Table1_Analysis of Drug-Induced Gastrointestinal Obstruction and Perforation Using the Japanese Adverse Drug Event Report Database.XLSX

Drug-induced gastrointestinal obstruction (DIGO) and gastrointestinal perforation (DIGP) may be the result of gastrointestinal hypomotility and severe constipation, which may lead to potentially fatal complications of bowel ischemia, sepsis and perforation. We evaluated the onset profile of DIGs (DIGO and DIGP) associated with prescription drugs by analyzing data in the Japanese Adverse Drug Event Report (JADER) database. We selected 161 DIG-related drugs and categorized them into 19 classes based on the Anatomical Therapeutic Chemical (ATC) Classification System. Finally, we focused on 58 drugs and conducted subsequent analyses for the time-to-onset and outcomes. We extracted 79 preferred terms (PTs) with the strings “ileus,” “stenosis,” “obstruction,” “obstructive,” “impaction,” “perforation,” “perforated,” “hypomotility,” and “intussusception” from the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) of SMQ20000104: gastrointestinal perforation, ulcer, hemorrhage, obstruction non-specific findings/procedures; SMQ20000105: gastrointestinal obstruction; and SMQ20000107: gastrointestinal perforation. Among the 667, 729 reports in the JADER database submitted between April 2004 and November 2020, we identified 11,351 occurrences of DIGs. The reporting odds ratios (RORs) (95% confidence interval) of “barium sulfate containing X-ray media,” “drugs for treatment of hyperkalemia and hyperphosphatemia,” and “oral bowel cleanser” were 142.0 (127.1–158.6), 25.8 (23.1–28.8), and 29.7 (24.8–35.6), respectively. The median number of days (interquartile range) until the onset of an adverse event caused by each drug category was as follows: barium sulfate containing X-ray contrast media [2.0 (1.0–3.0)], diazepines, oxazepines, thiazepines, and oxepines [8.0 (8.0–18.5)], drugs for treatment of hyperkalemia and hyperphosphatemia [29.0 (8.0–55.0)], non-selective monoamine reuptake inhibitors [19.0 (7.0–47.5)], and oral bowel cleanser [0.0 (0.0–0.0)]. Depending on the drug, the time to onset of side effects ranged from days to several months. Our results highlighted the need to perform detailed monitoring of each drug for possible association with DIGs, which might otherwise have fatal consequences.

药物诱发性胃肠道梗阻（Drug-induced gastrointestinal obstruction, DIGO）与药物诱发性胃肠道穿孔（Drug-induced gastrointestinal perforation, DIGP）可由胃肠道动力不足及重度便秘引发，进而可能导致肠缺血、脓毒症及穿孔等潜在致命性并发症。本研究通过分析日本药品不良反应报告（Japanese Adverse Drug Event Report, JADER）数据库中的数据，评估了与处方药相关的DIG事件（即DIGO与DIGP）的发病特征。研究共筛选出161种与DIG相关的药物，并依据解剖学治疗学化学（Anatomical Therapeutic Chemical, ATC）分类系统将其划分为19个类别。最终聚焦于58种药物，开展了发病时间及转归的后续分析。我们从监管活动医学词典（Standardized Medical Dictionary for Regulatory Activities, MedDRA）查询（SMQs）的以下3个词条中，提取了包含"肠梗阻""狭窄""梗阻""梗阻性""嵌塞""穿孔""穿孔性""动力不足"及"肠套叠"的79个首选术语（preferred terms, PTs）：SMQ20000104：胃肠道穿孔、溃疡、出血、梗阻非特异性表现/操作；SMQ20000105：胃肠道梗阻；SMQ20000107：胃肠道穿孔。在2004年4月至2020年11月间提交的667729份JADER数据库报告中，共识别出11351例DIG事件。"含硫酸钡的X射线造影剂""高钾血症与高磷血症治疗药物"以及"口服肠道清洁剂"的报告比值比（reporting odds ratios, RORs）（95%置信区间）分别为142.0（127.1~158.6）、25.8（23.1~28.8）及29.7（24.8~35.6）。各类药物所致不良反应的中位发病天数（四分位间距）如下：含硫酸钡的X射线造影剂[2.0（1.0~3.0）]、二氮䓬类、氧氮䓬类、噻氮䓬类及氧杂䓬类[8.0（8.0~18.5）]、高钾血症与高磷血症治疗药物[29.0（8.0~55.0）]、非选择性单胺再摄取抑制剂[19.0（7.0~47.5）]以及口服肠道清洁剂[0.0（0.0~0.0）]。不同药物的不良反应发病时间跨度从数日至数月不等。本研究结果凸显了对每种药物开展详细监测的必要性，以排查其与DIG事件的潜在关联，否则可能引发致命后果。