Hemophilia

Wilate® is the brand name for von Willebrand factor/coagulation factor VIII complex (human). It is supplied as a lyophilized powder, which is reconstituted in either 5 mL or 10 mL of water for injection with 0.1% polysorbate 80 diluent for intravenous injection. It is manufactured by Octapharma Pharmazeutika Produktionsges.m.b.H. to control bleeding in patients with severe von Willebrand disease (VWD).¹ 

Wilate is derived from human plasma collected in plasma donation centers in the United States. This plasma is purified and sterilized, undergoing multiple filtration steps and viral inactivation procedures. Treatments with an organic solvent/detergent mixture, terminal dry heat, and ion-exchange chromatography remove or inactivate any viruses present.¹ 

Wilate is manufactured from cryoprecipitate, which is reconstituted in a buffer and undergoes aluminum hydroxide treatment. It does not contain albumin as a stabilizer, nor does it contain any preservatives.¹ 

The 5-mL vial contains 500 IU each of factor VIII (FVIII) and von Willebrand factor:ristocetin cofactor (VWF:RCo), ≤7.5 mg of total protein, 50 mg of glycine, 50 mg of sucrose, 117 mg of sodium chloride, 14.7 mg of sodium citrate, 0.8 mg of calcium chloride, 5 mL of water for injection, and 1 mg/mL of polysorbate 80.¹ 

The 10-mL vial contains 1000 IU each of FVIII and VWF:RCo, ≤15.0 mg of total protein, 100 mg of glycine, 100 mg of sucrose, 234 mg of sodium chloride, 29.4 mg of sodium citrate, 1.5 mg of calcium chloride, 10 mL of water for injection, and 1 mg/mL of polysorbate 80.¹

Indications

Wilate is indicated in adults or children with VWD for acute bleeding episodes, bleeding prophylaxis, and management of pre- and postoperative bleeding. It was not originally intended to treat individuals with hemophilia A; however, this recommendation has recently changed based on a series of clinical trials studying the efficacy and safety of Wilate in previously treated patients with hemophilia A.^1,2 

Wilate was first approved by the US Food and Drug Administration (FDA) in 2009 for the treatment and control of bleeding episodes and perioperative bleeding management in children and adults with VWD. In 2019, Octapharma announced that the FDA recently approved Wilate to treat adults and adolescents with hemophilia A.²

Dosage and Administration

The proper dosage of Wilate is based upon the empirical finding that 1 IU VWF:RCo per kilogram of body weight raises the plasma VWF activity by approximately 2% of normal activity. The formula used for this calculation is as follows¹:

Required IU = body weight (kg) x desired VWF:RCo rise (%) (IU/dL) x 0.5 (IU/kg per IU/dL)

Expected VWF:RCo rise (% of normal) = 2 x administered IU/body weight (kg)  

The desired level of VWF:RCo activity depends upon the bleeding severity. Minor hemorrhaging requires a dosage between 20 and 40 IU of VWF:RCo/kg to elevate the VWF:RCo and FVIII activity levels above 30% of normal. Major hemorrhaging requires 40 to 60 IU of VWF:RCo/kg to elevate the VWF:RCo and FVIII activity levels above 50% of normal. Minor surgeries, including tooth extraction, require a dosage between 30 and 60 IU of VWF:RCo/kg to elevate the VWF:RCo and FVIII activity levels above 50% of normal. Major surgeries require 40 to 60 IU of VWF:RCo/kg to elevate the VWF:RCo and FVIII activity levels to 100% of normal. These dosages should be administered within 3 hours of the scheduled surgery.¹

Mechanism of Action

Wilate is derived from normal human plasma and replaces the missing VWF:RCo and FVIII in individuals with VWD, correcting the hemostatic defects in 2 ways.³ 

Individuals with VWD have abnormal platelet function due to deficient plasma concentrations of VWF.¹ Replacement of VWF allows for the immediate adhesion of platelets to the subendothelium of blood vessels that have been damaged, initiating primary hemostasis by shortening bleeding time.³ 

Replacement of VWF also corrects the associated FVIII deficiency in individuals with VWD by binding FVIII, which is produced normally by the patient. VWF is a carrier protein that stabilizes the FVIII protein before it rapidly degrades. While the stabilization of FVIII is slightly delayed, administration of an FVIII-containing product like Wilate quickly restores the plasma FVIII activity level to normal.³ Factor VIII is also an essential cofactor in the activation of factor X, which triggers the formation of thrombin and fibrin, necessary for clot production.¹

Get full prescribing information on Wilate at MPR

Trial Efficacy and Safety of Wilate

In 2009, a clinical study investigated the efficacy and safety of Wilate in the treatment of 1095 acute bleeding episodes in 44 individuals with all types of VWD, and it reported an efficacy rating of excellent or good in 96% of these cases. The bleeding stopped within 1 or 2 days in 81% of acute episodes, with gastrointestinal bleeds requiring higher doses and longer treatment times to resolve. Wilate prophylaxis in 19 patients (including 6 children) for longer than 3 months demonstrated a drop in frequency of bleeding episodes from a mean of 4.5 episodes per month to 1.4 episodes per month. Adverse reactions were rarely reported. Those that were reported were mild or moderate in intensity, demonstrating that Wilate is a safe and efficacious treatment in individuals of all ages with all types of VWD.⁴  

In 2011, a clinical study reported the efficacy and safety of the perioperative use of Wilate in 32 individuals with VWD undergoing 57 surgical procedures. In this study, Wilate had an efficacy rating of excellent or good in 51 of 53 (96%) surgical procedures and good or very good patient tolerability in 100% of the 27 major surgeries and in 29 of 30 (96.7%) minor surgeries.⁵

In 2017, researchers conducting a clinical study reported the efficacy and safety of Wilate in bleeding prophylaxis in 28 individuals with VWD undergoing 30 surgical procedures, 21 of which were major procedures. Surgical prophylaxis with Wilate was successful in 96.7% (29 of 30) of these cases and in 100% of the 21 surgeries in patients with type 3 VWD. No reports of VWF or FVIII accumulation, development of VWF or FVIII inhibitors, or thromboembolic events were reported.⁶ 

In 2021, investigators published real-world data detailing the efficacy and safety of Wilate in 111 individuals with VWD. Of these patients, 25 received prophylaxis, 29 received treatment for acute bleeds, and 62 received perioperative bleeding management. The results showed 100% patient and investigator efficacy ratings of excellent or good for the management of acute bleeding episodes, a 98% patient efficacy rating and 99% investigator efficacy rating for breakthrough bleeds during prophylactic use, and a 99% investigator efficacy rating for perioperative bleeding management. Patients rated tolerability to the drug as excellent in 96.2% of the 6497 infusions.⁷

The most common adverse effect reported was fever in 2 of the 136 (1.5%) individuals with hemophilia A who collectively participated in a series of 5 clinical trials focused on the safety of Wilate for prophylaxis, perioperative use, pharmacokinetics, and acute bleeding control. Other adverse reactions included pruritus, headache, and sleeping disturbances. In the routine prophylaxis study, 2 of 55 (3.6%) patients with severe hemophilia A experienced thrombocytosis. No patients developed FVIII or VWF inhibitors.⁸

Warnings, Precautions, and Adverse Reactions

Commonly reported side effects following Wilate administration include hypersensitivity reactions, dizziness, and urticaria. Hypersensitivity reactions comprise the most serious adverse reactions.¹ 

Hypersensitivity symptoms include headache, flushing, chills, pain at the infusion site, urticaria, chest tightness, tachycardia, hives, hypotension, lethargy, nausea, restlessness, vomiting, tingling, and wheezing, which may progress to severe anaphylaxis with or without fever.¹

Excessive rises in FVIII activity with continued use of Wilate, particularly perioperatively, increases the risk of thromboembolic events. Monitoring plasma VWF and FVIII levels is imperative with sustained use of the product. It is not recommended to exceed an FVIII activity level of 250%.¹

Due to Wilate containing human plasma material, there is a risk of transmitting infectious agents such as bloodborne viruses. Vaccination against hepatitis A and B is recommended for any individual receiving repeated administration of Wilate.¹

The development of neutralizing antibodies (inhibitors) against FVIII or VWF can occur with Wilate administration, which may lead to severe anaphylactic reactions or serious adverse events. Wilate is not effective in individuals who develop inhibitors to VWF or FVIII and may cause more harm than good; therefore, discontinuation of treatment is recommended.¹

No data is available for the use of Wilate in pregnant or breastfeeding women, and data in the geriatric population is insufficient to support recommendations for the use of Wilate.¹ 

References

1. Wilate. RxList. Updated April 20, 2018. Accessed January  3, 2021.
2. Octapharma’s Wilate® receives expanded approval from FDA. National Hemophilia Foundation. October 10, 2019. Accessed January 3, 2021. 
3. Wilate – von Willebrand factor/coagulation factor VIII complex (human). DailyMed. Updated August 20, 2010. Accessed January 3, 2021. 
4. Berntorp E, Windyga J; The European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand disease – efficacy and safety of Wilate®, a new generation von Willebrand factor/factor VIII concentrate. Haemophilia. 2009;15(1):122-130. doi:10.1111/j.1365-2516.2008.01901.x
5. Windyga J, von Depka-Prondzinski M; The European Wilate® Study Group. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate®) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery. Thromb Haemost. 2011;105(6):1072-1079. doi:10.1160/TH10-10-0631
6. Srivastava A, Serban M, Werner S, Schwartz BA, Kessler CM; The Wonders Study Investigators. Efficacy and safety of a VWF/FVIII concentrate (Wilate®) in inherited von Willebrand disease patients undergoing surgical procedures. Haemophilia. 2017;23(2):264-272. doi:10.1111/hae.13106
7. Sholzberg M, Khair K, Yaish H, et al. Real-world data on the effectiveness and safety of Wilate for the treatment of von Willebrand disease. TH Open. 2021;5(3):e264-e272. doi:10.1055/s-0041-1730283
8. Wilate®: hemophilia A drug safety & tolerance. Octapharma. Accessed January 3, 2021.

Reviewed by Debjyoti Talukdar, MD, on 12/31/2021.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.