The aim of our study was to assess the safety of the transition to generic imatinib in Dutch patients with GIST. Therefore, we analysed 201 patients who switched from Glivec to generic imatinib. We demonstrated that, depending on the generic form, 29.9–34.6% of patients experienced new or worsened adverse events following this switch, compared with 21.3% in the reference group. Patients who switched to Amarox were significantly more likely to experience new or worsened adverse events compared with the reference group. In addition, female patients who switched to Accord showed a significantly increased risk of adverse events. We demonstrated that plasma imatinib trough concentrations were not affected by the switch, and excipients were largely similar.

To our knowledge, this study is the first to assess the transition to generic imatinib in patients with GIST, but studies on this transition in patients with CML have been published. Compared with these studies, the new AEs reported in 29.9–34.6% of our patients appear high. For example, Scalzulli et al. reported a 20% increase among 168 patients who switched to Accord, and Bonifacio et al. found new or worsened adverse events in 17% of 294 patients who switched to generic Sandoz [9, 10]. A possible explanation for this variation in reported AEs could be differences in the definition of new or worsened events. While we included all reported events regardless of their potential correlation with the switch, other authors might have required possible causation as a condition when documenting new AEs. In addition, the duration of prior Glivec use may have played a role, as most AEs occur during the first 1–3 years of imatinib treatment [27]. While the median duration of Glivec use was 12 and 7.4 years in the two CML studies, respectively, it was only 2–3 years in our patients.

Furthermore, the results of the reference group provide important context for the frequency of AEs we observed. These results demonstrate that new or worsening AEs naturally occur over time, regardless of a formulation change. When patients are aware of a recent switch, they may mistakenly attribute these AEs to the new formulation. The reference group, however, suggests that most of these events are unrelated to the switch.

Nonetheless, we observed a substantial difference in AEs between the reference and generic groups, which was significant among all patients switching to Amarox and females switching to Accord. This indicates that the transition itself had an effect on adverse events. We believe several aspects contributed to this difference in AEs.

First to address is a potential difference in pharmacokinetics, as an increase in drug exposure can lead to increased AEs [8]. However, we demonstrated that after correcting for dose, age, treatment duration and sex, there was no difference in trough levels between Glivec and all three generic forms (Table 3). This is in line with findings in patients with CML , where both drug levels and molecular response were similar [9,10,11, 16, 17]. It should be noted, however, that we only measured trough levels in this study. Differences in excipients between formulations may have affected absorption kinetics, potentially leading to higher peak plasma concentrations, which could in turn contribute to an increase in adverse events. We conclude that on the basis of trough levels alone, we could not identify a pharmacokinetic explanation for the observed increase in AEs.

Second, a cause of new AEs could be a difference in excipients. For example, some severe anaphylactic cases have been described after a switch from branded to generic treatment, even though literature is in general reassuring [28, 29]. Because the excipients used in Glivec, Accord and Sandoz are identical, only the quantity of these excipients might differ, which seems an unlikely cause of new events. Unlike the other generics, Amarox contains titanium dioxide, which is an excipient that is widely used in several thousands of authorized products according to the EMA [30]. The highest quantities of titanium dioxide are found in candies, sweets and pastries [31]. As an excipient in drug formulations, the used quantities and exposure levels are considerably less than those used in foods [32]. Therefore, the use of titanium dioxide in Amarox tablets seems unlikely to have contributed to the reported AEs. Amarox tablets also differed in the absence of several excipients in the core. Absence of, for example, microcrystalline cellulose, a binding agent, could have led to rapid oral disintegration of the tablet, resulting in an unpleasant taste, which was reported in approximately one third of the patients in the Amarox group [33]. The impact of this should not be underestimated, because the high percentage of these patients who switched to another generic may be attributed to this unpleasant taste. Although we attempted to separate the unpleasant taste from the adverse events, it likely caused nausea in some patients, which could explain why it was more frequently reported compared with the other generics. In conclusion, while most generics used the same excipients, we think that the lack rather than the presence of certain excipients in Amarox tablets contributed to some new AEs.

Lastly, a potential cause of the increase in AEs is the nocebo effect, which describes worsened symptoms caused by negative expectations about the treatment. A 2024 systematic review by Car et al. investigated the nocebo effect across several biosimilar switching studies. Although biosimilar and generics are not the same, this review describes interesting findings regarding the nocebo effect: while all studies observed no changes in immunogenicity, efficacy nor safety, 4.8–28.2% of patients discontinued treatment [34]. Awareness of receiving a different formulation may provoke new symptoms or heighten patients’ attention towards symptoms they already have [35]. Regarding generic imatinib, one would expect that some of the most common imatinib-related adverse events, such as diarrhoea, nausea, muscle cramps and skin toxicity, are also the most reported new AEs after switching to a generic, which is exactly what we observed [36]. These are also the most frequently reported adverse events in studies assessing the same generics among patients with CML [9,10,11, 20]. Car et al. also describe how communication between patients on social media can play a pivotal role in shaping patients’ experience [34]. Within the Netherlands, patients with GIST maintain an active patient forum, on which patients might have talked about the switch to generic imatinib. Moreover, the questionnaire performed by the patient organization in March 2021, approximately 3 months after switch, while raising valid issues, might also have raised expectations about the treatment being poorly tolerated.

Interestingly, despite the reduced statistical power due to conducting sex-specific analyses, the switch to Accord in women specifically resulted in a significant increase in AEs. Although we were unable to demonstrate a significant difference between men and women, this finding is nonetheless noteworthy. In the hypothetical situation where an increase in statistical power would reveal a true sex-related difference, we consider it unlikely that this would be due to biological factors such as hormonal influences, given that Accord and Glivec contain the same excipients. Instead, we hypothesize that such an effect would more plausibly be attributed to the nocebo effect, which has been shown to be more pronounced in women [37].

We acknowledge certain limitations in our study, primarily due to its retrospective design. The assessment of AEs relied on reports from various physicians, which varied in detail from brief to extensive. As a result, some low-grade adverse events may not have been documented. Furthermore, being aware of AEs of other patients, the physician may have been more proactive in asking patients about specific symptoms. In addition, regarding the high switching rate among patients using Amarox, we could not explore whether this was driven by taste, tolerability or prescriber perceptions due to our retrospective study design. Finally, the exact influence of the nocebo effect could not be determined within this study design, and its magnitude can only be estimated by ruling out alternative explanations.