Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Abstract

Purpose In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti‐inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands: An interrupted time series regression analysis

“…This would be in keeping with the findings from a systematic review examining the impact of United States risk advisories, which suggested such advisories were more effective at decreasing initiation of targeted medicines and less effective at bringing about their discontinuation 2 . This has also been seen with another recent European study 20 . While the immediate rise in hydroxyzine discontinuation in England is considered an intended effect, it is uncertain why hydroxyzine discontinuation should have fallen in Denmark particularly when the rate of hydroxyzine initiation did not change.…”

“…However, other downstream factors may also have influenced this process and therefore we used the quarter when the referral concluded as our intervention time point when information first became public. Nevertheless, we add to the evidence demonstrating geographical variation in the impact of pharmacovigilance decisions can occur despite being subject to the same recommendations 3,20‐25 …”

“…Regulatory interventions may be associated with unintended consequences such as substitute prescribing or switching that may themselves lead to adverse effects 20,26 . Evaluating such effects, is often subject to methodological limitations 2,3 .…”

“…While the immediate rise in hydroxyzine discontinuation in England is considered an intended effect, it is uncertain why hydroxyzine discontinuation should have fallen in Denmark particularly when the rate of hydroxyzine initiation did not change. However, the post‐intervention negative trend in discontinuation in England may be because the pool of hydroxyzine initiators was falling, an effect seen elsewhere 20 …”

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis

“…Although the role of regulatory agencies is to alert prescribers to new safety information, the impact of such decisions on healthcare behaviour and health outcomes is challenging to measure and often poorly understood, with previous studies using heterogeneous and poor quality methods of evaluation 12–14 . We recently examined the impact of the 2013 EMA intervention on overall diclofenac prescribing, discontinuation and switching to alternative medicines in the general population 15 . We now report the impact of the 2013 EMA risk minimisation measures for diclofenac among patients specifically targeted by the intervention, namely among those with or at high risk of cardiovascular disease, across several EU countries to determine to what extent impact may have varied.…”