Inhibitor development, safety and efficacy of Advate® among previously treated patients with hemophilia A in a postmarketing surveillance in Japan

  • Katsuyuki FukutakeEmail author
  • Masashi Taki
  • Tadashi Matsushita
  • Keiji Nogami
  • Midori Shima
  • Akira Yoshioka
  • Junki Takamatsu
  • Haruhiko Uchikawa
  • Hiroshi Takagi
  • Morio Arai
  • Werner Engl
  • Akira Shirahata
Original Article


Rurioctocog alfa (recombinant factor VIII: Advate®) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the inhibitor development, safety, and efficacy of rurioctocog alfa, a non-interventional and observational postmarketing surveillance was conducted on 352 previously treated Japanese patients aged 1–76 years with ≥ 4 exposure days under the conditions of routine clinical practice. A post-hoc comparison of the mean annualized bleeding rates which required treatment with rurioctocog alfa detected a statistically significant difference (P < 0.0001) between patients treated on regular prophylaxis (8.5 bleeds/year) and patients treated on an on-demand basis (36.6 bleeds/year). Favorable prophylactic and on-demand hemostatic efficacy (“excellent” or “good”) were shown in 88.5–100% of patients across all treatment regimens. A total of 22 events of adverse drug reactions were reported in 13 male patients. Of the 352 patients, 3 (0.9%) patients, all of whom had ≤ 50 exposure days before enrollment, developed de novo FVIII inhibitor. No deaths or allergic reactions were reported. Rurioctocog alfa was found to be well-tolerated and effective among patients with hemophilia A in a postmarketing routine clinical practice.


Recombinant factor VIII Hemophilia A Previously treated patients Postmarketing surveillance Advate 



This manuscript is dedicated to the memory of our esteemed colleague Dr. Hideji Hanabusa, MD, whose untimely passing in October 2016 left a permanent void. He touched the lives of many as a mentor, scholar, collaborator, and friend. Dr. Hanabusa was instrumental in gaining approval for this product in Japan, and the creation and interpretation of the data included herein, and would have been a co-author of this manuscript. We thank Shire PMS and PV teams for the support of data clarification. We recognize with gratitude the patients and institutions that participated in the studies: Aichi Sannomaru Hospital, Aihara Internal Medicine and Pediatric Clinic, Asahikawa Medical University Hospital, Chiba Children’s Hospital, Dokkyo Medical University Hospital, Ehime University Hospital, Fukui-ken Saiseikai Hospital, Gunma University Hospital, Hasegawa Pediatric Clinic, Hayashi Pediatric Clinic, Higashiosaka City Medical Center, Hirano Internal Medicine, Hiroshima University Hospital, Hitachi General Hospital, Hokkaido Cancer Center, Hospital of the University of Occupational and Environmental Health Japan, Hyogo College of Medicine Hospital, Ibaraki Children’s Hospital, Iizuka Family Clinic, Iou Hospital, Ishinkai Yao General Hospital, Ishiyama Internal Medicine Clinic, Itoigawa Sogo Hospital, Iwaki Kyouritsu Hospital, Iwate Prefectural Miyako Hospital, Izumiotsu Municipal Hospital, Japanese Red Cross Morioka Hospital, Jichi Medical University Hospital, Jichi Medical University Saitama Medical Center, Jusendo General Hospital, Kagawa National Children’s Hospital, Kagawa University Hospital, Kanagawa Children’s Medical Center, Kariya Toyota General Hospital, Kitasato University Hospital, Kochi Health Sciences Center, Komatsu Municipal Hospital, Kumamoto University Hospital, Kurume University Hospital, Kyoto Okamoto Memorial Hospital, Kyushu Medical Center, Kyushu University Hospital, Matsudo City General Hospital, Mie Chuo Medical Center, Mie University Hospital, Miyoshi Central Hospital, Nagasaki University Hospital, Nagoya City University Hospital, Nagoya University Hospital, Nanbu Medical Center / Nanbu Child Medical Center, Nara Medical University Hospital, Nihonkai General Hospital, Niigata Saiseikai Sanjo Hospital, Nippon Medical School Tama Nagayama Hospital, Odate Municipal General Hospital, Ogaki Municipal Hospital, Ogikubo Hospital, Oita Memorial Hospital, Osaka City General Hospital, Osaka National Hospital, Rakusai Newtown Hospital, Saga University Hospital, Saitama Children’s Medical Center, Sakou Internal Medicine, Saku Central Hospital, Sanaikai Genaral Hospital, Sapporo Tokushukai Hospital, Sendai Medical Center, Sendai Nishitaga Hospital, Shibuya Children’s Clinic, Shizuoka Children’s Hospital, Shizuoka Medical Center, Soka Municipal Hospital, St. Marianna University School of Medicine Hospital, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Tatebayashi Kosei Hospital, The Jikei University Hospital, Tokuyama Central Hospital, Tokyo Dental College Ichikawa General Hospital, Tokyo Medical University Hospital, Tokyo Metropolitan Children’s Medical Center, Tokyo Women’s Medical University Medical Center East, Toyokawa City Hospital, University Hospital Kyoto Prefectural University of Medicine, Watari Hospital, Yakumo General Hospital, Yokohama City University Medical Center, and Yuri Kumiai General Hospital.

Author contributions

KF, MT, TM, KN, MS, AY, JT, and AS collected and interpreted data, and revised the manuscript. WE analyzed the statistics, interpreted data, and revised the manuscript. HU, HT, and MA interpreted data and drafted and revised the manuscript. All authors had full editorial control of the manuscript and provided their approvals for the content of the manuscript prior to submission.


This research was funded by Baxalta (part of Shire, Lexington, MA, USA).

Compliance with ethical standards

Conflict of interest

Katsuyuki Fukutake has received grants and personal fees from Shire outside the submitted work and holds concurrent posts as a professor for the Department of Molecular Genetics of Coagulation Disorders supported by CSL Behring without additional salary; is an advisory committee member of Chugai Pharmaceutical and consultant of Chugai Pharmaceutical; has received research funding from Bayer, Biogen/Bioverativ, Kaketsuken, Novo Nordisk, and Pfizer; has received honoraria for consulting, speaking or advising from Bayer, Biogen/Bioverativ, Chugai Pharm./Roche, CSL Behring, Japan Blood Products, Kaketsuken, MSD, Novo Nordisk, Octapharma, and Pfizer. Masashi Taki has received grants and personal fees from CSL Behring outside the submitted work, personal fees from Shire, Bayer, Bioverativ, Chugai, Kaketsuken, Pfizer, and Novo Nordisk outside the submitted work. Tadashi Matsushita has received personal fees from Shire for the submitted work; grants and personal fees from Bayer, Shire, Novo Nordisk, Kaketsuken, and Biogen-idec outside the submitted work. Keiji Nogami has received grants from Shire and funding for research from Shire, Bayer, Novo Nordisk, Bioverativ, Chugai, and honoraria from Shire, Bayer, Novo Nordisk, Bioverativ, CSL-Behring, Chugai outside the submitted work. Midori Shima has received personal fees and grants from Shire, Bayer, Novo Nordisk, CSL-Behring, Chugai, and Pfizer; personal fees from Bioverativ and Roche; grants from Kaketsuken outside the submitted work. Akira Yoshioka has received honoraria from Shire, Japan Red Cross, Daiichi Sankyo, and Bayer outside the submitted work. Junki Takamatsu and Akira Shirahata have declared no conflict of interest. Werner Engl, Haruhiko Uchikawa, Hiroshi Takagi, and Morio Arai are full-time employees of Shire; Werner Engl and Morio Arai own Shire stock.


  1. 1.
    Heim M, Wershavski M, Martinowitz U, Chechick A, Azaria M. Elbow joint, crutches and locomotion: special reference to persons with haemophilia. Haemophilia. 2000;6:556–61.CrossRefGoogle Scholar
  2. 2.
    Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012;379:1447–56.CrossRefGoogle Scholar
  3. 3.
    Oymak Y, Yildirim AT, Yaman Y, Gurcinar M, Firat A, Cubuckcu D, et al. The effectiveness of tools for monitoring hemophilic arthropathy. J Pediatr Hematol Oncol. 2015;37:e80-5.CrossRefGoogle Scholar
  4. 4.
    Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1–47.CrossRefGoogle Scholar
  5. 5.
    Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535–44.CrossRefGoogle Scholar
  6. 6.
    Tagliaferri A, Franchini M, Coppola A, Rivolta GF, Santoro C, Rossetti G, et al. Effects of secondary prophylaxis started in adolescent and adult haemophiliacs. Haemophilia. 2008;14:945–51.CrossRefGoogle Scholar
  7. 7.
    Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-months crossover study. J Thromb Haemost. 2010;8:83–9.CrossRefGoogle Scholar
  8. 8.
    Jiménez-Yuste V, Auerswald G, Benson G, Lambert T, Morfini M, Remor E, et al. Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future. Blood Transfus. 2014;12:314–9.Google Scholar
  9. 9.
    Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br J Clin Pharmacol. 2011;72:553–62.CrossRefGoogle Scholar
  10. 10.
    Peerlinck K, Hermans C. Epidemiology of inhibitor formation with recombinant factor VIII replacement therapy. Haemophilia. 2006;12:579–90.CrossRefGoogle Scholar
  11. 11.
    Dhillon S. Octocog alfa, antihaemophilic factor (recombinant), plasma/albumin free method (Advate®): a review of its use in the management of patients with haemophilia A. Drugs. 2012;72:987–1007.CrossRefGoogle Scholar
  12. 12.
    Pharmaceutical Administration. and Regulations in Japan (individual chapters) Chapter 4 Post-Marketing Surveillance Of Drugs.
  13. 13.
    den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia. 2011;17:41–4.CrossRefGoogle Scholar
  14. 14.
    White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.CrossRefGoogle Scholar
  15. 15.
    Oldenburg J, Goudemand J, Valentino L, Richards M, Luu H, Kriukov A, et al. Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immunogenicity in routine clinical practice. Haemophilia. 2010;16:866–77.CrossRefGoogle Scholar
  16. 16.
    Iorio A, Marcucci M, Cheng J, Oldenburg J, Schoenig-Diesing C, Matovinovic E, et al. Patient data meta-analysis of post-authorization safety surveillance (PASS) studies of haemophilia A patients treated with rAHF-PFM. Haemophilia. 2014;20:777–83.CrossRefGoogle Scholar
  17. 17.
    Khair K, Mazzucconi MG, Parra R, Santagostino E, Tsakiris DA, Hermans C, et al. Pattern of bleeding in a large prospective cohort of haemophilia A patients: a three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study. Haemophilia. 2018;24:85–96.CrossRefGoogle Scholar
  18. 18.
    Fujii T, Amano K, Atsumi T, Ishiguro A, Ohira K, Okamoto K, et al. Treatment guideline for hemophilia without inhibitor: 2013 update. Jpn J Thromb Hemost. 2013;24:619–39.CrossRefGoogle Scholar
  19. 19.
    McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of FVIII:C inhibitors. Blood. 1988;71:344–8.Google Scholar
  20. 20.
    Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A, et al. Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression. J Thromb Haemost. 2013;11:1655–62.CrossRefGoogle Scholar
  21. 21.
    Tarantino MD, Collins PW, Hay CR, Shapiro AD, Gruppo RA, Berntorp E, et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004;10:428–37.CrossRefGoogle Scholar
  22. 22.
    Fukutake K, Arai M, Inaba H, Hanabusa H, Miyama J, Takamatsu J, et al. A multi-center post-marketing surveillance study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. Jpn J Thromb Hemost. 2005;16:650–63.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Katsuyuki Fukutake
    • 1
    Email author
  • Masashi Taki
    • 2
  • Tadashi Matsushita
    • 3
  • Keiji Nogami
    • 4
  • Midori Shima
    • 4
  • Akira Yoshioka
    • 4
  • Junki Takamatsu
    • 5
  • Haruhiko Uchikawa
    • 6
  • Hiroshi Takagi
    • 7
  • Morio Arai
    • 7
  • Werner Engl
    • 8
  • Akira Shirahata
    • 9
  1. 1.Department of Laboratory MedicineTokyo Medical University HospitalTokyoJapan
  2. 2.Department of PediatricsSt. Marianna University School of Medicine Yokohama City Seibu HospitalYokohamaJapan
  3. 3.Department of Transfusion MedicineNagoya University HospitalNagoyaJapan
  4. 4.Department of PediatricsNara Medical UniversityKashiharaJapan
  5. 5.The Japanese Red Cross Tokai Hokuriku Block Blood CenterSetoJapan
  6. 6.Department of Clinical Scientific WritingShireTokyoJapan
  7. 7.Department of Medical AffairsShireTokyoJapan
  8. 8.Department of BiostatisticsShireViennaAustria
  9. 9.Kitakyushu Yahata-Higashi HospitalKitakyusyuJapan

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