All Title Author
Keywords Abstract

PLOS ONE  2011 

Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database

DOI: 10.1371/journal.pone.0028483

Full-Text   Cite this paper   Add to My Lib


Background In March 2007, a regulatory advisory was issued in Japan to restrict oseltamivir use in children aged 10-19 years because of safety concerns over abnormal behavior. The effectiveness and validity of regulatory risk minimization actions remain to be reviewed, despite their significant public health implications. To assess the impact of the regulatory actions on prescribing practices and safety reporting. Methodoloy/Prinicpal Findings In this retrospective review of a nationwide pharmacy database, we analyzed 100,344 dispensation records for oseltamivir and zanamivir for the period from November 2006 to March 2009. The time trend in dispensations for these antiviral agents was presented before and after the regulatory actions, contrasted with intensity of media coverage and the numbers of spontaneous adverse reaction reports with regard to antivirals. The 2007 regulatory actions, together with its intense media coverage, reduced oseltamivir dispensation in targeted patients in fiscal year 2008 to 20.4% of that in fiscal year 2006, although influenza activities were comparable between these fiscal years. In contrast, zanamivir dispensation increased approximately nine-fold across all age groups. The number of abnormal behavior reports associated with oseltamivir in children aged 10-19 years decreased from fiscal year 2006 to 2008 (24 to 9 cases); this decline was offset by the increased number of reports of abnormal behavior in children under age 10 (12 to 28 cases). The number of reports associated with zanamivir increased in proportion to increased dispensation of this drug (11 to 114 cases). Conclusions/Significance The 2007 actions effectively reduced oseltamivir prescriptions and the number of reports of abnormal behavior in the targeted group. The observed increase in abnormal behavior reports in oseltamivir patients under age 10 and in zanamivir patients suggests that these patient groups may also be at risk, calling into question the validity of the current discrimination by age and agent (translation is available in Japanese: Appendix S1).


[1]  Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, et al. (2006) Antivirals for influenza in healthy adults: systematic review. Lancet 367: 303–313.
[2]  Matheson NJ, Harnden AR, Perera R, Sheikh A, Symmonds-Abrahams M (2007) Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev. CD002744 p.
[3]  Satoh K, Nonaka R, Ogata A, Nakae D, Uehara S (2007) Effects of oseltamivir phosphate (Tamiflu) and its metabolite (GS4071) on monoamine neurotransmission in the rat brain. Biol Pharm Bull 30: 1816–1818.
[4]  The Federation of Pharmaceutical Manufacturers' Associations of Japan (2004) Drug Safety Update No. 129, June 2004 [in Japanese]. Tokyo, Japan.
[5]  Pharmaceuticals and Medical Devices Agency (2007) Regarding abnormal behaviors after Tamiful intake (Direction of issuance of a Dear Doctor letter), March 20, 2007 [in Japanese]. Tokyo, Japan.
[6]  The Federation of Pharmaceutical Manufacturers' Associations of Japan (2008) Drug Safety Update No. 166, January 2008 [in Japanese]. Tokyo, Japan.
[7]  Jefferson T, Jones M, Doshi P, Del Mar C (2009) Possible harms of oseltamivir–a call for urgent action. Lancet 374: 1312–1313.
[8]  Yorifuji T, Suzuki E, Tsuda T (2009) Oseltamivir and abnormal behaviors: true or not? Epidemiology 20: 619–621.
[9]  Center for Drug Evaluation and Research (2005) Pediatric safety update for Tamiflu, Pediatric Advisory Committee meeting. 18 November 2005. Silver Spring, MD: Food and Drug Administration.
[10]  Medicines and Healthcare Products Regulatory Agency (2010) Suspected Adverse Drug Reaction (ADR) Analysis, Influenza antivirals - oseltamivir (Tamiflu) and zanamivir (Relenza), February 4, 2010. London, UK.
[11]  Reaserch Division, Health Insurance Bureau (2010) Trend in Prescription Healthcare Cost, Fiscal Year 2008 [in Japanese]. Tokyo, Japan: Ministry of Health, Labour and Welfare. Available: Accessed April 5, 2010.
[12]  National Statistics Center (2008) Patient Survey, Portal Site of Official Statistics of Japan [in Japanese]. Statistics Bureau: Ministry of Internal Affairs and Communications with the collaboration of Ministries and Agencies. Available: Accessed January 5, 2010.
[13]  Chugai Pharmaceutical Co., Ltd. (2010) Tamiful? Package Insert, July 2010 [in Japanese]. 22 ed. Tokyo, Japan.
[14]  GlaxoSmithKline KK (2009) Relenza? Package Insert, October 2009 [in Japanese]. 12 ed. Tokyo, Japan.
[15]  Infectious Disease Surveillance Center (2010) Sentinel Surveillance [in Japanese]. Tokyo, Japan: Ministry of Health, Labour, and Welfare, National Institute of Infectious Diseases. Available: Accessed June 5, 2010.
[16]  G-Search Limited (2010) G-SEARCH database [in Japanese]. Available: Accessed January 5, 2010.
[17]  Pharmaceuticals and Medical Devices Agency (2010) Information service website on pharmaceuticals and medical devices, Information on suspected adverse reaction cases reported to Pharmaceuticals and Medical Devices Agency [in Japanese]. Tokyo, Japan: Available: Accessed January 5, 2010.
[18]  The Maintenance and Support Services Organization (2010) Medical Dictionary for Regulatory Activities. Available: Accessed June 29, 2010.
[19]  Yokota S (2006) Research report by the research group on occurence of influenza-associated complications, funded by the 2005 MHLW grants-in-aid [in Japanese]. Tokyo, Japan: Ministry of Health, Labour, and Welfare.
[20]  Yoshida M, Matsui T, Ohkusa Y, Kobayashi J, Ohyama T, et al. (2009) Seasonal influenza surveillance using prescription data for anti-influenza medications. Jpn J Infect Dis 62: 233–235.
[21]  Nikkei Medical (2010) Value and clinical features of inhaled zanamivir: a questionnaire survey on anti-influenza drug use by Japan Physicians Association [in Japanese]. Nikkei Continuing Medical Education. Japan.
[22]  Weatherby LB, Walker AM, Fife D, Vervaet P, Klausner MA (2001) Contraindicated medications dispensed with cisapride: temporal trends in relation to the sending of ‘Dear Doctor’ letters. Pharmacoepidemiol Drug Saf 10: 211–218.
[23]  Chugai Pharmaceutical Co, Ltd. (2009) The 15th periodic safety report on oseltamivir [in Japanese]. Tokyo, Japan.
[24]  Pariente A, Gregoire F, Fourrier-Reglat A, Haramburu F, Moore N (2007) Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf 30: 891–898.
[25]  Morishima T, Togashi T, Yokota S, Okuno Y, Miyazaki C, et al. (2002) Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 35: 512–517.
[26]  Subcommittee on Safety Measurement, Committee of Safety of Drugs, the Pharmaceutical Affairs and Food Sanitation Council (2009) The minutes of the first fiscal 2009 subcommittee on safety measurement regarding to oseltamivir phosphate (Tamiflu) held on June 16, 2009 [in Japanese]. Tokyo, Japan: Ministry of Health, Labour and Welfare.
[27]  Nakamura K, Schwartz BS, Lindegardh N, Keh C, Guglielmo BJ (2010) Possible neuropsychiatric reaction to high-dose oseltamivir during acute 2009 H1N1 influenza A infection. Clin Infect Dis 50: e47–49.
[28]  Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, et al. (2001) Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20: 127–133.
[29]  Blumentals WA, Song X (2007) The safety of oseltamivir in patients with influenza: analysis of healthcare claims data from six influenza seasons. MedGenMed 9: 23.
[30]  Smith JR, Sacks S (2009) Incidence of neuropsychiatric adverse events in influenza patients treated with oseltamivir or no antiviral treatment. Int J Clin Pract 63: 596–605.
[31]  Toovey S, Rayner C, Prinssen E, Chu T, Donner B, et al. (2008) Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf 31: 1097–1114.
[32]  Fujita T, Fujii Y, Watanabe Y, Osaka H, Wada T, et al. (2011) A Pharmacoepidemiologic Study on the Relationship between Neuropsychiatric Symptoms and Therapeutic Drugs after Infulenza Infection [in Japanese]. Jpn J Pharmacoepidemiol 15: 73–90.
[33]  Morgenstern H (1998) Ecologic Studies. In: Rothman KJ, Greenland S, editors. Modern Epidemiology. Second ed. Philadelphia: Lippincott Williams & Wilkins. 459 p.
[34]  Moore N, Hall G, Sturkenboom M, Mann R, Lagnaoui R, et al. (2003) Biases affecting the proportional reporting ratio (PPR) in spontaneous reports pharmacovigilance databases: the example of sertindole. Pharmacoepidemiol Drug Saf 12: 271–281.


comments powered by Disqus

Contact Us


微信:OALib Journal