A study of the regional differences in propacetamol-related adverse events using VigiBase data of the World Health Organization

Abstract

Upon withdrawal of propacetamol, an injectable formulation of the paracetamol prodrug, in Europe due to safety concerns, South Korea’s regulatory body requested a post-marketing surveillance study exploring its safety profile. We characterized regional disparities in adverse events (AE) associated with propacetamol between Asia and Europe using the World Health Organization’s pharmacovigilance database, VigiBase. We performed disproportionality analyses using reporting odds ratios (rOR) and information component (IC) to determine whether five AEs (anaphylaxis, Stevens–Johnson syndrome, thrombosis, contact dermatitis/eczema, injection site reaction [ISR]) were associated with propacetamol versus non-propacetamol injectable antipyretics in Asia and Europe, separately. In Asia, there was a high reporting ratio of propacetamol-related ISR (rOR 5.72, 95% CI 5.19–6.31; IC025 1.27), satisfying the signal criteria; there were no reports of thrombosis and contact dermatitis/eczema. Two signals were identified in Europe, with higher reporting ratios for thrombosis (rOR 7.45, 95% CI 5.19–10.71; IC025 1.92) and contact dermatitis/eczema (rOR 16.73, 95% CI 12.48–22.42; IC025 2.85). Reporting ratios of propacetamol-related anaphylaxis were low for Asia and Europe. While signals were found for thrombosis and contact dermatitis/eczema in Europe, these were not detected in Asia. These findings suggest potential ethnic differences in propacetamol-related AEs between Asia and Europe, which could serve as supportive data for future decision-making.

Evaluation of the Regulatory Required Post-Authorization Safety Study for Propacetamol: Nested Case-Control and Case-Time-Control Studies

“…2 In our previous research exploring regional variations in propacetamol-related adverse events between Asia and Europe, we found a correlation between the use of propacetamol and thrombosis, as well as contact dermatitis/eczema in Europe, but not in Asia. 9 Although, the present study did not identify any association between the use of propacetamol and thrombosis, thrombosis showed the highest frequency among adverse events of interest during the risk period. However, as a subtype of thrombosis, phlebitis may be related to injection site reactions owing to the nature of the formulation as an injection.…”

“… 22 In a study using a spontaneous adverse drug reaction reporting database, most cases were non-serious adverse events, and thrombosis was reported with a very low frequency. 9 Similarly, in our study, the limited number of patients treated with propacetamol and experiencing adverse events of interest presented a challenge in assessing the ORs. Taken together, despite using the national claims data, the low exposure to propacetamol prior to the occurrence of the adverse events of interest suggests the safety of propacetamol against these events.…”

“…In light of the reported cases of propacetamol-induced hypersensitivity in Europe, the possibility of hypersensitivity-related adverse events cannot be ruled out, thereby requiring a timely assessment of these conditions from a Korean perspective. Moreover, as a previous study on the safety of propacetamol suggested a potential ethnic difference between Asia and Europe in terms of serious hypersensitivity and thrombosis, 9 a comprehensive evaluation of the safety concerns raised in a large population is needed.…”