The data for this study was downloaded from the FAERS database (Bihan et al., 2020), which serves as the primary system for post-marketing surveillance of adverse drug reactions in the United States and is a key avenue for current pharmacovigilance research. “Voclosporin” and its trade name “LUPKYNIS” were used as keywords for drug retrieval. In the FAERS database, drug-event relationships are classified into four categories: primary suspect, secondary suspect, concomitant, and interacting. To enhance the reliability of the analysis, only reports in which voclosporin was designated as the primary suspect (PS) were retained. Ultimately, we extracted adverse drug reactions related to voclosporin spanning from 2021Q1 to 2024Q2. Following FDA suggestions, we selected the most recent FDA_DT with the same PRIMARYID, and when FDA_DT and CASEID were identical, we chose the higher PRIMARYID to eliminate duplicates prior to data analysis. The collected data included demographic information, drugs, therapies, indications, reactions, and outcomes from the adverse reaction reports. We employed the “Medical Dictionary for Regulatory Activities” (MedDRA) to standardize adverse events terms in the Preferred Term (PT) format, subsequently classifying PTs by their respective System Organ Classes (SOCs).

We employed reporting odds ratio (ROR) to investigate the associations between voclosporin and adverse events (AEs). The calculation of the ROR algorithm was based on a 2 × 2 columnar table, with the detailed algorithm presented in Supplementary Table S1. If the lower limit of 95% CI exceeded 1.0 with at least three AE reports, the ROR is a positive signal. Higher ROR values indicated stronger signal intensity, signifying a stronger association between the target drug and the specific AE.

To identify gender-specific and age-specific risks of ADRs, the ROR was utilized to detect disproportional signals among different subgroups following voclosporin administration, as described previously (Zou et al., 2024). The stratification was specifically into males and females, as well as adults aged 18–64 and the elderly aged 65 and above.

The time to onset of ADEs caused by voclosporin were defined as the interval between the reported ADEs onset date and the start date of voclosporin administration. This study initially assessed the overall time to ADRs following voclosporin use. Subsequently, based on the results of the disproportionality analysis, the onset times of SOC levels and PT levels were assessed. We summarized the onset times of AEs using the median, interquartile range (IQR), and applied the Kruskal-Wallis test to evaluate whether there were significant differences in the onset times between different SOCs or different PTs.

The statistical significance was set at p < 0.05 for all analyses. All statistical analyses were performed using GraphPad Prism 10 (GraphPad Software, CA, USA) and R 4.3.3.

From 2021Q1 to 2024Q2, a total of 3,407,094 case reports were obtained from the FAERS database. There were 4,013 case reports associated with voclosporin as the PS. Of these, AE reports from female accounted for 84.0%, significantly higher than those from males at 14.8%. According to the available age data, the most reports (26.4%) were in the age group of 18–44 years followed closely by 44–64 years (10.8%). The principal source of reports was the United States, contributing 4,006 reports (99.8%), and were generally reported by consumers (n = 3,329, 83.00%). Among the reported outcomes, hospitalization (n = 379, 9.4%) was the most common severe outcome (Table 1).

As shown in Figure 1, the AEs resulted from voclosporin usage impacted 27 SOCs. Among these, eight noteworthy SOCs emerged, meeting ROR algorithms, including gastrointestinal disorders (n = 1737, ROR = 2.03), investigations (n = 1,338, ROR = 2.07), nervous system disorders (n = 950, ROR = 1.12), infections and infestations (n = 835, ROR = 1.27), musculoskeletal and connective tissue disorders (n = 692, ROR = 1.15), renal and urinary disorders (n = 638, ROR = 2.86), surgical and medical procedures (n = 598, ROR = 3.66), vascular disorders (n = 544, ROR = 2.57).

The AEs associated with voclosporin encompassed 138 PT signals (Supplementary Table S2). To more accurately assess AEs directly related to voclosporin use, this study excluded AEs that could be attributed to drug characteristics or non-pharmacological factors, such as “injury, poisoning and procedural complications” and “product issues.” Tables 2, 3 list the top 50 PTs based on occurrence frequency and ROR values. Common AEs included hypertension (n = 442, ROR = 12.05), headache (n = 404, ROR = 3.79), nausea (n = 342, ROR = 2.62), diarrhea (n = 297, ROR = 2.4), and proteinuria (n = 231, ROR = 62.91), while AEs with higher ROR values primarily involved abnormalities in various investigations results. Most AEs were consistent with the results of clinical trials and the drug instruction. Notably, several unexpected AEs were also identified, including breath odour (n = 4, ROR = 12.5), menstrual disorder (n = 7, ROR = 5.82), acute pulmonary oedema (n = 3, ROR = 4.16), gastrooesophageal reflux disease (n = 23, ROR = 1.73), vision blurred (n = 32, ROR = 1.5), and insomnia (n = 61, ROR = 1.46), which had not been previously reported. Moreover, other AEs listed in the voclosporin package insert, such as malignancies, QT prolongation, and pure red cell aplasia, did not meet the criteria for positive signal.

To analyze the gender differences in safety signals of voclosporin, we employed the ROR algorithm to screen voclosporin-related AEs separately for males and females. In males, we identified 46 AEs (Supplementary Table S3), while in females, 122 AEs were identified (Supplementary Table S4). Comparing the AEs of different genders, we can find that 38 AEs can be observed in both male and female, while certain AEs were gender-specific. The top five AEs exclusive to females were nausea, dizziness, cough, urinary tract infection, and decreased appetite. The top five AEs exclusive to males were back pain, muscle spasms, vision impairment, neck pain, and dry mouth. Among the AEs common to both sexes, alopecia, headache, upper abdominal pain, and vomiting were more strongly associated with females, whereas gout, abnormal serum creatinine levels, elevated serum uric acid, and renal function abnormalities were more strongly associated with males (Figure 2A).

We also assessed the risk differences of safety signals between adults (aged 18–64) and the elderly (aged 65 and above). Within the 18–64 age group, we identified 96 AEs (Supplementary Table S5), whereas in the group aged 65 and above, we identified 15 AEs (Supplementary Table S6). Among individuals aged 18–64, the most frequently reported top five AEs were nausea, urine protein/creatinine ratio increased, dizziness, arthralgia, and renal impairment. In contrast, AEs exclusive to those aged 65 and above included joint swelling, arthritis, fluid retention, memory impairment, hyperkalaemia, white blood cell count decreased, and dry mouth. Further analysis revealed that among the 11 shared positive PT signals in both age subgroups, patients aged 65 and above had a higher relative risk for hyperkalaemia and anaemia compared to those aged 18–64 (Figure 2B).

We analyzed 1,797 case reports of voclosporin-related AEs with known onset times. The median initiation period stood at 99 days (IQR 20–250). Nearly one-third of the AEs (n = 536, 29.8%) occurred within the first month of initiating voclosporin. Furthermore, 17.9% of AEs were reported between 180 and 360 days, and 16.4% occurred after 360 days (Figure 3A). Further analysis at the primary SOC level showed significant differences in the onset times of AEs among various SOCs (p < 0.01). In the reports of “renal and urinary disorders” and “infections and infestations,” the median onset times of adverse events were 133 days (IQR 56–335.3) and 130.5 days (IQR 48–294.3), respectively, which were significantly later than the median times for “gastrointestinal disorders” (median time 54 days, IQR 6–147) and “nervous system disorders” (median time 33 days, IQR 5–128.5) (Figure 3B). For clarity on the onset time of individual PTs in the SOC, we analyzed and compared the detailed onset times of AEs at the PT level according to the SOC. The Kruskal-Wallis test revealed statistically significant differences in the onset times of PT within “investigations” (P < 0.001) (Figure 3C). Specifically, the median onset time for blood pressure increased was the shortest (28, IQR 6–156.5), while that for increased urinary protein/creatinine ratio was the longest (251, IQR 109–550) (Supplementary Table S7). Ultimately, the Weibull parameter test results indicated that the onset times of adverse events in the “renal and urinary disorders” and “surgical and medical procedures” exhibited characteristics of a random failure type, while other SOCs showed an early failure type (Figure 3D).

Our study indicated that the proportion of AEs was higher in females (84%) compared to males (14.8%) and a higher proportion aged between 18 and 44 years (26.4%). This finding aligns with epidemiological studies on LN, which reported that the prevalence of LN in females is approximately three to four times that in males, with a median age at diagnosis of about 38.4 years (Hocaoǧlu et al., 2023; Feldman et al., 2013). Notably, only 20% of reports contained clear outcome data, potentially due to a significant number of reports being submitted by consumers, which may have led to underreporting of outcome information. This highlights the need for increased vigilance among clinicians and pharmacists regarding voclosporin-related AEs. In addition, among the available outcome reports, more than 50% indicated serious adverse events (hospitalization, death, disability). Although this may be attributed to the severity or progression of the underlying condition, it still warrants attention from clinicians. Regarding reporting by country, the number of AEs in the United States significantly surpassed those in other countries, likely due to the earlier availability and higher prescription volume of the drug in the country. Given that the mechanisms and effectiveness of therapeutic interventions for LN vary among racial and ethnic subgroups (Isenberg et al., 2010), our analytical findings might differ in other regions. Thus, studies across different ethnicities and regions are required to validate our findings.

Voclosporin is the first oral agent approved for the treatment of LN that was developed through structural modification of CsA. Like CsA, voclosporin inhibits T-cell activation by suppressing calcineurin. However, structural modification endows voclosporin with stronger immunosuppressive effects (Kuglstatter et al., 2011), which has been confirmed in vivo using a 32P-labelled calcineurin activity assay (Stalder et al., 2003). When compared to another CNI, tacrolimus, voclosporin also demonstrated comparable immunosuppressive efficacy in preventing renal transplant rejection (Anglade et al., 2008). Although voclosporin is associated with a lower metabolite burden associated with nephrotoxicity compared to CsA (Roby and Shaw, 1993; Ling et al., 2014), the AEs remain inevitable. In our study, we observed a substantial number of nephrotoxicity-related AEs, such as blood creatinine increased (n = 148, ROR = 13.79), eGFR reduced (n = 143, ROR = 57.83), and acute kidney injury (n = 54, ROR = 1.4). Therefore, during voclosporin treatment, regular monitoring of renal function is necessary to adjust the dosage based on the eGFR.

Hypertension is common in patients treated with voclosporin. Integrated analysis of published AURA-LV and AURORA 1 trials revealed that up to 19.1% of LN patients receiving voclosporin experienced hypertension (Arriens et al., 2023). This finding corroborated our study, where hypertension (n = 442, ROR = 12.02) was the most frequently reported AE. Hypertension is also a relatively common AE among other CNI. The underlying mechanisms are believed to include activation of the renin-angiotensin system and the sympathetic nervous system, induction of oxidative stress, and alteration of the nitric oxide (NO) signaling pathway, leading to systemic vasoconstriction and elevated blood pressure (Hošková et al., 2017). Blood pressure abnormalities during voclosporin treatment are generally transient, and no patients had treatment discontinued due to hypertension (Arriens et al., 2023). Nevertheless, monitoring blood pressure remains necessary during treatment. Some calcium channel blockers (verapamil and diltiazem) may increase voclosporin blood concentrations (Ling et al., 2014), necessitating a reduction in the dose of voclosporin. If elevated blood pressure is not controlled by a reduction in voclosporin dosage alone, further medical interventions may be required. Besides hypertension, diabetes is also one of the classically CNI-attributed complications. In our study, no positive AEs related to diabetes were observed, and several other studies also proved the superiority of voclosporin in this regard (Rovin et al., 2019; Rovin et al., 2021; Kolic et al., 2020; Busque et al., 2011). Voclosporin has a milder impact on pancreatic islet function compared to other CNIs, which address the clinical needs of diabetes patients for CNI therapy.

Voclosporin’s prescribing information contains a black box warning about the increased risk of serious infection and malignancies, potentially leading to hospitalization or death, which is one of the unavoidable side effects of immunosuppressants (Chua et al., 2020). In the AURA-LV and AURORA 1 randomized controlled trials, infections were the most common AEs in both the voclosporin group and the placebo group, with 40 cases (15%) and 30 cases (11.3%) of patients considered treatment-related. Infection was also considered as the positive signal in our study, including COVID-19 (n = 196, ROR = 2.56) and urinary tract infection (n = 82, ROR = 2.47). Malignancies did not meet the positive criteria for this study. Patients treated with immunomodulatory agents are generally at an increased risk of developing malignant tumors (Munagala and Phancao, 2022; Prakash et al., 2002), with risk factors including male gender and advanced age (Ilham et al., 2023; Pendón-Ruiz de Mier et al., 2015). However, these factors differ from the epidemiological characteristics of LN (). Moreover, the relatively short time since the market introduction may also explain the negative signal for malignant tumors observed in this study. Notably, multiple studies have pointed out that compared to other immunosuppressants, CNIs were associated more with the development of malignancies (Pendón-Ruiz de Mier et al., 2015; Doesch et al., 2010; Kulbat et al., 2023). Therefore, it is recommended that healthcare professionals continue vigilant monitoring for malignant AEs during the clinical use of voclosporin.

In our study, positive SOC signals related to the primary disease were also reported, including “musculoskeletal and connective tissue disorders” and “investigations.” LN is secondary to SLE. The numerous positive AEs observed in this study, such as arthralgia (n = 143, ROR = 1.69), pain in extremity (n = 71, ROR = 1.39), malar rash (n = 109, ROR = 13.24), and proteinuria detection (n = 33, ROR = 33.08), represented the different organ manifestations of SLE (Kiriakidou and Ching, 2020). Given that 80% of the reports in this study were submitted by consumers, we have reason to believe that, although LN is not a rare disease, it remains poorly understood. This highlights the necessity for patients on voclosporin to be well-informed about the manifestations of LN progression and to distinguish them from drug adverse reactions.

Among the SOC of nervous system disorders, a large number of AEs were also reported, such as headaches (n = 404, ROR = 3.79), dizziness (n = 129, ROR = 1.59), and migraine (n = 60, ROR = 3.25). This could be attributable to the neurotoxicity of CNIs (Faravelli et al., 2021), as described in the product instructions. Previous studies found that the incidence of gastrointestinal-related AEs was higher in the treatment group compared with the placebo group (Rovin et al., 2021). In our study, gastrointestinal-related AEs (n = 1737, ROR = 2.03) notably exceeded expectations and represented the highest number of AEs across all SOC. Common AEs included nausea (n = 342, ROR = 2.62), diarrhea (n = 297, ROR = 2.4), and vomiting (n = 185, ROR = 2.42). Although not being explicitly detailed in the product instruction, it is necessary for physicians to inform patients about the potential risk of gastrointestinal-related AEs. Additionally, our findings revealed some rare and unexpected AEs including breath odor (n = 4, ROR = 12.5), gastroesophageal reflux disease (n = 23, ROR = 1.73), menstrual disorder (n = 7, ROR = 5.82), vision blurred (n = 32, ROR = 1.5), insomnia (n = 61, ROR = 1.46), and acute pulmonary oedema (n = 3, ROR = 4.16). These adverse reactions require further research to elucidate their specific mechanisms of occurrence.

Gender differences have been shown to influence drug bioavailability, distribution, metabolism, and elimination (Zopf et al., 2009), leading to disparities in ADEs between males and females. However, there is a lack of reports on gender-specific ADEs associated with voclosporin treatment. In our study, we observed a greater number of positive signal values for ADEs in females compared to males. Alopecia, headache, upper abdominal pain, and vomiting exhibited a stronger correlation with females, while gout, abnormal serum creatinine levels, increased serum uric acid, and abnormal renal function tests demonstrated a stronger correlation with males. Some of these adverse reactions are inherently gender-specific; for example, the incidence of headache was higher in females than in males (Silberstein, 2000). Serum uric acid levels tend to increase steadily in males before the age of 50, while levels remain stable in females (Zitt et al., 2020). This might have been the reason why the uric acid metabolism in males was more susceptible to the effects of medications. In the age subgroup analysis, we found that older adults had a higher relative risk of hyperkalemia and anemia compared to younger adults. Hyperkalemia is a common electrolyte disturbance induced by CNIs, which can lead to life-threatening arrhythmias. This ionic disturbance is more challenging to regulate due to the presence of underlying kidney disease in patients. A strong positive correlation exists between the severity of hyperkalemia and mortality risk (Sun et al., 2024), making early identification and treatment of hyperkalemia crucial. Healthcare providers need to implement interventions to enhance patient awareness of hyperkalemia. In summary, our findings provide insights into population-specific side effects. While these findings require further validation, they offer improved guidance for drug monitoring in diverse populations.

In this study, 31.35% of AEs associated with voclosporin occurred within the first month of treatment, notably gastrointestinal and neurological AEs; the total number of AEs decreased monthly thereafter. At the specific SOC level, the median reporting times for renal and infectious AEs were observed to be later. In summary, clinical monitoring strategies should continue to be optimized, with a particular emphasis on the early detection and management, especially during the first month of voclosporin treatment. Furthermore, heightened vigilance is required for renal and infectious adverse reactions during prolonged therapy.

This study was subject to several limitations. Firstly, the FAERS database is an open, voluntary reporting system. The AE information might be delayed, incomplete, and inaccurate due to the different reporters (professionals and non-professionals). For example, 60.5% of the reports in this study did not provide age information and 80.7% did not provide treatment outcomes. Second, voclosporin often combines with other immunosuppressive drugs. The FDA analyzes all collected adverse drug events, which may confound some adverse reactions, as they might be the result of combination therapy or different treatment strategies. Moreover, our research could only provide a statistical association between voclosporin and AEs, the true incidence of each AE could not be calculated due to the absence of data on the total number of cases occurring in the population. Therefore, while the research provides valuable insights, further investigation is still required to get a comprehensive understanding of the risk associated with voclosporin use.