This article was downloaded by: [Gazi University] On: 30 April 2015, At: 18:55 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Aging & Mental Health Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/camh20
Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects a
b
b
b
b
Ayami Kajiwara , Masato Yamamura , Motoji Murase , Haruo Koda , Seisuke Hirota , cd
a
a
a
Tadao Ishizuka , Kazunori Morita , Kentaro Oniki , Junji Saruwatari & Kazuko ad
Nakagawa a
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan b
Kumamoto Pharmaceutical Association, Kumamoto, Japan
c
Division of Pharmaceutical Molecular Design, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Click for updates
d
Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan Published online: 14 Apr 2015.
To cite this article: Ayami Kajiwara, Masato Yamamura, Motoji Murase, Haruo Koda, Seisuke Hirota, Tadao Ishizuka, Kazunori Morita, Kentaro Oniki, Junji Saruwatari & Kazuko Nakagawa (2015): Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects, Aging & Mental Health, DOI: 10.1080/13607863.2015.1031640 To link to this article: http://dx.doi.org/10.1080/13607863.2015.1031640
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Aging & Mental Health, 2015 http://dx.doi.org/10.1080/13607863.2015.1031640
Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects Ayami Kajiwaraa, Masato Yamamurab, Motoji Muraseb, Haruo Kodab, Seisuke Hirotab, Tadao Ishizukac,d, Kazunori Moritaa, Kentaro Onikia, Junji Saruwataria and Kazuko Nakagawaa,d* a
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; b Kumamoto Pharmaceutical Association, Kumamoto, Japan; cDivision of Pharmaceutical Molecular Design, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; dCenter for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Downloaded by [Gazi University] at 18:55 30 April 2015
(Received 17 December 2014; accepted 10 March 2015) Objectives: Prescriptions of non-benzodiazepine sedative hypnotics, e.g. zolpidem, for insomnia in elderly subjects 80 years of age or older have markedly increased in the USA. However, a meta-analysis of the risks and benefits of hypnotics in older people reported the benefits associated with hypnotics use are outweighed by the risks. This study aimed to investigate the safety of zolpidem administration in extremely old elderly. Methods: The prevalence of adverse reactions to zolpidem was investigated in a subpopulation of participants in the Drug Event Monitoring project of the Japan Pharmaceutical Association. A total of 1011 (316 males and 695 females) zolpidem users, including 261 (25.8%) subjects 80 years of age or older without cognitive or mental complications, were eligible for the analysis. Results: The elderly and female patients were prescribed significantly lower doses of zolpidem than their counterparts. Adverse symptoms after the last prescription were reported by 60 (5.9%) subjects. The most common symptoms were impaired balance and/or falls (1.8%) and morning drowsiness (1.3%). The multiple logistic regression analyses showed that subjects 80 years of age or older were at lower risk of adverse symptoms (odds ratio 0.39, 95% confidence intervals: 0.17 0.88). Conclusion: Our findings in a real-world clinical setting suggest that low-dose zolpidem can be safely prescribed to subjects 80 years of age or older without cognitive or mental complications. Keywords: adverse event monitoring; older people; self-report; sleep disorders; zolpidem
Introduction Zolpidem is one of the most widely used non-benzodiazepine sedative hypnotics (Greenblatt, Harmatz, & Shader, 2011; Greenblatt & Roth, 2012; The Japanese Pharmaceutical Association [JPA], 2009), and its prescription in 2009 was reported to exceed over 30 million in the USA alone (Greenblatt et al., 2011). Likewise, prescriptions of hypnotics for insomnia in elderly subjects 80 years of age or older (extremely old elderly) have increased markedly from 1993 to 2007 (Bertisch, Herzig, Winkelman, & Buettner, 2014). Meanwhile, a large retrospective cohort study in the UK recently demonstrated that anxiolytic and hypnotic drugs are associated with a significantly increased risk of mortality (Weich et al., 2014). A meta-analysis of the risks and benefits of hypnotics in people over 60 years of age reported that the benefits associated with sedative use are marginal and are outweighed by the risks, particularly if the patient is at high risk for falls or cognitive impairment (Glass, Lanctot, Herrmann, Sproule, & Busto, 2005). However, other reports have indicated that insomnia itself, rather than hypnotic use, is associated with a greater risk of falls and affects the quality of life (QOL) in older people (Ancoli-Israel, *Corresponding author. Email: [email protected] Ó 2015 Taylor & Francis
2009; Avidan et al., 2005; Fagerstrom & Hellstrom, 2011; Stone et al., 2008). Although zolpidem has a short half-life (approximately two hours), it preserves the sleep architecture and is well tolerated, and also its dose should be individualized (Greenblatt et al., 2013; Greenblatt & Roth, 2012; Salva & Costa, 1995). In 2013, the Food and Drug Administration (FDA) revised the dosing recommendations for labels on zolpidem-containing products, lowering the doses for females as well as elderly patients due to their reduced clearance of zolpidem (Greenblatt et al., 2013; Greenblatt et al., 2014; Olubodun et al., 2003; Salva & Costa, 1995). Area under the curve (AUC) values were reported to be approximately 40% 50% higher in young females and 60% higher in elderly females than in males partly due to the difference in body weight (Greenblatt et al., 2014; Salva & Costa, 1995). It was also revealed that the pharmacodynamics effects of zolpidem were greater in females due to a combination of higher plasma concentration and greater intrinsic sensitivity (Greenblatt et al., 2014). We, therefore, aimed to investigate adverse reactions induced by zolpidem in a real-world clinical setting, with particular attention to the risks in extremely old elderly and (older) females.
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A. Kajiwara et al.
Downloaded by [Gazi University] at 18:55 30 April 2015
Methods We conducted a sub-analysis of an annual nationwide surveillance study, the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association (JPA) (Kajiwara et al., 2013). Although three short-acting hypnotics (zolpidem, triazolam and zopiclone) were investigated in 2009 (JPA, 2009), we restricted the present analysis to zolpidem. Every patient receiving a target drug from pharmacies affiliated with the JPA DEM project who visited there with a prescription for any drug(s) during the surveillance period from February 16 through 22, 2009 was asked to participate in the project. This survey included patients receiving one of the target drugs and excluded those receiving two or more hypnotics, sedatives, antidepressants or psychotropic agents. The participants were interviewed by pharmacists using structured questionnaires to assess the self-perception of adverse symptoms after the last prescription of the target drug. The questionnaires included open questions regarding demographic information and adverse symptoms and a checklist of symptoms that can be caused by the target drugs (Supplemental Table 1). The pharmacists further questioned the participants regarding their symptoms as needed and completed the checklist. Six hundred and twenty-four (86.4%) pharmacies in Kumamoto prefecture, Japan, participated in the survey (mean days of participation: 4.0 days/pharmacy). The survey results obtained at each pharmacy were summarized via a web-based system linked to a reporting portal in the KUMAYAKU Network for Community Pharmacies in Kumamoto. This protocol was approved by the institutional ethics committee of the Faculty of Life Sciences, Kumamoto University. We assessed the influence of older age and female sex on the prevalence of adverse symptoms during treatment with zolpidem. We categorized age into three groups (
Aging & Mental Health Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/camh20
Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects a
b
b
b
b
Ayami Kajiwara , Masato Yamamura , Motoji Murase , Haruo Koda , Seisuke Hirota , cd
a
a
a
Tadao Ishizuka , Kazunori Morita , Kentaro Oniki , Junji Saruwatari & Kazuko ad
Nakagawa a
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan b
Kumamoto Pharmaceutical Association, Kumamoto, Japan
c
Division of Pharmaceutical Molecular Design, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Click for updates
d
Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan Published online: 14 Apr 2015.
To cite this article: Ayami Kajiwara, Masato Yamamura, Motoji Murase, Haruo Koda, Seisuke Hirota, Tadao Ishizuka, Kazunori Morita, Kentaro Oniki, Junji Saruwatari & Kazuko Nakagawa (2015): Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects, Aging & Mental Health, DOI: 10.1080/13607863.2015.1031640 To link to this article: http://dx.doi.org/10.1080/13607863.2015.1031640
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Aging & Mental Health, 2015 http://dx.doi.org/10.1080/13607863.2015.1031640
Safety analysis of zolpidem in elderly subjects 80 years of age or older: adverse event monitoring in Japanese subjects Ayami Kajiwaraa, Masato Yamamurab, Motoji Muraseb, Haruo Kodab, Seisuke Hirotab, Tadao Ishizukac,d, Kazunori Moritaa, Kentaro Onikia, Junji Saruwataria and Kazuko Nakagawaa,d* a
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; b Kumamoto Pharmaceutical Association, Kumamoto, Japan; cDivision of Pharmaceutical Molecular Design, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; dCenter for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Downloaded by [Gazi University] at 18:55 30 April 2015
(Received 17 December 2014; accepted 10 March 2015) Objectives: Prescriptions of non-benzodiazepine sedative hypnotics, e.g. zolpidem, for insomnia in elderly subjects 80 years of age or older have markedly increased in the USA. However, a meta-analysis of the risks and benefits of hypnotics in older people reported the benefits associated with hypnotics use are outweighed by the risks. This study aimed to investigate the safety of zolpidem administration in extremely old elderly. Methods: The prevalence of adverse reactions to zolpidem was investigated in a subpopulation of participants in the Drug Event Monitoring project of the Japan Pharmaceutical Association. A total of 1011 (316 males and 695 females) zolpidem users, including 261 (25.8%) subjects 80 years of age or older without cognitive or mental complications, were eligible for the analysis. Results: The elderly and female patients were prescribed significantly lower doses of zolpidem than their counterparts. Adverse symptoms after the last prescription were reported by 60 (5.9%) subjects. The most common symptoms were impaired balance and/or falls (1.8%) and morning drowsiness (1.3%). The multiple logistic regression analyses showed that subjects 80 years of age or older were at lower risk of adverse symptoms (odds ratio 0.39, 95% confidence intervals: 0.17 0.88). Conclusion: Our findings in a real-world clinical setting suggest that low-dose zolpidem can be safely prescribed to subjects 80 years of age or older without cognitive or mental complications. Keywords: adverse event monitoring; older people; self-report; sleep disorders; zolpidem
Introduction Zolpidem is one of the most widely used non-benzodiazepine sedative hypnotics (Greenblatt, Harmatz, & Shader, 2011; Greenblatt & Roth, 2012; The Japanese Pharmaceutical Association [JPA], 2009), and its prescription in 2009 was reported to exceed over 30 million in the USA alone (Greenblatt et al., 2011). Likewise, prescriptions of hypnotics for insomnia in elderly subjects 80 years of age or older (extremely old elderly) have increased markedly from 1993 to 2007 (Bertisch, Herzig, Winkelman, & Buettner, 2014). Meanwhile, a large retrospective cohort study in the UK recently demonstrated that anxiolytic and hypnotic drugs are associated with a significantly increased risk of mortality (Weich et al., 2014). A meta-analysis of the risks and benefits of hypnotics in people over 60 years of age reported that the benefits associated with sedative use are marginal and are outweighed by the risks, particularly if the patient is at high risk for falls or cognitive impairment (Glass, Lanctot, Herrmann, Sproule, & Busto, 2005). However, other reports have indicated that insomnia itself, rather than hypnotic use, is associated with a greater risk of falls and affects the quality of life (QOL) in older people (Ancoli-Israel, *Corresponding author. Email: [email protected] Ó 2015 Taylor & Francis
2009; Avidan et al., 2005; Fagerstrom & Hellstrom, 2011; Stone et al., 2008). Although zolpidem has a short half-life (approximately two hours), it preserves the sleep architecture and is well tolerated, and also its dose should be individualized (Greenblatt et al., 2013; Greenblatt & Roth, 2012; Salva & Costa, 1995). In 2013, the Food and Drug Administration (FDA) revised the dosing recommendations for labels on zolpidem-containing products, lowering the doses for females as well as elderly patients due to their reduced clearance of zolpidem (Greenblatt et al., 2013; Greenblatt et al., 2014; Olubodun et al., 2003; Salva & Costa, 1995). Area under the curve (AUC) values were reported to be approximately 40% 50% higher in young females and 60% higher in elderly females than in males partly due to the difference in body weight (Greenblatt et al., 2014; Salva & Costa, 1995). It was also revealed that the pharmacodynamics effects of zolpidem were greater in females due to a combination of higher plasma concentration and greater intrinsic sensitivity (Greenblatt et al., 2014). We, therefore, aimed to investigate adverse reactions induced by zolpidem in a real-world clinical setting, with particular attention to the risks in extremely old elderly and (older) females.
2
A. Kajiwara et al.
Downloaded by [Gazi University] at 18:55 30 April 2015
Methods We conducted a sub-analysis of an annual nationwide surveillance study, the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association (JPA) (Kajiwara et al., 2013). Although three short-acting hypnotics (zolpidem, triazolam and zopiclone) were investigated in 2009 (JPA, 2009), we restricted the present analysis to zolpidem. Every patient receiving a target drug from pharmacies affiliated with the JPA DEM project who visited there with a prescription for any drug(s) during the surveillance period from February 16 through 22, 2009 was asked to participate in the project. This survey included patients receiving one of the target drugs and excluded those receiving two or more hypnotics, sedatives, antidepressants or psychotropic agents. The participants were interviewed by pharmacists using structured questionnaires to assess the self-perception of adverse symptoms after the last prescription of the target drug. The questionnaires included open questions regarding demographic information and adverse symptoms and a checklist of symptoms that can be caused by the target drugs (Supplemental Table 1). The pharmacists further questioned the participants regarding their symptoms as needed and completed the checklist. Six hundred and twenty-four (86.4%) pharmacies in Kumamoto prefecture, Japan, participated in the survey (mean days of participation: 4.0 days/pharmacy). The survey results obtained at each pharmacy were summarized via a web-based system linked to a reporting portal in the KUMAYAKU Network for Community Pharmacies in Kumamoto. This protocol was approved by the institutional ethics committee of the Faculty of Life Sciences, Kumamoto University. We assessed the influence of older age and female sex on the prevalence of adverse symptoms during treatment with zolpidem. We categorized age into three groups (
