, Volume 72, Issue 7, pp 987–1007 | Cite as

Octocog Alfa, Antihaemophilic Factor (Recombinant), Plasma/Albumin Free Method (Advate®)

A Review of its Use in the Management of Patients with Haemophilia A
Adis Drug Evaluation


Octocog alfa, antihaemophilic factor, plasma/albumin free method (Advate®) is a recombinant, human, full-length coagulation factor VIII that does not contain human- or animal-derived plasma proteins. It is indicated for the control and prevention of bleeding episodes, for perioperative management and for routine prophylaxis in children and adults with haemophilia A. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of Advate® in these patients.

In previously treated paediatric and adult patients with moderately severe or severe haemophilia A, Advate® administered prophylactically, on demand or during surgery was effective for the prevention and treatment of bleeding episodes in three pivotal, uncontrolled clinical trials. The haemostatic efficacy of Advate® in these trials was rated as ‘excellent’ or ‘good’ in most bleeding episodes, with the majority of episodes being managed with one infusion. These findings were supported by pooled analyses of clinical trials and routine clinical practice studies, including the Post-Authorization Safety Study.

Additionally, in a comparative study, routine prophylaxis with Advate® administered in a standard regimen or in a pharmacokinetic-tailored regimen was effective for the prevention of bleeding episodes in patients with moderately severe or severe haemophilia A, with no significant difference between the two regimens in terms of efficacy. Moreover, any routine prophylaxis with Advate® was found to be more effective in preventing bleeding episodes than on-demand therapy with Advate®.

Advate® was generally well tolerated in clinical trials and postmarketing studies, with the most common treatment-emergent adverse events being pyrexia and headache. Serious adverse events with Advate® therapy are development of high-titre factor VIII inhibitors (usually in previously untreated patients) and hypersensitivity reactions. As expected, the incidence of factor VIII inhibitors (any titre) appeared to be lower in previously treated patients (≤1.8%) than in previously untreated patients (≤20%).

There are no head-to-head comparative trials of Advate® and other factor VIII concentrates. Nevertheless, current evidence indicates that Advate® is an effective option for the management of paediatric and adult patients with haemophilia A.


  1. 1.
    Shapiro AD. Anti-hemophilic factor (recombinant), plasma/albumin-free method (octocog-alpha; ADVATE®) in the management of haemophilia A. Vasc Health Risk Manag 2007; 3(5): 555–65PubMedGoogle Scholar
  2. 2.
    National Haemophilia Foundation. Haemophilia A (factor VIII deficiency) [online]. Available from URL: http://www.haemophilia.org [Accessed 2012 Feb 14]
  3. 3.
    White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in haemophilia: 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 Mar; 85(3): 560PubMedGoogle Scholar
  4. 4.
    Schulman S. Treatment of haemophilia [online]. Available from URL: http://www.wfh.org/2/docs/Publications/Diagnosis_and_Treatment/TOH-41_Mild-Haemophilia.pdf [Accessed 2012 Mar 29]
  5. 5.
    Larsson SA, Nilsson IM, Blomback M. Current status of Swedish haemophiliacs. I. A demographic survey. Acta Med Scand 1982; 212(4): 195–200PubMedCrossRefGoogle Scholar
  6. 6.
    World Federation of Haemophilia. Report on the annual global survey 2010 [online]. Available from URL: http://www.wfh.org/2/docs/Publications/Statistics/2010_WFH_Global_Survey_Report.pdf [Accessed 2012 Feb 13]
  7. 7.
    Ananyeva N, Khrenov A, Darr F, et al. Treating haemophilia A with recombinant blood factors: a comparison. Expert Opin Pharmacother 2004 May; 5(5): 1061–70PubMedCrossRefGoogle Scholar
  8. 8.
    Wong T, Recht M. Current options and new developments in the treatment of haemophilia. Drugs 2011; 71(3): 305–20PubMedCrossRefGoogle Scholar
  9. 9.
    Powell JS. Recombinant factor VIII in the management of haemophilia A: current use and future promise. Ther Clin Risk Manag 2009 Apr; 5(2): 391–402PubMedCrossRefGoogle Scholar
  10. 10.
    Franchini M, Lippi G. Recombinant factor VIII concentrates. Semin Thromb Hemost 2010 Jul; 36(5): 493–7PubMedCrossRefGoogle Scholar
  11. 11.
    European Medicines Agency. Advate: summary of product characteistics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000520/WC500022467.pdf [Accessed 2012 Feb 8]
  12. 12.
    Klinge J, Ananyeva NM, Hauser CA, et al. Haemophilia A: from basic science to clinical practice. Semin Thromb Hemost 2002 Jun; 28(3): 309–22PubMedCrossRefGoogle Scholar
  13. 13.
    Baxter Healthcare Corp. Antihaemophilic factor (recombinant), plasma/albumin-free method (Advate): US prescribing information [online]. Available from URL: http://advate.com/pdf/advate_iri_pi.pdf [Accessed 2012 Feb 1]
  14. 14.
    Parti R, Schoppmann A, Lee H, et al. Stability of lyophilized and reconstituted plasma/albumin-free recombinant human factor VIII (ADVATE rAHF-PFM). Haemophilia 2005 Sep; 11(5): 492–6PubMedCrossRefGoogle Scholar
  15. 15.
    Fernandez M, Yu T, Bjornson E, et al. Stability of AD-VATE, antihaemophilic factor (recombinant) plasma/albumin-free method, during simulated continuous infusion. Blood Coagul Fibrinolysis 2006 Apr; 17(3): 165–71PubMedCrossRefGoogle Scholar
  16. 16.
    European Medicines Agency. Scientific discussion [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000520/WC500022464.pdf [Accessed 2012 Feb 8]
  17. 17.
    Tarantino MD, Collins PW, Hay CR, et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: phar-macokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004 Sep; 10(5): 428–37PubMedCrossRefGoogle Scholar
  18. 18.
    Blanchette VS, Shapiro AD, Liesner RJ, et al., on behalf of the rAHF-PFM Clinical Study Group. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated paediatric patients. J Thromb Haemost 2008 Aug; 6(8): 1319–26PubMedCrossRefGoogle Scholar
  19. 19.
    Collins PW, Blanchette VS, Fischer K, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe haemophilia A. J Thromb Haemost 2009 Mar; 7(3): 413–20PubMedCrossRefGoogle Scholar
  20. 20.
    Shapiro A, Gruppo R, Pabinger I, et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with haemophilia A. Expert Opin Biol Ther 2009 Mar; 9(3): 273–83PubMedCrossRefGoogle Scholar
  21. 21.
    Björkman S, Blanchette VS, Fischer K, et al. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010 Apr; 8(4): 730–6PubMedCrossRefGoogle Scholar
  22. 22.
    Di Paola J, Smith MP, Klamroth R, et al. ReFacto® and Advate®: a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with haemophilia A. Haemophilia 2007 Mar; 13(2): 124–30PubMedCrossRefGoogle Scholar
  23. 23.
    Collins PW, Bjorkman S, Fischer K, et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe haemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2010 Feb; 8(2): 269–75PubMedCrossRefGoogle Scholar
  24. 24.
    Bjorkman S, Oh M, Spotts G, et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012 Jan 12; 119(2): 612–8PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang L, Zhao Y, Sun J, et al. Clinical observation on safety and efficacy of a plasma- and albumin-free recombinant factor VIII for on-demand treatment of Chinese patients with haemophilia A. Haemophilia 2011 Mar; 17(2): 191–5PubMedCrossRefGoogle Scholar
  26. 26.
    Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012 Mar; 10(3): 359–67PubMedCrossRefGoogle Scholar
  27. 27.
    Oldenburg J, Goudemand J, Valentino L, et al. Post-authorization safety surveillance of ADVATE [antihae-mophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immuno-genicity in routine clinical practice. Haemophilia 2010 Nov; 16(6): 866–77PubMedCrossRefGoogle Scholar
  28. 28.
    Négrier C, Shapiro A, Berntorp E, et al. Surgical evaluation of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of Advate in previously treated patients. Thromb Haemost 2008 Aug; 100(2): 217–23PubMedGoogle Scholar
  29. 29.
    Shapiro A, Abshire T, Hernadez F, et al. Efficacy and safety of advate rAHF-PFM for perioperative management of hemostasis in previously treated children with haemophilia A. XXVIIth International Congress of the World Federation of Haemophilia; 2006 May 21–25; Vancouver (BC)Google Scholar
  30. 30.
    Fischer K, Collins P, Bjorkman S, et al. Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. Haemophilia 2011 May; 17(3): 433–8PubMedCrossRefGoogle Scholar
  31. 31.
    Fukutake K, Hanabusa H, Taki M, et al. The Post-Authorization Safety Surveillance (PASS) program confirmed actual clinical safety and efficacy of recombinant plasma/albumin-free method factor VIII in JPN [abstract no. P-TU-502]. J Thromb Haemost 2011; 9 Suppl. 2: 466Google Scholar
  32. 32.
    Taki M, Hanabusa H, Fukutake K, et al. Clinical experience of previously untreated patients with antihaemophilic factor (recombinant), plasma/albumin-free method from post-authorization safety surveillance in JPN [abstract no. P-TU-510]. J Thromb Haemost 2011; 9 Suppl. 2: 468Google Scholar
  33. 33.
    Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, et al. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment. Haemophilia 2009 Nov; 15(6): 1215–8CrossRefGoogle Scholar
  34. 34.
    Bacon CL, Singleton E, Brady B, et al. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®). Haemophilia 2011 May; 17(3): 407–11PubMedCrossRefGoogle Scholar
  35. 35.
    Escobar MA. Health economics in haemophilia: a review from the clinician’s perspective. Haemophilia 2010 May; 16 Suppl. 3: 29–34PubMedCrossRefGoogle Scholar
  36. 36.
    Scalone L, Mantovani LG, Mannucci PM, et al. Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors. Haemophilia 2006 Mar; 12(2): 154–62PubMedCrossRefGoogle Scholar
  37. 37.
    Klamroth R, Pollmann H, Hermans C, et al. The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE post-authorization safety surveillance (PASS) study. Haemophilia 2011 May; 17(3): 412–21PubMedCrossRefGoogle Scholar
  38. 38.
    Rodriguez-Merchan EC, Jimenez-Yuste V, Aznar JA, et al. Joint protection in haemophilia. Haemophilia 2011 Sep; 17 Suppl. 2: 1–23PubMedCrossRefGoogle Scholar
  39. 39.
    World Federation of Haemophilia. Guidelines for the management of haemophilia [online]. Available from URL: http://www.wfh.org/2/docs/Publications/Diagnosis_and_Treatment/Guidelines_Mng_Haemophilia.pdf [Accessed 2012 Feb 16]
  40. 40.
    Coppola A, Di Capua M, Di Minno MN, et al. Treatment of haemophilia: a review of current advances and ongoing issues. J Blood Med 2010; 1: 183–95PubMedCrossRefGoogle Scholar
  41. 41.
    Coppola A, Tagliaferri A, Di Capua M, et al. Prophylaxis in children with haemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012 Feb; 38(1): 79–94PubMedCrossRefGoogle Scholar
  42. 42.
    US National Haemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of haemophilia and other bleeding disorders (revised Nov 2011) [online]. Available from URL: http://www.haemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac190.pdf [Accessed 2010 Feb 17]
  43. 43.
    Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with haemophilia A (the ESPRIT study). J Thromb Haemost 2011 Apr; 9(4): 700–10PubMedCrossRefGoogle Scholar
  44. 44.
    Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med 2007 Aug 9; 357(6): 535–44PubMedCrossRefGoogle Scholar
  45. 45.
    Blanchette VS. Prophylaxis in the haemophilia population. Haemophilia 2010 Jul; 16 Suppl. 5: 181–8PubMedCrossRefGoogle Scholar
  46. 46.
    Hay CR. Prophylaxis in adults with haemophilia. Haemophilia 2007 Sep; 13 Suppl. 2: 10–5PubMedCrossRefGoogle Scholar
  47. 47.
    Collins P, Faradji A, Morfini M, et al. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe haemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010 Jan; 8(1): 83–9PubMedCrossRefGoogle Scholar
  48. 48.
    Richards M, Williams M, Chalmers E, et al. A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Br J Haematol 2010 May; 149(4): 498–507PubMedCrossRefGoogle Scholar
  49. 49.
    National Haemophilia Foundation. MASAC recommendation concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding) [document #179; online]. Available from URL: http://www.haemophilia.org [Accessed 2012 Feb 21]
  50. 50.
    Collins PW, Fischer K, Morfini M, et al., on behalf of the International Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia 2011 Jan; 17(1): 2–10PubMedCrossRefGoogle Scholar
  51. 51.
    Thornburg CD. Prophylactic factor infusions for patients with haemophilia: challenges with treatment adherence. J Coagul Dis 2009; 2 (1)Google Scholar
  52. 52.
    Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003 Jul; 9(4): 418–35PubMedCrossRefGoogle Scholar
  53. 53.
    Coppola A, Santoro C, Tagliaferri A, et al. Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies. Haemophilia 2010 Jan; 16 Suppl. 1: 13–9PubMedCrossRefGoogle Scholar
  54. 54.
    Gouw SC, van den Berg HM, LE Cessie S, et al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe haemophilia A. J Thromb Haemost 2007 Jul; 5(7): 1383–90PubMedCrossRefGoogle Scholar
  55. 55.
    Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with haemophilia A: the CANAL cohort study. Blood 2007 Jun 1; 109(11): 4648–54PubMedCrossRefGoogle Scholar
  56. 56.
    Santagostino E, Mancuso ME, Rocino A, et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005 Aug; 130(3): 422–7PubMedCrossRefGoogle Scholar
  57. 57.
    Franchini M, Lippi G. Immune tolerance induction for patients with severe haemophilia A: a critical literature review. J Thromb Thrombolysis 2011 Nov; 32(4): 439–47PubMedCrossRefGoogle Scholar
  58. 58.
    Hay CR, Brown S, Collins PW, et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006 Jun; 133(6): 591–605PubMedCrossRefGoogle Scholar
  59. 59.
    City of Hope Medical Center. Study of first time immunotolerance induction in severe haemophilia A patients with inhibitor at high risk of failure: comparison with FVIII concentrates with or without von Willebrand Factor — RES.I.S.T. Naive (RESIST NAIVE) [ClinicalTrials.gov identifier NCT01051544]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2012 Feb 9]
  60. 60.
    City of Hope Medical Center. Rescue immunotolerance study in induction of immune tolerance (ITI)-experienced patients (RES.I.S.T. Experienced) (RESIST EXP) [ClinicalTrials.gov identifier NCT01051076]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2012 Feb 9]
  61. 61.
    Dimichele DM, Hay CR. The international immune tolerance study: a multicenter prospective randomized trial in progress [letter]. J Thromb Haemost 2006 Oct; 4(10): 2271–3PubMedCrossRefGoogle Scholar
  62. 62.
    Valentino LA, Recht M, Dipaola J, et al. Experience with a third generation recombinant factor VIII concentrate (Advate) for immune tolerance induction in patients with haemophilia A. Haemophilia 2009; 15(3): 718–26PubMedCrossRefGoogle Scholar
  63. 63.
    Spotts G, Abbuehl BE, Luu HD, et al. Safety and efficacy profile of rAHF-PFM for immune tolerance induction as assessed in 3 clinical trials (PUP ITI, PRE-PAIR, and PAIR) [abstract no. 3670]. Blood (ASH Annual Meeting Abstracts) 2010; 116 (21)Google Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  1. 1.AdisAucklandNew Zealand

Personalised recommendations