van Sabben Joris M, van der Kleij Maud B A, Roets Evelyne, Tissier Renaud L M, van Balen Dorieke E M, Huitema Alwin D R, Desar Ingrid M E, Reyners Anna K L, Gelderblom Hans, Steeghs Neeltje
Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Oncol Ther. 2025 Jul 1. doi: 10.1007/s40487-025-00353-3.
Following patent expiration of branded imatinib (Glivec®), all Dutch patients with gastrointestinal stromal tumours (GIST) switched from Glivec to generic forms. Following this switch, many patients reported new symptoms. Therefore, we conducted this observational study to assess safety of generic imatinib among patients with GIST in the Netherlands.
We included patients with GIST from four hospitals that switched from Glivec to generic imatinib. Within these patients, adverse events (AEs) without the switch to a generic were compared with AEs after the switch using a self-controlled case series design. The reference group was formed by the subset of patients who used imatinib for at least 1 year prior to the switch. As potential causes of increased AEs, we reviewed excipients and analysed plasma trough levels from 1 year prior to 1 year after the switch.
In total, 201 patients switched to three generics: Accord® (n = 107), Amarox® (n = 81), and Sandoz® (n = 13). In the reference group (n = 150), 21.3% experienced new AEs, compared with 29.9-34.6% in the different generic groups. All patients that switched to Amarox (odds ratio 2.3; 95% confidence interval (CI): 1.2-4.5) and females that switched to Accord (odds ratio 2.7; 95% CI: 1.1-7.0) experienced a significant increase in AEs. Plasma trough levels were similar among all different formulations. Apart from titanium dioxide in Amarox, no additional excipients were used in any generic form.
The transition to generic imatinib in Dutch patients with GIST was safe. After switching to generic imatinib, up to 34.6% of patients experienced new AEs, compared with 21.3% in the reference group, indicating that many AEs may have been mistakenly attributed to the switch. The small increase in AEs that we found was unlikely due to pharmacokinetics or excipients. Therefore, we argue that the nocebo effect, where negative expectations about treatment lead to worsened symptoms, played a large role.
在原研伊马替尼（格列卫®）专利到期后，荷兰所有胃肠道间质瘤（GIST）患者都从格列卫换成了仿制药。换药后，许多患者报告出现了新症状。因此，我们开展了这项观察性研究，以评估荷兰GIST患者使用仿制药伊马替尼的安全性。
我们纳入了来自四家医院的从格列卫换成仿制药伊马替尼的GIST患者。在这些患者中，使用自控病例系列设计，将未换药时的不良事件（AE）与换药后的AE进行比较。参照组由换药前使用伊马替尼至少1年的患者子集组成。作为AE增加的潜在原因，我们审查了辅料，并分析了换药前1年至换药后1年的血浆谷浓度。
共有201名患者换成了三种仿制药：Accord®（n = 107）、Amarox®（n = 81）和山德士®（n = 13）。在参照组（n = 150）中，21.3%的患者出现了新的AE，而不同仿制药组的这一比例为29.9% - 34.6%。所有换成Amarox的患者（比值比2.3；95%置信区间（CI）：1.2 - 4.5）以及换成Accord的女性患者（比值比2.7；95% CI：1.1 - 7.0）的AE显著增加。所有不同制剂的血浆谷浓度相似。除了Amarox中的二氧化钛外，任何仿制药形式都未使用其他辅料。
荷兰GIST患者换成仿制药伊马替尼的过程是安全的。换成仿制药伊马替尼后，高达34.6%的患者出现了新的AE，而参照组为21.3%，这表明许多AE可能被错误地归因于换药。我们发现的AE的小幅增加不太可能是由于药代动力学或辅料。因此，我们认为，对治疗的负面预期导致症状恶化的反安慰剂效应起到了很大作用。
