Characterizing clinical patterns and associated factors of zinc-induced copper deficiency: Insights from large-scale...

Zinc-induced copper deficiency (ZICD) is a severe complication of zinc therapy; however, its reporting trends and associated patient characteristics remain unclear. This study aimed to identify clinical patterns and factors potentially associated with ZICD using large-scale pharmacovigilance databases.

We retrospectively analyzed the Japanese Adverse Drug Event Report database (JADER) and performed a supplementary exploratory analysis using VigiBase. Adult patients receiving oral zinc were included. Multivariable logistic regression explored factors potentially associated with copper deficiency.

Among 2646 JADER patients, copper deficiency was reported in 100 (3.8%). Multivariable analysis indicated zinc dosage (per 1-mg/kg/day increase; adjusted reporting odds ratio [aROR], 3.51; 95% confidence interval (CI), 2.51-4.90), chronic kidney disease (CKD; aROR, 9.29; 95% CI, 5.88-14.67), advanced age (≥70 years; aROR, 1.93; 95% CI, 1.21-3.08), and female (aROR, 1.64; 95% CI, 1.06-2.52) as potential copper deficiency-associated factors, whereas acid suppressants were inversely associated. The median onset was 137 days, occurring earlier in patients with CKD than in those without (119.5 vs. 260 days). Among co-reports with copper deficiency, cytopenia was the predominant adverse event (JADER, 93%; VigiBase, 85%). In VigiBase, these reports were concentrated in the Western Pacific Region (93.5%), where a similar trend was observed for advanced age, but not for female.

Advanced age, CKD, and higher zinc dosages are potentially associated with ZICD. The geographical concentration of reports suggests reporting disparities contributing to a global under-recognition of this complication, necessitating continued international vigilance and rigorous copper and hematological monitoring during zinc therapy.