Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin

Drug Safety, Jan 2018

Introduction We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. Methods To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. Results Thirty patient reports were identified. The age range was 23–88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3–16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. Serious infection occurred in 54.5% (12 of 22 patients with information). Polypharmacy (five or more medicines daily) was used by 36.7% of patients long term, increasing acutely to 83.3%, including additional potentially interacting medicines. Warfarin daily dose (1.5–13.0 mg, mean 4.4, median 4.0, standard deviation 2.2) was moderate to low. Pre-roxithromycin international normalised ratio values ranged from 1.4 to 3.7, mean and median 2.5, standard deviation 0.5. A high proportion of interactions were observed between warfarin and roxithromycin compared with other macrolides and compared with cytochrome P450 3A4-related macrolide interactions. The pattern was similar to published Australian data. Conclusion In this case series, the high prevalence of acute polypharmacy, including potentially interacting medicines, and serious infection suggests that they may have contributed to warfarin potentiation and increased the clinical significance of a roxithromycin/warfarin interaction.

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Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin

Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin Ruth L. Savage 0 1 2 Michael V. Tatley 0 1 2 Key Points 0 1 2 0 Department of General Practice, University of Otago , Christchurch , New Zealand 1 New Zealand Pharmacovigilance Centre, Dunedin School of Medicine, University of Otago , PO Box 913, Dunedin 9054 , New Zealand 2 & Ruth L. Savage Introduction We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. Methods To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. Results Thirty patient reports were identified. The age range was 23-88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3-16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. - Despite previous assumptions, inhibition of the cytochrome P450 enzyme is unlikely to explain the rapid and intense potentiation of warfarin observed The findings support international normalised ratio measurement within 3 days when roxithromycin is added to warfarin and limiting roxithromycin in patients taking warfarin to infections for which macrolides are first choice. 1 Introduction Roxithromycin is a macrolide antibiotic with an antibacterial spectrum of activity similar to that of erythromycin but with a longer half-life, which allows for twice-daily dosing [ 1 ]. When roxithromycin became available, erythromycin was already known to interact with warfarin but a small study of healthy volunteers had not demonstrated an interaction between roxithromycin and warfarin [ 2 ]. Since then, roxithromycin has not been well represented in studies of warfarin interactions with antibiotics. However, evidence for an interaction was first published in 1995 as a case series from New Zealand and Australia [ 3 ]. Reporters were aware of the interaction between erythromycin and warfarin and shared their concern that roxithromycin appeared to be interacting similarly. Erythromycin is known to be a potent cytochrome P450 (CYP)3A4 inhibitor and roxithromycin a weak inhibitor [ 4 ]. It was assumed that roxithromycin is therefore less likely to interact with warfarin [ 3 ]. However, only (R)warfarin, the less active enantiomer, is a substrate for CYP3A4, thus inhibition of its metabolism by this mechanism appears an unlikely explanation for rapid intense warfarin potentiation with roxithromycin observed in ongoing reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) since the 1995 publication. For example, two recent reports describe international normalised ratios (INRs) of 16.1 and 8.4 observed as early as day 3 and 4 after roxithromycin was added to warfarin treatment [ 5, 6 ]. In support of these observations, in 2015, an Australian study identified 72 anticoagulated elderly patients who required vitamin K administration because of INR values[10. Five of these had taken roxithromycin with warfarin [7]. It has been suggested that the interaction may be more clinically significant with polypharmacy, severe illness, renal dysfunction, and in those who are elderly or otherwise at risk of increased warfarin sensitivity [ 3, 7, 8 ]. Patients taking low doses of warfarin may be most at risk as clearance is already low [ 9 ]. Infection, antibiotic use in general and high target INR values have been shown to potentiate warfarin activity in some studies [ 10, 11 ]. The origins of recent reports for roxithromycin in VigiBase, the World Health Organization Global Database for Individual Case Safety Reports [ 12 ], indicate that it is used in Australia, New Zealand, Asia, including China and India, and parts of Europe. It is not marketed in the UK or USA, which may, in part, explain why it is not well represented in studies of antibiotic interactions with warfarin. Development of prescribing advice is challenging because of the paucity of information about the mecha (...truncated)


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Ruth L. Savage, Michael V. Tatley. Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin, Drug Safety, 2018, pp. 1-7, DOI: 10.1007/s40264-017-0634-y