The FDA Adverse Event Reporting System (FAERS) has yielded significant new insights into the safety profile of voclosporin, the novel calcineurin inhibitor approved in January 2021 for treating active lupus nephritis. A comprehensive analysis of post-marketing surveillance data from 2021 to 2024 has identified several previously unreported adverse events and clarified the timing and demographic patterns of known side effects.
Key Safety Findings
Researchers analyzed 4,013 reports listing voclosporin as the "primary suspected" drug among over 3.4 million total reports in the FAERS database. The analysis identified eight positive System Organ Class (SOC) signals and 138 positive Preferred Term (PT) signals.
The most frequently reported adverse events 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 many of these align with findings from clinical trials, several unexpected adverse events emerged, including breath odor, menstrual disorders, acute pulmonary edema, gastroesophageal reflux disease, blurred vision, and insomnia.
"This study clarified the characteristics of voclosporin-related adverse drug reactions, providing strong support for clinical monitoring and risk identification of voclosporin," noted the researchers.
Timing of Adverse Events
The time-to-onset analysis revealed that nearly one-third of adverse events (29.8%) occurred within the first month of initiating voclosporin treatment, with a median onset time of 99 days. Gastrointestinal and neurological side effects typically appeared earlier, while renal and infectious complications emerged later in the treatment course.
Specifically, renal and urinary disorders had a median onset time of 133 days, and infections had a median onset time of 130.5 days. In contrast, gastrointestinal disorders appeared at a median of 54 days, and nervous system disorders at 33 days.
Demographic Patterns
The study revealed significant gender differences in adverse event patterns. Among the 4,013 reports, 84% came from female patients and 14.8% from males, reflecting the higher prevalence of lupus nephritis in women.
Female patients showed stronger associations with adverse events like alopecia, headache, upper abdominal pain, and vomiting. Male patients, meanwhile, demonstrated stronger correlations with gout, abnormal serum creatinine levels, elevated serum uric acid, and renal function abnormalities.
Age-related differences were also observed. In the 18-64 age group, 96 adverse events were identified, while only 15 were found in those 65 and older. Notably, older patients had a higher relative risk for hyperkalemia and anemia compared to younger patients.
Gastrointestinal Concerns
One of the most significant findings was the unexpectedly high number of gastrointestinal-related adverse events (n=1,737, ROR=2.03), which represented the highest number across all system organ classes. Common gastrointestinal issues included nausea, diarrhea, and vomiting.
"Although not being explicitly detailed in the product instruction, it is necessary for physicians to inform patients about the potential risk of gastrointestinal-related adverse events," the researchers emphasized.
Renal Toxicity and Hypertension
Despite structural modifications designed to reduce nephrotoxicity compared to cyclosporine, voclosporin still showed substantial renal-related adverse events, including increased blood creatinine (n=148, ROR=13.79), reduced estimated glomerular filtration rate (n=143, ROR=57.83), and acute kidney injury (n=54, ROR=1.4).
Hypertension was the most frequently reported adverse event overall, consistent with the known effects of calcineurin inhibitors on the renin-angiotensin system, sympathetic nervous system, and nitric oxide signaling pathways.
Infections and Malignancies
While voclosporin carries a black box warning about increased risks of serious infections and malignancies, only infections emerged as a positive signal in this study, including COVID-19 (n=196, ROR=2.56) and urinary tract infections (n=82, ROR=2.47). Malignancies did not meet the criteria for a positive signal, possibly due to the relatively short time since market introduction.
Clinical Implications
The findings suggest that monitoring strategies should be optimized with particular emphasis on the first month of treatment when adverse events are most common. Additionally, heightened vigilance is needed for renal and infectious complications during prolonged therapy.
Dr. Zhen Wang, the study's lead author, noted, "Our study has unearthed numerous voclosporin safety signals consistent with clinical trials, such as renal and urinary disorders and infections. Notably, the number of gastrointestinal disease-related adverse events reported exceeded expectations and were not mentioned in the product instruction, necessitating further evaluation."
The researchers acknowledged several limitations, including the voluntary nature of the FAERS reporting system, potential confounding from combination therapies, and the inability to calculate true incidence rates. Nevertheless, the study provides valuable real-world insights into voclosporin's safety profile that complement data from controlled clinical trials.
Healthcare providers are advised to implement regular monitoring of renal function, blood pressure, and electrolyte levels, particularly potassium, during voclosporin treatment. Patients should be educated about potential side effects, especially those occurring early in treatment, and the importance of promptly reporting any new symptoms.
