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

Daniel R. Morales; Tatiana Macfarlane; Thomas M. MacDonald; Jesper Hallas; Martin Thomsen Ernst; Ron M.C. Herings; Elisabeth Smits; Jetty A. Overbeek; Lyn Mitchell; Steven Morant; Isla Mackenzie; Alexander S.F. Doney; Chris Robertson; Marion Bennie; Li Wei; Lizzie Nicholson; Carole Morris; Robert W.F. Flynn

doi:10.1002/pds.5191

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

Daniel R. Morales^*
, Tatiana Macfarlane
, Thomas M. MacDonald
, Jesper Hallas
, Martin Thomsen Ernst
, Ron M.C. Herings
, Elisabeth Smits
, Jetty A. Overbeek
, Lyn Mitchell
, Steven Morant
, Isla Mackenzie
, Alexander S.F. Doney
, Chris Robertson
, Marion Bennie
, Li Wei
, Lizzie Nicholson
, Carole Morris
, Robert W.F. Flynn

^*Corresponding author for this work

Clinical Pharmacology, Pharmacy and Environmental Medicine

University of Dundee
PHARMO Institute for Drug Outcomes Research
University of Strathclyde
NHS National Services Scotland
University College London

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	Pharmacoepidemiology and Drug Safety
Volume	30
Issue number	4
Pages (from-to)	482-491
ISSN	1053-8569
DOIs	https://doi.org/10.1002/pds.5191
Publication status	Published - Apr 2021

Funding

The authors acknowledge the Electronic Data Research and Innovation Service (eDRIS) of ISD Scotland for providing the Scottish data and for the general practices that contributed data to CPRD for public health purposes. The study was funded by the European Medicines Agency (Procurement procedure EMA/2014/50/RE). The EMA approved the final study protocol and had no influence on the results or decision to publish. Elisabeth Smitsm Jetty A. Overbeek and Ron M. C. Herings are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. TMM's university holds research grants from Novartis, Ipsen, Teijin & Menarini. He is or has been the Principal Investigator on trials paid for by Novartis, Ipsen, Teijin, RTI, GlaxoSmithKline, SHIRE and Menarini. In the last 3 years he has been paid consulting fees by Novartis and Merck. None of these studies relate to hydroxyzine.

Keywords

hydroxyzine
pharmacoepidemiology
pharmacovigilance
prescribing
regulation
time-series

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Morales, D. R., Macfarlane, T., MacDonald, T. M., Hallas, J., Ernst, M. T., Herings, R. M. C., Smits, E., Overbeek, J. A., Mitchell, L., Morant, S., Mackenzie, I., Doney, A. S. F., Robertson, C., Bennie, M., Wei, L., Nicholson, L., Morris, C., & Flynn, R. 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), 482-491. https://doi.org/10.1002/pds.5191

@article{cbc9759003624c2f8ee2e20192c7e03a,

title = "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",

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.",

keywords = "hydroxyzine, pharmacoepidemiology, pharmacovigilance, prescribing, regulation, time-series",

author = "Morales, \{Daniel R.\} and Tatiana Macfarlane and MacDonald, \{Thomas M.\} and Jesper Hallas and Ernst, \{Martin Thomsen\} and Herings, \{Ron M.C.\} and Elisabeth Smits and Overbeek, \{Jetty A.\} and Lyn Mitchell and Steven Morant and Isla Mackenzie and Doney, \{Alexander S.F.\} and Chris Robertson and Marion Bennie and Li Wei and Lizzie Nicholson and Carole Morris and Flynn, \{Robert W.F.\}",

note = "Funding Information: The authors acknowledge the Electronic Data Research and Innovation Service (eDRIS) of ISD Scotland for providing the Scottish data and for the general practices that contributed data to CPRD for public health purposes. The study was funded by the European Medicines Agency (Procurement procedure EMA/2014/50/RE). The EMA approved the final study protocol and had no influence on the results or decision to publish. Funding Information: Elisabeth Smitsm Jetty A. Overbeek and Ron M. C. Herings are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. TMM's university holds research grants from Novartis, Ipsen, Teijin \& Menarini. He is or has been the Principal Investigator on trials paid for by Novartis, Ipsen, Teijin, RTI, GlaxoSmithKline, SHIRE and Menarini. In the last 3 years he has been paid consulting fees by Novartis and Merck. None of these studies relate to hydroxyzine. Publisher Copyright: {\textcopyright} 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley \& Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = apr,

doi = "10.1002/pds.5191",

language = "English",

volume = "30",

pages = "482--491",

journal = "Pharmacoepidemiology and Drug Safety",

issn = "1053-8569",

publisher = "Wiley",

number = "4",

}

Morales, DR, Macfarlane, T, MacDonald, TM, Hallas, J , Ernst, MT, Herings, RMC, Smits, E, Overbeek, JA, Mitchell, L, Morant, S, Mackenzie, I, Doney, ASF, Robertson, C, Bennie, M, Wei, L, Nicholson, L, Morris, C & Flynn, RWF 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, vol. 30, no. 4, pp. 482-491. https://doi.org/10.1002/pds.5191

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.; Macfarlane, Tatiana; MacDonald, Thomas M. et al.
In: Pharmacoepidemiology and Drug Safety, Vol. 30, No. 4, 04.2021, p. 482-491.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands

T2 - An interrupted time series regression analysis

AU - Morales, Daniel R.

AU - Macfarlane, Tatiana

AU - MacDonald, Thomas M.

AU - Hallas, Jesper

AU - Ernst, Martin Thomsen

AU - Herings, Ron M.C.

AU - Smits, Elisabeth

AU - Overbeek, Jetty A.

AU - Mitchell, Lyn

AU - Morant, Steven

AU - Mackenzie, Isla

AU - Doney, Alexander S.F.

AU - Robertson, Chris

AU - Bennie, Marion

AU - Wei, Li

AU - Nicholson, Lizzie

AU - Morris, Carole

AU - Flynn, Robert W.F.

N1 - Funding Information: The authors acknowledge the Electronic Data Research and Innovation Service (eDRIS) of ISD Scotland for providing the Scottish data and for the general practices that contributed data to CPRD for public health purposes. The study was funded by the European Medicines Agency (Procurement procedure EMA/2014/50/RE). The EMA approved the final study protocol and had no influence on the results or decision to publish. Funding Information: Elisabeth Smitsm Jetty A. Overbeek and Ron M. C. Herings are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. TMM's university holds research grants from Novartis, Ipsen, Teijin & Menarini. He is or has been the Principal Investigator on trials paid for by Novartis, Ipsen, Teijin, RTI, GlaxoSmithKline, SHIRE and Menarini. In the last 3 years he has been paid consulting fees by Novartis and Merck. None of these studies relate to hydroxyzine. Publisher Copyright: © 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

KW - hydroxyzine

KW - pharmacoepidemiology

KW - pharmacovigilance

KW - prescribing

KW - regulation

KW - time-series

U2 - 10.1002/pds.5191

DO - 10.1002/pds.5191

M3 - Journal article

C2 - 33386650

AN - SCOPUS:85099667259

SN - 1053-8569

VL - 30

SP - 482

EP - 491

JO - Pharmacoepidemiology and Drug Safety

JF - Pharmacoepidemiology and Drug Safety

IS - 4

ER -

Morales DR, Macfarlane T, MacDonald TM, Hallas J , Ernst MT, Herings RMC et al. 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. 2021 Apr;30(4):482-491. doi: 10.1002/pds.5191