REPRINTENCLOSED
Efficacy and Safety of a VWF/FVIII Concentrate (wilate®) in Inherited von Willebrand Disease Patients Undergoing Surgical Procedures
A. Srivastava,* M. Serban,† S. Werner,‡ B. A. Schwartz,‡ and C. M. Kessler§ for the WONDERS Study Investigators
* Department of Haematology, Christian Medical College, Vellore, India; †University Emergency Pediatric Hospital Louis Turcanu, Timisoara, Romania; ‡Octapharma Clinical Research, Hoboken, NJ, USA; and §Hemophilia and Thrombosis Comprehensive Treatment Center and the Division of Coagulation, Georgetown University Medical Center, Washington, DC, USA. Haemophilia. 2017;23:264-272.
Introduction:
• Patients with von Willebrand disease (VWD) undergoing surgery may require prophylaxis with von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding
• Wilate is a plasma-derived, double virus-inactivated, highly purified VWF/FVIII concentrate containing both factors in a physiological activity ratio of 1:1
Methods:
• Prospective, open-label multinational study in 28 VWD patients undergoing 30 surgical procedures (pediatric [N=3], adult [N=25])
• All patients received 60 IU/kg of wilate for the in vivo recovery (IVR) investigation at study start to calculate the recommended dosing for surgeries
• Additional dosing guidelines:
– Major surgery: loading dose of 40−60 IU/kg within 3 hours of start of procedure to achieve peak plasma
VWF:RCo level of 100%. Maintenance dose of 20−40 IU/kg or half of the loading dose every 12−24 hours
– Minor surgery: loading dose of 30−60 IU/kg within 3 hours of start of procedure to achieve peak plasma
VWF:RCo level of 50%. Maintenance dose of 20−40 IU/kg or half of the loading dose every 12−24 hours
Dosing recommendations were adjusted using results of baseline IVR and at the investigator’s discretion
• This prospective study used stringent, objective efficacy criteria to assess the efficacy of wilate during and after surgical procedures
• In addition, blinded adjudication of all efficacy assessments by the Independent Data Monitoring Committee (IDMC) and statistical analysis provide a conservative, unbiased efficacy assessment of wilate
Indications and Usage
Wilate® is a von Willebrand Factor/Coagulation Factor VIII Complex (Human) indicated in children and adults with von Willebrand disease for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding. wilate is also indicated in adolescents and adults with hemophilia A for routine prophylaxis to reduce the frequency of bleeding episodes, and for on-demand treatment and control of bleeding episodes.
Important Safety Information
Wilate is contraindicated in patients with known hypersensitivity reactions, including anaphylactic or severe systemic reactions, to human plasma-derived products, any ingredient in the formulation, or components of the container. Wilate is made from human plasma and carries the risk of transmitting infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease agent.
Please see accompanying full Prescribing Information.
Highly Effective Surgical Prophylaxis
Hemostatic Efficacy by Type of Surgery and VWD*†
*Based on intra- and postoperative assessment of the IDMC (blood loss, transfusion requirements, postoperative bleeding, and oozing).
†For efficacy by VWD type, two patients were enrolled for 2 surgeries each; therefore, there were 28 individual patients.
• Efficacy was excellent or good in all pediatric procedures (3 surgeries in 3 patients)
Low Loading and Maintenance Dosing in Minor and Major Surgeries
Majorsurgeries
Minorsurgeries
No Accumulation of FVIII After Repeat Dosing
Mean Peak Plasma Levels Over Time in Major Surgeries
• Peak FVIII:C plasma levels were between 125%–150%
Mean Trough Plasma Levels Over Time in Major Surgeries
# of patients
2118181718161618148
• Trough FVIII:C plasma levels were between 75%–100%
• Mean total loading dose: 51.4 IU VWF:RCo/kg per infusion (median 52.1)
• Mean maintenance dose: 28.5 IU VWF:RCo/kg per infusion (median 28.5)
NO ACCUMULATION OF FVIII:C was observed over time and no thromboembolic events occurred IN STUDIES WITH HUMATE-P®, patients undergoing surgery received a median loading dose of 82.3 IU VWF:RCo/kg per infusion, and a median maintenance dose of 52.8 IU VWF:RCo/kg per infusion
Important Safety Information
Important Safety Information
The most common adverse reactions (≥1%) in patients with VWD were hypersensitivity reactions, urticaria, and dizziness. The most serious adverse reactions in patients with VWD were hypersensitivity reactions.
Please see accompanying full Prescribing Information.
Monitor plasma levels of FVIII activity to avoid sustained excessive FVIII levels, which may increase the risk of thromboembolic events. Development of neutralizing antibodies to FVIII and to VWF, especially in VWD type 3 patients, may occur.
Please see accompanying full Prescribing Information.
Summary
Wilate demonstrated highly effective prevention and treatment of bleeding in VWD patients undergoing surgery, with no clinically significant safety concerns
• The overall success rate of wilate treatment was 96.7%
• Efficacy was particularly noteworthy considering that 70% of surgeries were major and 70% of patients were severe Type 3 VWD
• Wilate dosing was lower than dosing reported for Humate-P® in VWD patients*
• There was no accumulation of VWF or FVIII after repeat dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed
*Presentation of Humate-P dosing information is not intended to claim or imply inferiority, equivalence, or superiority to wilate in efficacy, safety, or other conditions of use.
Important Safety Information
Contraindications
Wilate is contraindicated in patients with known hypersensitivity reactions, including anaphylactic or severe systemic reactions, to human plasma-derived products, any ingredient in the formulation, or components of the container.
Warnings and Precautions
Thromboembolic events may occur. Monitor plasma levels of FVIII activity. Development of neutralizing antibodies to FVIII and to VWF, especially in VWD type 3 patients, may occur. Wilate is made from human plasma and carries the risk of transmitting infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease agent.
Adverse Reactions
The most common adverse reactions (≥ 1%) in clinical studies on VWD were hypersensitivity reactions, urticaria, and dizziness. The most common adverse reaction (≥ 1%) in clinical studies in hemophilia A was pyrexia (fever).
Please see accompanying full Prescribing Information.