Ototoxic Adverse Drug Reactions: A Disproportionality Analysis Using the Italian Spontaneous Reporting Database
Ototoxic Adverse Drug Reactions: A Disproportionality Analysis Using the Italian Spontaneous Reporting Database
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DOI：
10.3389/fphar.2019.01161
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发表时间：
2019-10-08
影响因子：
5.6
通讯作者：
Spina, Edoardo
中科院分区：
文献类型：
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作者：
Barbieri, Maria Antonietta;Cicala, Giuseppe;Spina, Edoardo
简介：在过去的几十年里，药物引起的耳毒性的范围已经扩大;此外，上市后数据是更好地了解耳毒性药物不良反应（ADR）所必需的。本研究的目的是进行分析的ADR报告，描述药物引起的耳毒性从意大利自发报告系统（SRS）。方法：作为一项措施的可靠性，我们计算了报告的比值比（RORs）和95%的置信区间（CI）的情况下/非情况下的方法。病例均为2001年至2017年收集到意大利SRS中的药物性耳毒性疑似ADR报告。非病例包括同期报告的所有其他ADR。结果：在325，980份报告中，652份包括至少一种耳毒性ADR，而非病例为325，328份。心血管疾病、泌尿系统药物、特立哌酮、阿米卡星、普卢利沙星、利福平和异烟肼、顺铂、激素拮抗剂、他克莫司、泊马度胺、曲马多和抗抑郁药的校正ROR具有统计学显著性。多沙唑嗪也观察到与耳鸣相关的显著调整ROR（ROR 5.55，95% CI 2.06-14.93），比索洛尔（4.28，1.59-11.53），奈必洛尔（8.06，3.32-19.56），分枝杆菌（3.96，2.17-7.23），厄贝沙坦（19.60，9.19-41.80），beta2（4.01，1.28-12.52），阿氟沙星（4.56，1.71-12.34），乙胺丁醇（12.25，3.89-38.57），依法韦仑（16.82，5.34-52.96），索非布韦/ledipasvir（5.95，1.90-18.61），依托泊苷（7.09、2.63-19.12），阿巴西普（6.51，2.42-17.53），吲哚美辛（6.30，2.02-19.72）、依托考昔（5.00，2.23-11.23）、他喷他多（4.37，1.09-17.62）和噻吗洛尔复方制剂（23.29，9.53-56.95）。此外，克拉霉素对听力减退的显著调整ROR（3.95，1.86-8.40），阿奇霉素（10.23，5.03-20.79），万古霉素（6.72，2.14-21.11），甲氨蝶呤（3.13，1.00-9.81），培美曲塞（4.38，1.40-13.76），长春新碱（5.93，1.88-18.70），长春瑞滨（21.60，8.83-52.82），紫杉醇（2.34，1.03-5.30），利妥昔单抗（3.20，1.19-8.63），干扰素α-2b（17.44，8.56-35.53），沙利度胺（16.92，6.92-41.38），地拉罗司（41.06，20.07-84.01）。然而，普罗帕酮、抗结核药、激素拮抗剂、特立帕肽、曲马多和泊马度胺是否具有耳毒性尚不清楚。使用长春瑞滨、甲氨蝶呤和培美曲塞后的听力减退是意料之外的，例如与依托泊苷、奈必洛尔、贝替洛尔、阿巴西普、索非布韦/ledipasvir和他喷他多相关的耳鸣，但由于缺乏数据，这些考虑因素需要进一步研究以更好地确定风险。此外，医生应了解耳毒性的临床意义，并意识到其对自发报告的重要性。
Introduction: The panorama of drug-induced ototoxicity has widened in the last decades; moreover, post-marketing data are necessary to gain a better insight on ototoxic adverse drug reactions (ADRs). The aim of this study was to perform an analysis of ADR reports describing drug-induced ototoxicity from the Italian spontaneous reporting system (SRS).Methods: As a measure of disproportionality, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs) with a case/non-case methodology. Cases were all suspected ADR reports regarding drug-induced ototoxicity collected into the Italian SRS from 2001 to 2017. Non-cases included all other ADRs reported in the same period.Results: Of 325,980 reports, 652 included at least one ototoxic ADR, compared with 325,328 non-cases. Statistically significant adjusted RORs were found for drugs for cardiovascular disorders, urologicals, teriparatide, amikacin, prulifloxacin, rifampicin and isoniazid, cisplatin, hormone antagonists, tacrolimus, pomalidomide, tramadol, and antidepressants. Significant adjusted RORs in relation to tinnitus were also observed for doxazosin (ROR 5.55, 95% CI 2.06-14.93), bisoprolol (4.28, 1.59-11.53), nebivolol (8.06, 3.32-19.56), ramipril (3.96, 2.17-7.23), irbesartan (19.60, 9.19-41.80), betamethasone (4.01, 1.28-12.52), moxifloxacin (4.56, 1.71-12.34), ethambutol (12.25, 3.89-38.57), efavirenz (16.82, 5.34-52.96), sofosbuvir/ledipasvir (5.95, 1.90-18.61), etoposide (7.09, 2.63-19.12), abatacept (6.51, 2.42-17.53), indometacin (6.30, 2.02-19.72), etoricoxib (5.00, 2.23-11.23), tapentadol (4.37, 1.09-17.62), and timolol combinations (23.29, 9.53-56.95). Moreover, significant adjusted RORs for hypoacusis regarded clarithromycin (3.95, 1.86-8.40), azithromycin (10.23, 5.03-20.79), vancomycin (6.72, 2.14-21.11), methotrexate (3.13, 1.00-9.81), pemetrexed (4.38, 1.40-13.76), vincristine (5.93, 1.88-18.70), vinorelbine (21.60, 8.83-52.82), paclitaxel (2.34, 1.03-5.30), rituximab (3.20, 1.19-8.63), interferon alfa-2b (17.44, 8.56-35.53), thalidomide (16.92, 6.92-41.38), and deferasirox (41.06, 20.07-84.01).Conclusions: This study is largely consistent with results from literature. Nevertheless, propafenone, antituberculars, hormone antagonists, teriparatide, tramadol, and pomalidomide are unknown for being ototoxic. Hypoacusis after the use of vinorelbine, methotrexate, and pemetrexed is unexpected, such as tinnitus related with etoposide, nebivolol, betamethasone, abatacept, sofosbuvir/ledipasvir, and tapentadol, but these considerations require further investigation to better define the risk due to the paucity of data. Moreover, physicians should be aware of the clinical significance of ototoxicity and be conscious about the importance of their contribution to spontaneous reporting.