The Effect of Flucloxacillin on Warfarin Anticoagulation: A Swedish Register-Based Nationwide Cohort Study
01 April 2019
29 May 2019
28 July 2019 (eFirst)
Background Data indicate that codispensing flucloxacillin to patients already on warfarin may result in decreased warfarin efficacy.
Objectives This article investigates the effect of flucloxacillin on warfarin anticoagulation.
Patients and Methods In a retrospective cohort study of warfarin users, using three nationwide registers we included 5,848 patients receiving 10 days flucloxacillin treatment and 201 with ≥30 days treatment. To assess the potential for confounding by indication, we also identified 21,430 individuals initiating phenoxymethylpenicillin. International normalized ratio (INR) values and warfarin doses were calculated day-by-day and proportion of patients with a subtherapeutic INR week-by-week during cotreatment.
Results Following initiation of flucloxacillin with a planned treatment duration of 10 days and ≥30 days, the mean INR decreased from 2.36 (95% confidence interval [CI] 2.34; 2.37) to 2.20 (95% CI 2.19; 2.21) and from 2.24 (95% CI 2.16; 2.32) to 1.96 (95% CI 1.89; 2.02), respectively. Consequently, for individuals with 10 days treatment the proportion of patients with a subtherapeutic INR of < 2 increased from 22% in the week preceding flucloxacillin initiation to 35% in the third week after initiation of flucloxacillin. In patients with 30 days treatment, the proportion increased from 34 to 63% by week 6. In individuals initiating phenoxymethylpenicillin, INR levels did not decrease.
Conclusion One in three patients with 10 days flucloxacillin and almost two in three patients initiating long-term treatment, was exposed to a subsequent subtherapeutic anticoagulant effect. To avoid unnecessary thromboembolic complications, the initiation of flucloxacillin should be accompanied by closer INR monitoring which may be especially important among individuals with lengthy treatments.
Keywordsflucloxacillin - cytochrome P-450 CYP2C9 - drug interactions - international normalized ratio - warfarin
All authors contributed to study design and the writing of manuscript. J.L. was responsible for the analysis of data.
- 1 Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF. Effect of warfarin nonadherence on control of the international normalized ratio. Am J Health Syst Pharm 2004; 61 (12) 1258-1264
- 2 Holbrook AM, Pereira JA, Labiris R. , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
- 3 Self TH, Oliphant CS, Reaves AB, Richardson AM, Sands CW. Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms. Thromb Res 2015; 135 (01) 5-8
- 4 Martín-Pérez M, Gaist D, de Abajo FJ, Rodríguez LAG. Population impact of drug interactions with warfarin: a real-world data approach. Thromb Haemost 2018; 118 (03) 461-470
- 5 Hellfritzsch M, Pottegård A, Pedersen AJ. , et al. Topical antimycotics for oral candidiasis in warfarin users. Basic Clin Pharmacol Toxicol 2017; 120 (04) 368-372
- 6 Holm J, Lindh JD, Andersson ML, Mannheimer B. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2017; 15 (03) 446-453
- 7 Andersson ML, Lindh JD, Mannheimer B. The impact of interacting drugs on dispensed doses of warfarin in the Swedish population: a novel use of population based drug registers. J Clin Pharmacol 2013; 53 (12) 1322-1327
- 8 Mannheimer B, Andersson ML, Järnbert-Pettersson H, Lindh JD. The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2016; 14 (04) 765-771
- 9 Romankiewicz JA, Ehrman M. Rifampin and warfarin: a drug interaction. Ann Intern Med 1975; 82 (02) 224-225
- 10 Pottegård A, Henriksen DP, Madsen KG, Hellfritzsch M, Damkier P, Stage TB. Change in international normalized ratio among patients treated with dicloxacillin and vitamin K antagonists. JAMA 2015; 314 (03) 296-297
- 11 Stage TB, Graff M, Wong S. , et al. Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro. Br J Clin Pharmacol 2018; 84 (03) 510-519
- 12 Aujla RS, Bryson DJ, Gulihar A, Taylor GJ. Trends in orthopaedic antimicrobial prophylaxis in the UK between 2005 and 2011. Ann R Coll Surg Engl 2013; 95 (07) 495-502
- 13 Francis NA, Hood K, Lyons R, Butler CC. Understanding flucloxacillin prescribing trends and treatment non-response in UK primary care: a Clinical Practice Research Datalink (CPRD) study. J Antimicrob Chemother 2016; 71 (07) 2037-2046
- 14 Auricula. Available at: http://www.ucr.uu.se/auricula/ . Accessed February 2019
- 15 Journalia. Available at: http://www.journalia.se/ . Accessed February 2019
- 16 Wettermark B, Hammar N, Fored CM. , et al. The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 2007; 16 (07) 726-735
- 17 Bertilsson L, Tomson T, Tybring G. Pharmacokinetics: time-dependent changes--autoinduction of carbamazepine epoxidation. J Clin Pharmacol 1986; 26 (06) 459-462
- 18 Böttiger Y, Laine K, Andersson ML. , et al. SFINX-a drug-drug interaction database designed for clinical decision support systems. Eur J Clin Pharmacol 2009; 65 (06) 627-633
- 19 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69 (03) 236-239
- 20 R Core team. R: a language and environment for statistical computing; 2013 . Available at: http://www.R-project.org/ . Accessed February 2019
- 21 Hylek EM, Go AS, Chang Y. , et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349 (11) 1019-1026
- 22 Nelson WW, Wang L, Baser O, Damaraju CV, Schein JR. Out-of-range INR values and outcomes among new warfarin patients with non-valvular atrial fibrillation. Int J Clin Pharm 2015; 37 (01) 53-59
- 23 Wan Y, Heneghan C, Perera R. , et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes 2008; 1 (02) 84-91