Von Willebrand Factor

The most common adverse reaction observed in ≥ 2% of subjects in clinical trials (n=66) was generalized pruritus.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety profile of VONVENDI was evaluated in three prospective, multicenter trials; two were conducted in subjects with von Willebrand disease (n=66) and one was conducted in subjects with hemophilia A (n=12). The adverse reactions reported in the two von Willebrand disease trials are listed in Table 2.

Table 2 : Summary of Adverse Reactions in Patients with von Willebrand Diseasea

The immunogenicity of VONVENDI was assessed in clinical trials by assessing the development of neutralizing antibodies against rVWF and rFVIII, as well as binding antibodies against rVWF, rFurin, Chinese hamster ovary (CHO) protein and mouse IgG. No treatment-related development of binding or neutralizing antibodies against VWF or of neutralizing antibodies against FVIII was observed. Moreover, binding antibodies against potential impurities such as rFurin, CHO-protein or mouse IgG did not develop after treatment with VONVENDI.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to VONVENDI in the studies described above with the incidence of antibodies in other studies or to other products.

Read the entire FDA prescribing information for Vonvendi (von Willebrand factor (Recombinant) for Injection)

This is not a complete list of von Willebrand factordrug interactions. Ask your doctor or pharmacist for more information.

Wilate is contraindicated for patients who have known anaphylactic or severe systemic reaction to plasma-derived products, any ingredient in the formulation, or components of the container. For a complete listing of ingredients, see Description ( 11 ).

The most common adverse reactions to treatment with Wilate in patients with VWD have been urticaria and dizziness.

The most serious adverse reactions to treatment with Wilate in patients with VWD have been hypersensitivity reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trails of another drug and may not reflect the rates observed in clinical practice.

There were 92 VWD patients who received Wilate on 5676 occasions including clinical studies that involved prophylactic use, treatment on demand, surgery, and pharmacokinetics. Their safety data showed that the most common adverse reactions were urticaria and dizziness (each with 2 patients; 2.2%). There were also four patients (4.4%) who showed seroconversion for antibodies to parvovirus B19 not accompanied by clinical signs of disease. Seroconversion has not been reported since implementation of minipool testing of plasma used for the manufacture of Wilate.

Post-Marketing Experience

The following adverse reactions have been identified during the post approval use of Wilate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

Post-marketing adverse reactions reported in patients treated for VWD include hypersensitivity reactions, dyspnea, nausea, vomiting, and cough.

No interactions with other medicinal products are known.

Wilate is a human plasma-derived, sterile, purified, double virus inactivated Von Willebrand Factor/Coagulation Factor VIII Complex (Human). Wilate is supplied as a lyophilized powder for reconstitution for intravenous injection.

Wilate is labeled with the actual VWF:RCo and FVIII activities in IU per vial. The VWF activity (VWF:RCo) is determined using a manual agglutination method referenced to the current “WHO International Standard for Von Willebrand Factor Concentrate”. The FVIII activity is determined using a chromogenic substrate assay referenced to the current “WHO International Standard for Human Coagulation Factor VIII Concentrate”. The assay methodologies are according to European Pharmacopoeia (Ph.Eur.).

Wilate contains no preservative. The diluent for reconstitution of the lyophilized powder is Water for Injection with 0.1% Polysorbate 80.

No albumin is added as a stabilizer. The resulting specific activity of Wilate is ≥ 60 IU VWF:RCo and ≥ 60 IU FVIII activities per mg of total protein.

The nominal composition of Wilate is as follows:

Wilate is derived from large pools of human plasma collected in U.S. FDA approved plasma donation centers. All plasma donations are tested for viral markers in compliance with requirements of EU CPMP and FDA guidances. In addition, the limit for the titer of human parvovirus B19 DNA in the manufacturing pool is set not to exceed 10 4 IU/mL.

The product is manufactured from cryoprecipitate, which is reconstituted in a buffer and treated with aluminum hydroxide followed by two different chromatography steps, ultra- and diafiltration, and sterile filtration. The manufacturing process includes two virus inactivation steps, namely, treatment with an organic solvent/detergent (S/D) mixture, composed of tri-n-butyl phosphate (TNBP) and Octoxynol-9, and a terminal dry heat (TDH) treatment of the lyophilized product in final container [at +100°C (212°F) for 120 minutes at a specified residual moisture level of 0. 7 – 1.6%]. In addition, the ion-exchange chromatography step utilized during Wilate manufacturing also removes some viruses [ 7 ]. The mean cumulative virus reduction factors of these steps are summarized in Table 2 .

Table 2 Virus Reduction During Wilate Manufacturing

na: not applicable

nd: not done (S/D reagents present)

HIV-1: Human Immunodeficiency Virus - 1

SBV: Sindbis Virus

BVDV: Bovine Viral Diarrhea Virus

PRV: Pseudorabies Virus

REO 3: Reovirus Type 3

HAV: Hepatitis A Virus

PPV: Porcine Parvovirus

Clinical efficacy of Wilate in the control of bleeding in patients with VWD was determined in four prospective clinical studies. This included treatment of 1068 bleeding episodes (BEs). Data were obtained from 70 VWD patients, of which 37 were type 3. BEs are summarized in Table 5 . The treated BEs were analyzed for efficacy using a set of objective criteria in addition to a subjective 4-point hemostatic efficacy scale (excellent, good, moderate and none). In assessing the efficacy using these objective criteria, the treatment of a bleeding episode was classified as a success only if none of the criteria listed below was fulfilled:

• the episode was additionally treated with another VWF-containing product (excluding whole blood),
• the patient received a blood transfusion during the episode,
• follow-up treatment with a daily dosage of Wilate that was equal or more than 50% (≥ 50%) above the initial dose (for bleeding episodes with more than 1 day of treatment),
• treatment duration of more than 4 days (> 4 days) in cases of severe bleeding (other than gastrointestinal),
• treatment duration of more than 3 days (> 3 days) in cases of moderate bleeding (other than gastrointestinal),
• treatment duration of more than 2 days (> 2 days) in cases of minor bleeding (other than gastrointestinal),
• the last efficacy rating of the bleeding episode was 'moderate' or 'none'.

Among the 70 VWD patients administered Wilate in clinical studies (excluding the PK study), 45 of them received on demand treatment for BEs. Using the above objective criteria, corresponding efficacy for each bleeding event was rated as being successful in 84% of the episodes. In these 45 patients with BEs, 93% of the successfully treated BEs occurred in VWD type 3 patients (n=25).

Table 5 Proportion of successful treatments of bleeding episodes with Wilate (n=45)

The dosing information for the 972 successfully treated “bleeding episodes” (1423 infusions) for regional bleeding is summarized in Table 6 . For the purpose of assigning success/failure to regional bleeding that occurred at the same time, the bleeding at different sites over the same time span would be counted as separate BEs. Thus, the number of these “episodes” would be different from that in the overall evaluation for success/failure of Wilate in the treatment of bleeding episodes in Table 5 .

Table 6 Administered dosages (VWF:RCo in IU/kg) in bleeding episodes* successfully treated with Wilate: Mean ± SD (Range) (n=45)

**“Other” Includes mostly muscle bleeds, hematuria, ecchymosis, hematoma and other miscellaneous sites of bleeding

The majority of BEs were treated for 1-3 days. In patients with GI bleeds, the duration for product use to control bleeding could be much longer (up to 7 days).

For pediatric patients (≤16 yrs), a summary of the number of BEs treated and corresponding objective efficacy ratings are provided in Table 7 .

Table 7 Efficacy in bleeding episodes in pediatric population (5 to 16 yrs) (n=11) – Proportion of successful treatments of bleeding episodes with Wilate

The dosing information for the 211 successfully treated bleeding episodes (289 infusions) is summarized in Table 8 . Multiple bleeding sites are counted as separate episodes.

Table 8 Administered dosages (VWF:RCo in IU/kg) in bleeding episodes* successfully treated with Wilate in pediatric population (5 to 16 yrs) (n=11): Mean ± SD (Range)

**“Other” Includes mostly muscle bleeds, hematuria, ecchymosis, hematoma and other miscellaneous sites of bleeding

• Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic symptoms occur, patients should discontinue the administration immediately and contact their physician [see Warnings and Precautions ( 5.1 )].
• Inform patients that undergoing multiple treatments with Wilate may increase the risk of thrombotic events thereby requiring frequent monitoring of plasma VWF:RCo and FVIII activities. [see Warnings and Precautions ( 5.2 )].
• Inform patients that there is a potential of developing inhibitors to VWF, leading to an inadequate clinical response. Thus, if the expected VWF activity plasma levels are not attained, or if bleeding is not controlled with an adequate dose or repeated dosing, contact the treating physician.[ 2 ] [see Warnings and Precautions ( 5.3 )].
• Inform patients that despite procedures for screening donors and plasma as well as those for inactivation or removal of infectious agents, the possibility of transmitting infective agents with plasma-derived products cannot be totally excluded [see Warnings and Precautions ( 5.4 )].

Manufactured by:

Octapharma Pharmazeutika Produktionsges.m.b.H.

Oberlaaer Strasse 235

A-1100 Vienna, Austria

U.S. License No. 1646

Distributed by:

Octapharma USA Inc.

121 River Street, 12th floor

Hoboken, NJ 07030

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL

Von Willebrand Factor/Coagulation Factor VIII Complex (Human)

Octapharma Pharmazeutika Produktionsges.m.b.H

500IU/5mL

NDC 67467-182-01

1000IU/10mL

NDC 67467-182-02