Background: Cyclosporine, a narrow therapeutic index drug, is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Although generic cyclosporine has been shown to provide adequate immunosuppression and has the potential for cost savings, evidence in their safety profile compared to brand reference product remains limited.
Objectives: To compare safety outcomes of generic cyclosporine with the innovator brand (Neoral®) in solid organ transplant patients.
Methods: We searched MEDLINE Ovid, IPA, APA Psychinfo, and CINAHL from inception until February 1, 2021 for studies evaluating comparative safety outcomes of brand versus generic cyclosporine in transplant patients. Primary safety outcome was serum creatinine concentration or other markers of nephrotoxicity (e.g. glomerular filtration rate (GFR)). Secondary outcomes were- infection, other serious adverse events (AE), treatment discontinuation, and death. Two reviewers independently assessed study eligibility and risk of bias, and extracted study-level data. Mean difference (MD) and relative risk (RR) with 95% confidence intervals (CI) for meta-analyses were calculated using fixed or random-effects method. Heterogeneity was assessed using I2 index. Risk of bias was evaluated using Cochrane Collaboration and National Institute of Health (NIH) Study Quality Assessment Tools.
Results: Of 1,401 publications identified from database searching, 14 studies were included in the review and meta-analyses. Most of the studies had moderate (n=7) and high risk of bias (n=4). Serum creatinine was significantly lower in patients treated with generic cyclosporine compared to those with brand cyclosporine at 1 month [MD (95% CI)= -0.07 (−0.09, -0.06) mg/dL; I2= 0%], while there were no significant differences at 4 months [MD (95% CI)= -0.34 (−1.09, 0.41) mg/dL; I2= 98%], 6 months [MD (95% CI)= -0.03 (−0.10, 0.05) mg/dL; I2= 0%], and 12 months [MD (95% CI)= -0.04 (−0.18,0.10) mg/dL; I2= 61%]. Among the studies reporting the rate of infections (n=3), no significant difference was observed between patients treated with brand versus generic cyclosporine products [RR (95% CI)= 0.69 (0.40-1.19); I2= 0%]. None of the studies reported any significant difference in other AEs.
Conclusions: Overall, the assessed safety outcomes were similar between brand versus generic cyclosporine products in transplant patients. However, given that most studies included in our meta-analysis had moderate or high risk of bias, high quality post-marketing studies evaluating safety of generic cyclosporine are needed.
