Mortality and adverse events with brand and generic clopidogrel in the US Food and Drug Administration Adverse Event Reporting System

Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful.

We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square ${(\mathrm{\chi }}^2$). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32–0.43; ${\mathrm{\chi }}^2=369.7;\mathrm{ }P<0.0001$] for total FAERS, and consistent for late 2010–2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37–0.45; ${\mathrm{\chi }}^2=286.2;\mathrm{ }P<0.004$) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0–1.25; ${\mathrm{\chi }}^2=3.5;\mathrm{ }P<0.06$). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33–1.57; ${\mathrm{\chi }}^2=75.8;\mathrm{ }P<0.0001$), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0–1.44; ${\mathrm{\chi }}^2=3.75;\mathrm{ }P<0.05$) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation.

The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.