New Zealand Pharmacovigilance Centre, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
Department of General Practice, University of Otago, Christchurch, New Zealand.
Drug Saf. 2018 May;41(5):515-521. doi: 10.1007/s40264-017-0634-y.
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.
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.
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.
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.
在最近两例报告描述了强烈的快速华法林增效作用后，我们对新西兰不良反应监测中心报告的所有关于罗红霉素/华法林相互作用的报告进行了分析。该相互作用于 1995 年首次发表。细胞色素 P450 3A4 抑制作用已被提出，但生物学上的合理性有限。有迹象表明，严重疾病、多种药物治疗、肾功能不全、年龄较大和增加的华法林敏感性可能增加相互作用的临床意义。
为了研究罗红霉素在新西兰病例系列中的华法林增强作用，我们回顾了报告，以确定有风险的患者，比较报告模式与已发表的澳大利亚数据，并评估当前处方建议的适当性。
确定了 30 例患者报告。年龄范围为 23-88 岁，平均年龄 66.8 岁，中位数 73.0 岁（标准差 17.7），罗红霉素开始后国际标准化比值范围为 3.6-16.7（平均 7.6，中位数 7.6，标准差 3.6）。对于 8 名在第 3 天有测量值的患者，国际标准化比值为 4.3-16.7（平均 10.4，中位数 8.8，标准差 4.4）。4 名患者发生严重出血。罗红霉素的适应证为多种呼吸道感染。大多数患者在急性感染前抗凝稳定。22 名有信息的患者中有 54.5%（12 名）发生严重感染。长期使用 36.7%（患者）的药物（每天 5 种或更多药物），急性时增加到 83.3%，包括其他可能相互作用的药物。华法林每日剂量（1.5-13.0mg，平均 4.4mg，中位数 4.0mg，标准差 2.2mg）为中低水平。罗红霉素前国际标准化比值范围为 1.4-3.7，平均和中位数为 2.5，标准差为 0.5。与其他大环内酯类药物和与细胞色素 P450 3A4 相关的大环内酯类药物相互作用相比，观察到华法林与罗红霉素之间的相互作用比例较高。这种模式与已发表的澳大利亚数据相似。
在本病例系列中，急性多种药物治疗（包括可能相互作用的药物）和严重感染的高患病率表明，它们可能促成了华法林增效作用，并增加了罗红霉素/华法林相互作用的临床意义。
