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

Morales, Daniel R. and Macfarlane, Tatiana and MacDonald, Thomas M. and Hallas, Jesper and Ernst, Martin Thomsen and Herings, Ron M. C. and Smits, Elisabeth and Overbeek, Jetty A. and Mitchell, Lyn and Morant, Steven and Mackenzie, Isla and Doney, Alexander S. F. and Robertson, Chris and Bennie, Marion and Wei, Li and Nicholson, Lizzie and Morris, Carole and Flynn, Robert W.F. (2021) 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. Pharmacoepidemiology and Drug Safety, 30 (4). pp. 482-491. ISSN 1053-8569 (https://doi.org/10.1002/pds.5191)

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Abstract

Background: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. Method: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. Results: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (−12.05, 95%CI −18.47 to −5.63) and Scotland (−19.01, 95%CI −26.99 to −11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (−1.72, 95%CI −2.69 to −0.75) and Scotland (−2.38, 95%CI −3.32 to −1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. Conclusion: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

ORCID iDs

Morales, Daniel R., Macfarlane, Tatiana, MacDonald, Thomas M., Hallas, Jesper, Ernst, Martin Thomsen, Herings, Ron M. C., Smits, Elisabeth, Overbeek, Jetty A., Mitchell, Lyn, Morant, Steven, Mackenzie, Isla, Doney, Alexander S. F., Robertson, Chris, Bennie, Marion ORCID logoORCID: https://orcid.org/0000-0002-4046-629X, Wei, Li, Nicholson, Lizzie, Morris, Carole and Flynn, Robert W.F.;
CORE (COnnecting REpositories)