Epirubicin, the 4′-epimer of doxorubicin, was introduced into clinical use more than 40 years ago and soon established a vital place in cancer chemotherapy (Mouridsen et al., 1990; Pavone-MacalusoTripi et al., 1993). Epirubicin and doxorubicin have different properties due to the different spatial orientation of the hydroxyl group at 4'. Compared to doxorubicin, epirubicin has been shown to cause less myelosuppression, fewer cardiac toxicities, fewer non-hematologic toxicities, and less nausea and vomiting (Henderson et al., 2003; Burnell et al., 2010). The anti-tumor mechanisms of epirubicin appear to intercalate with DNA, inhibit the activity of topoisomerase II, generate free radicals and oxygen, and thus disturb the synthesis of DNA, RNA, and proteins, resulting in its anti-tumor function (Khasraw et al., 2012).

Since its approval by the U.S. Food and Drug Administration (FDA), epirubicin has been widely used to treat many malignancies, including bladder cancer, breast cancer, liver cancer, and non-small cell lung cancer (NSCLC) (Plosker and Faulds, 1993; de Azambuja et al., 2009). Bladder cancer accounts for approximately 90%–95% of urothelial cancers and 4% of malignant cancers in adults (Richters et al., 2020). Since 1985, many studies have shown that epirubicin has good therapeutic effects and high efficacy in preventing bladder cancer recurrence (Tripi et al., 1986; Oosterlinck et al., 1993). Previous clinical trials have shown that, in patients with bladder cancer, the main adverse events of epirubicin are hematuria, cystitis, urinary tract infection, and systemic side effects, which include fever, tiredness, nausea, abdominal pain, and headache—listed on the instruction label (Onrust et al., 1999; Hendricksen et al., 2008). Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer (Forner et al., 2018). Transarterial chemoembolization using doxorubicin (TACE-DOX) is recommended for the therapy of hepatocellular carcinoma (Laface et al., 2021). According to Ellis et al. (1995), epirubicin is well tolerated by patients with hepatocellular carcinoma and has a good curative effect. A study published in 2015 suggested that, compared to patients with hepatocellular carcinoma treated with miriplatin, patients treated with miriplatin-plus-epirubicin were more likely to develop adverse events such as neutropenia and anorexia (Tawada et al., 2015). These adverse events (AEs) have been marked on the instruction label; however, it is worth noting that the majority of safety-related information comes from premarket randomized controlled trials (RCTs) and a few case reports on AEs; these lack extensive real-world data.

A thorough understanding of their possible side effects is essential for the safe use of drugs. Given the limitations of clinical trials and case reports, public databases containing extensive information on drug use, such as the FDA Adverse Event Reporting System (FAERS), have emerged. FAERS contains large-scale information submitted by healthcare professionals, consumers, and manufacturers; therefore, it can help identify AEs that have not been marked on the instruction label (Sakaeda et al., 2013). In this study, the AEs of epirubicin were identified and analyzed using four rigorous algorithms based on the FAERS database. AEs not specified on the medicine labels were observed when the safety of epirubicin was reviewed and analyzed. The findings of this study offer suggestions for the therapeutic application of epirubicin.

Despite being approved by the FDA, serious but less-common safety problems can emerge once the drug is post-marketed (Garashi et al., 2022; Kong et al., 2023). This phenomenon may be partly caused by: i) a larger patient population, making the detection of rare AEs more feasible; ii) a wider range of patients with underlying diseases and co-medications, making it easier to detect interactions between drugs and diseases, as well as drugs and drugs; iii) drug abuse; and iv) drug misuse (Schick et al., 2017). Given these problems, the public FAERS database could help investigation into less common adverse drug reactions and provide guidance for clinical drug use. To our knowledge, this is the first study to investigate epirubicin-related AEs using real-world data from the FAERS database.

Our study analyzed the signal strength of AEs ranked by case number, the three most frequent of which were blood and lymphatic system disorders, cardiac disorders, and neoplasms benign, malignant, and unspecified (including cysts and polyps) consistent with the drug instructions (Schneeweiss et al., 2018). In addition, the number of AEs associated with hepatobiliary disorders and the signal intensity were both high, indicating that these disorders were closely related to epirubicin.

Among the top five results generated from all four algorithms and ranked by the value of the EBGM, which is a stringent algorithm, we found that hepatic artery stenosis and hepatic artery occlusion were associated with hepatobiliary disorders, and gait apraxia was associated with nervous system disorders. Neither type of disorder was listed on the epirubicin label.

Hepatic artery stenosis and occlusion may be partly due to transarterial chemotherapy (Matsui et al., 2017a; Matsui et al., 2017b). Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, has left many people annually facing the threat of death (Okuda et al., 1985; Bosch et al., 2004). Hepatic artery damage (HAD) associated with transcatheter arterial chemoembolization (TACE) (Idée and Guiu, 2013) may affect clinical treatment outcomes. A previous study comprehensively analyzed the occurrence of HAD in 33 patients treated with TACE alone using a mixture of epirubicin, iodized oil, and gelatin sponge (Maeda et al., 2008). The results of this study indicated that accumulated epirubicin dose was significantly associated with HAD (p = 0.001). Our study also suggests that hepatic artery stenosis and occlusion are potential side effects of epirubicin. Therefore, during the course of clinical use, more attention should be paid to liver artery damage caused by epirubicin.

Other drugs associated with gait apraxia were also investigated. Gabapentin, an anticonvulsant, has been widely reported to be associated with gait apraxia (Meng et al., 2014; Wiffen et al., 2017). Based on the four algorithms used in our study, we also identified that gabapentin can cause gait apraxia, which is consistent with previous studies, indicating the high robustness and reliability of the four algorithms. We also found that the patient IDs reported for other drugs were inconsistent with those reported for epirubicin, indicating that gait apraxia caused by epirubicin was not caused by other drug ingredients.

Gait apraxia has been widely used to describe gait disturbances accompanied by normal-pressure hydrocephalus, cerebral small vessel disease, and other frontal disorders (Dale et al., 2018). Gait apraxia, a nervous system disease, may indicate that epirubicin has damaged the nervous system. Gait apraxia is also referred to as a gait disturbance and is associated with many signs, including locomotor abnormalities, disequilibrium, loss of gait ignition, and inappropriate postural responses (Della Sala et al., 2002). It is widely accepted that injury to the frontal lobe and cerebellum and damage to the connections between the frontal lobe, basal ganglia, cerebellum, and brainstem may be the cause of gait apraxia (Thompson, 2012). Since its approval for cancer treatment, epirubicin-induced cerebral lesions have attracted increasing attention. Although the blood–brain barrier restricts many therapeutic molecules from entering the brain, chemotherapy, including epirubicin therapy, can damage the microscopic structure of the cerebral tissue through direct neurotoxicity (Meyers, 2008). The following reports support this hypothesis. Chen et al. (2023) found that, compared with breast cancer survivors who did not receive chemotherapy (docetaxel and epirubicin), survivors who received chemotherapy had reduced white matter integrity in the middle frontal gyrus (MFG). Deprez et al. (2012) found that, compared with controls, patients with breast cancer who were exposed to chemotherapy (epirubicin, fluorouracil, and cyclophosphamide) had significant decreases in fractional anisotropy (FA) in the frontal WM tracts after treatment, suggesting poor connectivity of the brain microstructure. Considering the important role of the frontal lobe and the connections between it, the basal ganglia, and the cerebellum, it is reasonable to conclude that epirubicin may cause gait apraxia.

To date, we have not found studies that have shown that gait apraxia is associated with the use of epirubicin, which seems to indicate that there is only a correlation, not a causation. However, we still pay more attention to the occurrence of gait apraxia associated with the clinical use of epirubicin.

It is worth emphasizing that we found many ADRs that have not been listed on the drug label, such as intestinal atresia and Miller Fisher syndrome, which should be paid closer attention in future clinical drug use.

This study has some limitations that should be considered. First, although ROR and PRR have high stability and specificity, BCPNN has higher sensitivity, stability, and specificity than ROR and PRR (Zhang et al., 2023). To make our results more robust, we used four algorithms to filter the AEs associated with the use of epirubicin: PRR, ROR, BCPNN, and EBGM. AEs were considered to have occurred only when all four algorithms met simultaneously, thereby guaranteeing the accuracy of their detection. Second, owing to the small number of patients treated with epirubicin, we could not determine the incidence of adverse reactions. Third, because the sources of reports in the FAERS are diverse, there are differences in the quality of data submitted by reporters, leading to omissions and errors. Fourth, we could not completely avoid the occurrence of false-positive signals, although four algorithms were utilized. Moreover, each patient’s additional prescription drugs may not be fully disclosed in their medical records. It is therefore difficult to determine whether an adverse reaction was caused by the target drug, a companion drug, or a combination of the two. Therefore, more effort should be made to address these limitations and investigate the safety of epirubicin.

The findings of this study provide several insights into the clinical applications of epirubicin. Several unexpected AEs such as hepatic artery stenosis, gait apraxia, and intestinal atresia are associated with the use of epirubicin. Clinicians should be careful when prescribing epirubicin to patients to prevent the emergence of these AEs. Further clinical studies are required to validate these findings. To better protect patients, the safety of epirubicin must be continuously explored in the real world.