Table1_Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.DOCX

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system.
Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients’ hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals.
Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug’s SmPC and in 1 case the risk prevention material was updated.
Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

引言：上市后识别与报告未知药品不良反应（Adverse Drug Reaction，ADR）对患者安全至关重要。然而，自发呈报ADR时，往往难以获取未知ADR的完整信息，这可能会削弱其对药物警戒系统的价值。

方法：为明确呈报时及随访阶段未知ADR的严重程度与转归，并分析其对推动药物警戒监管行动的作用，本研究针对2016年1月至2021年12月某医院收治患者的自发ADR呈报案例开展回顾性观察研究。研究从患者的住院病历中提取人口学、临床及辅助检查相关信息。为评估其对药物警戒系统的贡献，我们查阅了欧盟药品说明书（Summary of Product Characteristics，SmPC）、药物警戒风险评估委员会（Pharmacovigilance Risk Assessment Committee）讨论的药物警戒信号清单，以及该委员会发布的安全信号建议报告。

结果：本研究期间，共有15.2%的自发呈报病例包含至少1组未知药物-ADR配对。经排除后，最终纳入295组未知药物-ADR配对，其中受累频次最高的器官/系统为：皮肤及皮下组织（34组，11.5%）、肝胆系统疾病（28组，9.5%）、心脏疾病（28组，9.5%）及中枢神经系统疾病（27组，9.2%）。最常见的ADR为天疱疮（7组，2.4%），溶细胞性肝炎、猝死、皮肤血管炎及胎儿生长受限各6组（占比2%）。涉及频次最高的药物亚组包括新冠疫苗与肺炎球菌疫苗（68组，21.3%）、抗肿瘤药（紫杉醇、曲妥珠单抗、长春新碱，39组，12.2%）及免疫抑制剂（甲氨蝶呤、托珠单抗，35组，11%）。最常见的未知药物-ADR配对为单用或联合使用羟氯喹导致的猝死（4组，1.4%），以及长春新碱引发的氨基转移酶升高（n=3，1%）。其中共计269组（91.2%）为严重ADR。82.7%的未知ADR配对实施了辅助检查，其中18.3%的配对通过检查得以明确关联。共计18组（6.1%）未知药物-ADR配对由欧洲药品管理局（European Medicines Agency，EMA）评估，其中8组（2.7%）的相关信息被纳入对应药物的SmPC，1组的风险防控材料得到更新。

结论：对未知ADR的识别与随访，对保障患者安全及完善药物警戒系统均具有重要意义。