See How VONVENDI is Unique. One factor. Three Indications.1

VONVENDI [von Willebrand factor (Recombinant)]
for von Willebrand disease (VWD)

Only VONVENDI for von Willebrand disease is indicated for the following in adults with VWD1:

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Prophylaxis (severe type 3)

Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 VWD receiving on-demand therapy
Read the data

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On-demand

On-demand treatment and control of bleeding episodes
Read the data

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Surgery

Perioperative management of bleeding
Read the data

Selected Important Risk Information
WARNINGS AND PRECAUTIONS
Embolism and Thrombosis

Thromboembolic reactions, including disseminated intravascular coagulation, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and institute prophylaxis measures against thromboembolism based on current recommendations.

In patients requiring frequent doses of VONVENDI in combination with recombinant factor VIII, monitor plasma levels for FVIII:C activity because sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events.

One out of 100 subjects treated with VONVENDI in clinical trials developed proximal deep vein thrombosis in perioperative period after total hip replacement surgery.

VONVENDI mechanism of action and pharmacokinetics
Watch VONVENDI® mechanism of action and pharmacokinetics video.

VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor (rVWF) indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management of bleeding
  • Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

Please see Detailed Important Risk Information at the end of this video. Please see full VONVENDI Prescribing Information at VONVENDIPRO.com

VONVENDI: Mechanism of Action and Pharmacokinetics

von Willebrand disease, or VWD, is the most common hereditary bleeding disorder. Patients with VWD may experience prolonged or excessive bleeding episodes, which range in frequency, anatomical location, and severity.

VONVENDI is a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes and for perioperative management of bleeding in adults with all VWD types. It is also approved for routine prophylaxis in adults with severe type 3 VWD who were previously receiving on-demand therapy.

The underlying cause of VWD is either a quantitative deficiency or qualitative defect in VWF.

VONVENDI contains the full range of VWF multimers, similar to what is produced naturally in the body. These VWF multimers range from low and intermediate molecular weight to high molecular weight and ultra-large multimers, or ULMs. VONVENDI is not exposed to proteolysis by ADAMTS13 during the manufacturing process, allowing its ULMs to remain intact.

How VONVENDI Works in Hemostasis

When VONVENDI is administered to patients with VWD, its multimers enter the bloodstream.

Like naturally occurring VWF, VONVENDI multimers bind to factor VIII molecules, which protects factor VIII from degradation and reduces its clearance. The binding capacity and affinity of VONVENDI to factor VIII in plasma is comparable to that of naturally-occurring VWF.

In addition, sheer stress may cause VONVENDI ULMs to uncoil, allowing the patient’s own ADAMTS13 protein to cleave the uncoiled VONVENDI ULMs into multimers of varying sizes. This process is similar to how naturally-occurring VWF ULMs are broken down.

As a factor replacement product, VONVENDI assumes VWF’s role in hemostasis for patients with VWD.

Upon blood vessel injury, VONVENDI binds to collagen and platelets to facilitate platelet plug formation in primary hemostasis. The adhesive activity of these multimers depends on their size, with larger multimers being the most effective in supporting interactions with collagen and platelet receptors.

During secondary hemostasis, the circulating VONVENDI molecules that had been acting as carrier proteins for factor VIII contribute to factor VIII activation and release near the injury site, which is a crucial component of the coagulation cascade that leads to formation of a stable clot.

How VONVENDI Works in Hemostasis

When VONVENDI is administered to patients with VWD, its multimers enter the bloodstream.

Like naturally occurring VWF, VONVENDI multimers bind to factor VIII molecules, which protects factor VIII from degradation and reduces its clearance. The binding capacity and affinity of VONVENDI to factor VIII in plasma is comparable to that of naturally-occurring VWF.

In addition, sheer stress may cause VONVENDI ULMs to uncoil, allowing the patient’s own ADAMTS13 protein to cleave the uncoiled VONVENDI ULMs into multimers of varying sizes. This process is similar to how naturally-occurring VWF ULMs are broken down.

As a factor replacement product, VONVENDI assumes VWF’s role in hemostasis for patients with VWD.

Upon blood vessel injury, VONVENDI binds to collagen and platelets to facilitate platelet plug formation in primary hemostasis. The adhesive activity of these multimers depends on their size, with larger multimers being the most effective in supporting interactions with collagen and platelet receptors.

During secondary hemostasis, the circulating VONVENDI molecules that had been acting as carrier proteins for factor VIII contribute to factor VIII activation and release near the injury site, which is a crucial component of the coagulation cascade that leads to formation of a stable clot.

VONVENDI and Factor VIII PKPD Data

Patients with von Willebrand disease have a quantitative deficiency or qualitative defect in VWF. Since VWF normally protects factor VIII in circulation, some patients with VWD may experience increased clearance of factor VIII due to absence of the protection provided by functional VWF. However, their ability to produce factor VIII is typically unaffected.

Infusing adult VWD patients with VONVENDI may help reinstate the protection that functional VWF offers to factor VIII and reduce factor VIII clearance over time. This has been observed in pharmacokinetic and pharmacodynamic analyses of the VONVENDI on-demand trial.

This chart depicts VWF and factor VIII activity post VONVENDI infusion. When VONVENDI was infused at time zero, VWF concentration rose, as depicted by the dotted white line. This infusion of VONVENDI caused patients' own factor VIII levels—represented by the green line—to rise. This increase was sustained over 72 hours post-infusion.

In addition, data from the trials demonstrate that VONVENDI promoted an increase in VWF activity levels—the mean half-life was 19.1 and 22.6 hours after infusion with 80 IU/kg and 50 IU/kg doses of VONVENDI, respectively.

Summary: VONVENDI for Adult VWD Patients

In conclusion, VONVENDI exhibits similar properties to naturally occurring VWF, and plays 2 key roles in adult patients with VWD: binding collagen and platelets to facilitate platelet plug formation to promote hemostasis, and stabilizing factor VIII to protect it from clearance.

Based on patient need as determined by monitoring levels and clinical judgment, VONVENDI may be dosed with or without recombinant factor VIII. This enables healthcare providers to manage VWF and factor VIII levels separately and specifically.

Indications and Detailed Important Risk Information

Indications
VONVENDI [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor (rVWF) indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management of bleeding
  • Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy

Detailed Important Risk Information

CONTRAINDICATIONS

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

WARNINGS AND PRECAUTIONS

Embolism and Thrombosis

Thromboembolic reactions, including disseminated intravascular coagulation, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and institute prophylaxis measures against thromboembolism based on current recommendations.

In patients requiring frequent doses of VONVENDI in combination with recombinant factor VIII, monitor plasma levels for FVIII:C activity because sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events.

One out of 100 subjects treated with VONVENDI in clinical trials developed proximal deep vein thrombosis in perioperative period after total hip replacement surgery.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred with VONVENDI. These reactions can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, wheezing and/or acute respiratory distress. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies (Inhibitors)

Inhibitors to VWF and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-factor VIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either VWD or hemophilia A.

In patients with high levels of inhibitors to VWF or factor VIII, VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions observed in ≥2% of subjects (n=100) were headache, vomiting, nausea, dizziness, arthralgia, joint injury, vertigo, ALT increased and generalized pruritus.

One subject treated with VONVENDI in perioperative setting developed deep vein thrombosis after total hip replacement surgery.

Please see VONVENDI full Prescribing Information at VONVENDIPRO.com.

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There are no data to indicate that VONVENDI efficacy is enhanced due to its multimeric composition or its mechanism of action

As the only recombinant VWF for VWD, VONVENDI is made to be different1,2
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VONVENDI has a purity of >99%, leaving only trace amounts of factor VIII (FVIII), mouse immunoglobulins, and hamster proteins1,3

Plasma protein icon.

As a recombinant product manufactured in the absence of animal or human plasma proteins, VONVENDI virtually eliminates the risk of blood-borne pathogen transmission3,4

VONVENDI contains the full range of von Willebrand factor (VWF) multimers1

VONVENDI has a similar multimeric profile to what is produced naturally in the body, including ultra-large multimers (ULMs)

Diagram showing ultra-large multimers.

Because of the recombinant manufacturing process for VONVENDI, it is not exposed to proteolysis by ADAMTS13, allowing its ULMs to remain intact1

Upon administration, VONVENDI is cleaved by the patient’s own ADAMTS13 enzymes into multimers of various sizes, similar to naturally produced VWF1

The adhesive activity of VWF depends on the size of its multimers, with larger multimers being the most effective in supporting interactions with collagen and platelet receptors1

There are no data to indicate that VONVENDI efficacy is enhanced due to its multimeric composition or its mechanism of action

Selected Important Risk Information
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions

Hypersensitivity reactions have occurred with VONVENDI. These reactions can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, wheezing and/or acute respiratory distress. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment.

VONVENDI half-life is uniquely long1
VONVENDI promoted an increase in VWF activity levels (VWF:RCo)
Mean VWF:RCo Half-life in
Hours (SD)a
DOSE 50 IU/kg
Number 22.6.
(5.34)
Mean VWF:RCo Half-life in
Hours (SD)a
DOSE 80 IU/kg
Number 19.1.
(4.32)
aThe pharmacokinetic (PK) profile of VONVENDI was determined based on data analyses from two clinical trials.
Subjects were evaluated in the non-bleeding state.
Selected Important Risk Information
WARNINGS AND PRECAUTIONS
Neutralizing Antibodies (Inhibitors)

Inhibitors to VWF and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-factor VIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either VWD or hemophilia A.

In patients with high levels of inhibitors to VWF or factor VIII, VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.

VONVENDI alone enables a sustained rise in FVIII levels1
Endogenous FVIII:C levels rose at a mean rate of 7.7% per hour (range 1.0%-17.2%) for the first 6 hours1,5,6

PK analyses were performed post-hoc from pooled data across on-demand and
surgery trials (N=40)6

ENDOGENOUS FVIII:C LEVELS WERE SUSTAINED OVER 72 HOURS POST-INFUSION2,a

Chart showing endogenous FVIII:C levels were sustained over 72 hours post‐infusion.

aPK analyses were performed in both the on-demand and surgery trials, in a non-bleeding state. Data shown on the graph correspond to the on-demand trial (50 IU VWF:RCo/kg; n=16).2,5

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VONVENDI prophylaxis led to a sustained FVIII rise in patients with severe Type 3 VWD1

  • Pre-dose FVIII:C (FVIII level before VONVENDI administration) was evaluated in adults with severe Type 3 VWD enrolled in the prophylaxis trial who were previously receiving on-demand therapy
  • This analysis was performed at baseline (before the first dose of VONVENDI prophylaxis) and before VONVENDI prophylaxis dosing at Months 1, 2, 3, 6, 9, and 12
  • The median (range) pre-dose FVIII:C at baseline after washout (N=10) was 2.0% (2.0-4.0) and the FVIII:C value was ≥10.5% (1.0-148) across the prophylactic visits at Months 1, 2, 3, 6, 9, and 12 (Month 12, N=8)