999, 19:902-908; Potential interaction between azithromycin and warfarin
Azithromycin is considered unlikely to interact with warfarin. Unlike other macrolide antibiotics, it is not hepatically metabolized and did not produce an interaction with warfarin in a single-dose study. A 71- year-old woman with a prosthetic heart valve, stabilized with warfarin, had international normalized ratios (INRs) maintained between 2.5 and 3.5. Six days after she received a prescription for a 5-day course of azithromycin, her INR was 15.16. Phytonadione 10 mg was administered subcutaneously, and warfarin was held for 3 days until her INR fell to 2.10. She then was restabilized with warfarin. Until more information is known about the safety of warfarin and azithromycin, caution is advised when the agents are given together. Close monitoring of INR is recommended, and warfarin dosage adjustment may be necessary
Recker MW;Kier KL, Ann Pharmacother, 1997, 31:996-998; Potential interaction between clarithromycin and warfarin
OBJECTIVE: To report a possible drug interaction between clarithromycin and warfarin in a patient with chronic atrial fibrillation. CASE SUMMARY: A patient with chronic atrial fibrillation was placed on warfarin therapy. International normalized ratios (INRs) ranged from 1.61 to 3.99 while the dosage was being adjusted during the first 5 months of warfarin therapy. The dosage was titrated to 20 mg/wk; laboratory tests obtained 2 weeks after this dosage was started indicated an INR of 2.1. The same dosage was continued. Clarithromycin 500 mg bid was started for an acute exacerbation of bronchitis 10 days after the last INR was obtained and was continued for 14 days of therapy. An INR obtained 3 days after completion of the clarithromycin therapy was 16.8. The warfarin was withheld and vitamin K 20 mg im was administered. The INR obtained the next day was 1.52. The warfarin was restarted and the dosage was titrated to between 22.5 and 25 mg/wk, with INRs ranging from 0.85 to 3.14. DISCUSSION: Many factors influence the metabolism of warfarin, including disease states, medications, age, and diet. Data collected in this case suggested clarithromycin may have contributed to the increase in the effect of warfarin. Inhibition of the cytochrome P450 oxidizing system appears to be the reason for the increase. Numerous drugs and disease states affect the rate at which this system metabolizes drugs. CONCLUSIONS: The potential interaction between clarithromycin and warfarin warrants prudent monitoring of the INR during concurrent administration of these drugs. Warfarin dosages may need to be reduced during concurrent clarithromycin therapy to prevent bleeding complications. Further controlled clinical trials are needed to substantiate the interaction between clarithromycin and warfarin
Beckey NP;Parra D;Colon A, Pharmacotherapy, 2000, a, 20:1055-1059; Retrospective evaluation of a potential interaction between azithromycine and warfarin in patients stabilized on warfarin
STUDY OBJECTIVE: To investigate a potential interaction between azithromycin and warfarin. DESIGN: Retrospective case-control study. SETTING: Veterans Affairs medical center. PATIENTS: Fifty-two patients stable on anticoagulation therapy. INTERVENTION: Patients who received a prescription for azithromycin and warfarin at any time since the hospital was opened, June 1, 1995, to July 22, 1999, were identified through a computerized report generated from the pharmacy prescription package. MEASUREMENTS AND MAIN RESULTS: Patients having a stable international normalized ratio (INR; defined as a therapeutic INR +/- 0.2) for at least two consecutive visits before receiving an azithromycin prescription were reviewed. Changes in INR from before and after addition of azithromycin were compared with changes in a control group. Controls were identified from a computer-generated report of patients who received a prescription for terazosin and warfarin at any time since the hospital was opened to July 22, 1999 (terazosin was chosen as it has no known interaction with warfarin). These patients also had a stable INR for at least two consecutive visits before receiving the terazosin prescription. In patients with INRs on record within 14 days after starting azithromycin or terazosin (9 patients/group), the average change in INR was 0.18 +/- 0.48 in the azithromycin group and 0.07 +/- 0.49 in the terazosin group (p=0.60). For patients with an INR on record within 30 days after starting azithromycin or terazosin (26 patients/group), the average change in INR was 0.25 +/- 0.67 in the azithromycin group and 0.05 +/- 0.55 in the terazosin group (p=0.18). CONCLUSION: An interaction between azithromycin and warfarin was not observed in this retrospective review of patients with a stable INR receiving the combination
Penning-Van-Beest FJA;Koerselman J;Herings RMC, J Thromb Haemost, 2008, 6:284-290; Risk of major bleeding during concomitant use of antibiotic drugs and coumarin anticoagulants
Background: Coumarin anticoagulants are prone to drug-drug interactions. For example, antibiotic drugs may enhance the anticoagulant effect of coumarins. However, whether such interactions are associated with an increased risk of bleeding, and if so, how frequently this occurs remains unknown. Objective: To assess the risk of major bleeding associated with the concomitant use of antibiotic drugs and coumarin anticoagulant therapy. Methods: We analyzed a retrospective cohort study including all users of acenocoumarol or phenprocoumon in the PHARMO Record Linkage System (age range: 40-80 years). All patients were followed up until end of last coumarin treatment, hospitalization for bleeding, death, or end of study period. For each patient, the number of days on either coumarins alone, or on coumarins in combination with antibiotic drugs was determined. From these data, the relative risks of major bleeding were calculated. Results: A total of 52102 users of acenocoumarol and 7885 users of phenprocoumon met the inclusion criteria of our study cohort and contributed 139159 person-years of follow-up. During follow-up, 838 patients (1.4%) were hospitalized for a bleeding while taking coumarins. Of the 62 different antibiotics taken by study members, 19 were associated with a bleeding episode. Of these, 10 were associated with a statistically significant increased bleeding risk. The relative risk of bleeding was three to five for doxycycline, amoxicillin, amoxicillin/ clavulanic acid, ciprofloxacin, cotrimoxazole, azithromycin and pheneticillin, nine for tetracycline and 43 for cefradine and neomycin. Conclusion: Based on relative risks and incidence of use, amoxicillin (alone or with clavulanic acid) and doxycycline are the main antibiotic drugs associated with major bleeding when used in combination with coumarin. copyright 2007 International Society on Thrombosis and Haemostasis
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
Dandekar SS;Laidlaw DA, J R Soc Med, 2001, 94:583-584; Suprachoroidal haemorrhage after addition of clarithromycin to warfarin
Hassell D;Utt JK, South Med J, 1985, 78:1015-1016; Suspected interaction: warfarin and erythromycin
The patient described had a markedly enhanced response to warfarin when he was given erythromycin concomitantly. Before the initiation of erythromycin, his warfarin anticoagulation had been well controlled. After withdrawal of erythromycin, his response to warfarin returned to normal. These findings and previously reported clinical and laboratory data lead to the conclusion that, at least in some patients, a potentially serious interaction between erythromycin and warfarin can occur
Bachmann K;Schwartz JI;Forney R;Frogameni A;Jauregui LE, Pharmacology, 1984, 28:171-176; The effect of erythromycin on the disposition kinetics of warfarin
Erythromycin is generally regarded as innocuous in regard to adverse interactions with other drugs. Recently, however, its potentiation of theophylline and warfarin has been reported. The present investigation defined more specifically the kinetics of the interaction between erythromycin and warfarin. Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 h for 8 days decreased warfarin clearance by 14% (p less than 0.001). Warfarin's apparent volume of distribution was not affected. Further, the effect of erythromycin was greatest among subjects whose control phase warfarin clearance was relatively slow, and least among those whose control phase warfarin clearance was relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively with control warfarin clearance (r = -0.89, p less than 0.005). These data are consistent with the interpretation that erythromycin can potentiate warfarin-induced hypoprothrombinemia by slowing warfarin clearance
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
Sato RI;Gray DR;Brown SE, Arch Intern Med, 1984, 144:2413-2414; Warfarin interaction with erythromycin
The drug interaction between warfarin and erythromycin is not well known. We report a case in which erythromycin was observed to markedly potentiate warfarin anticoagulation, resulting in hemorrhage in a patient treated for Legionella pneumonia. The morbidity of this drug interaction is enhanced in elderly patients who have infection accompanied by anorexia and/or fever and who are receiving intravenous erythromycin. The well-documented, temporal relationship established erythromycin as the interacting drug
Wood,G.D.; Deeble,T., Dent Update , 1993, 20:350, 352-350, 353; Warfarin: dangers with antibiotics
There are no clear recommendations for prescribing antibiotics to patients taking warfarin. The risks of enhancing the anticoagulant properties of warfarin when it is taken concurrently with an antibiotic are seldom discussed. This article attempts to address this problem and to alert dentists to the risks of prescribing antibiotics to patients taking warfarin. A regimen is recommended for patients taking warfarin who require antibiotic dental treatment
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