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infusion of VONVENDI® [von Willebrand factor (Recombinant)] achieved hemostatic levels of factor VIII coagulation activity (FVIII:C) in the pivotal phase 3 clinical studies over time1-3

Hemostatic FVIII levels were observed in patients with all types of von Willebrand disease (VWD) in pharmacokinetic (PK) evaluations performed in a non-bleeding state.2,3

Dosing of VONVENDI, with or without recombinant factor VIII (rFVIII), should be based on patient need as determined by monitoring levels and clinical judgment.

Endogenous FVIII:C levels rose at a mean rate of 7.7% per hour (range 1.0%-17.2%) for the first 6 hours in the clinical trials1,4

  • PK analyses were performed post-hoc from pooled data across on-demand and surgery trials (N=40)4
  • VONVENDI promoted an increase in von Willebrand factor (VWF) activity levels per Ristocetin cofactor assay (VWF:RCo)1
  • Mean (SD) half-life was 19.1 (4.32) hours for PK80 and 22.6 (5.34) hours for PK501

aPK analyses were performed in both the on-demand and surgery trials, in a non-bleeding state. Data shown on the graph corresponds to the on- demand trial (50 IU VWF:RCo/kg; n=16).2,3

On-Demand Dosing in Adult VWD Patients

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factor may be dosed independently of rFVIII1,a

For the first dose, administer VONVENDI alone if FVIII:C level is ≥40% or if an immediate rise in FVIII:C is not necessary.1

Dosing guidelines for treatment of minor and major hemorrhages1
Hemorrhagic event Initial doseb Subsequent dose
Minor (eg, readily managed epistaxis, oral bleeding, menorrhagia) 40 to 50 IU/kg 40 to 50 IU/kg every 8 to 24 hours (as clinically required)
Majorc (eg, severe or refractory epistaxis, menorrhagia, gastrointestinal (GI) bleeding, central nervous system (CNS) trauma, hemarthrosis, or traumatic hemorrhage) 50 to 80 IU/kg 40 to 60 IU/kg every 8 to 24 hours for approximately 2 to 3 days (as clinically required)

Dosing of VONVENDI, with or without rFVIII, should be based on patient need as determined by monitoring levels and clinical judgment

aVONVENDI contains only trace amounts of rFVIII.
bIf rFVIII is administered, see rFVIII package insert for reconstitution and administration instructions.
cA bleed could be considered major if red blood cell transfusion is either required or potentially indicated or if bleeding occurs in a critical anatomical site (eg, intracranial or gastrointestinal hemorrhage).

Surgical Dosing in Adult VWD Patients

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factor may also be dosed independently of rFVIII for perioperative management of bleeding in adult VWD patients during elective surgery1,a

Preoperative dosing of VONVENDI for elective surgeryb

Preoperative dosing for elective surgery: VONVENDI may be administered alone if a patient's presurgical plasma FVIII:C level is ≥ 30% for minor surgeries and ≥ 60% for major surgeries.

12-24 hours prior to surgery1

  • VONVENDI may be administered to allow endogenous FVIII levels to increase

Within 3 hours prior to surgery1

  • Assess FVIII:C to ensure minimum target levels are achieved
  • Administer VONVENDI within 1 hour prior to surgery with or without rFVIII
    • Administer VONVENDI alone if FVIII:C is at or greater than minimum target levels
    • Administer VONVENDI with rFVIII if FVIII:C is below minimum target levels
    • If rFVIII is administered, see rFVIII package insert for reconstitution and administration instructions1
PreOPERATIVE Calculation of Vonvendi DOSING1
Type of Surgery Baseline FVIII:C, VWF:RCo, IRc Target Peak
Plasma Levels
Known Unknown VWF:RCo FVIII:Cd
Calculation of
VONVENDI Dose (IU VWF:RCo required)
VWF:RCo (IU VWF:RCo/ kg BW) FVIII:C (IU FVIII:C/ kg BW)
Minor
VWF:RCo Target peak
-
VWF:RCo Baseline
x
BW (kg)
IR
25 to 30 IU/kg 20 to 25 IU/kg 50% to 60% 40% to 50%
Major 50 ± 10 IU/kg 40 to 50 IU/kg 100% 80% to 100%

aVONVENDI contains only trace amounts of rFVIII.
bPlease see full Prescribing Information for VONVENDI dosing in the emergency setting.
cIR = Incremental Recovery as measured in the subject. If the IR is not available, assume an IR of 2.0% per IU/kg.
dAdditional rFVIII may be required to attain the recommended FVIII:C target peak plasma levels. Dosing guidance should be based on the IR.

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postoperative dose may be administered up to every other day (every 12-48 hours)1

The following postoperative dosing guidelines should be kept top of mind for VONVENDI:

  • Monitor VWF:RCo and FVIII:C plasma levels starting at 12-24 hours and at least every 24 hours1
  • Dose VONVENDI based on patient need. If necessary, the frequency of VONVENDI dosing should range between twice a day and every 48 hours1
POSTOPERATIVE DOSING: RECOMMENDED VWF:RCo AND FVIII:C MINIMUM TARGET PLASMA LEVELS1
Type of Surgery VWF:RCo Minimum Target Plasma Level FVIII:C Minimum Target Plasma Level Minimum Duration of Treatment Frequency of Dosing
Up to 72 hours post surgery After 72 hours post surgery Up to 72 hours post surgery After 72 hours post surgery
Minor ≥ 30% - > 30% - 48 hours Every 12-24 hrs to every other day
Major > 50% > 30% > 50% > 30% 72 hours
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Reference: 1. VONVENDI [von Willebrand factor (recombinant)] Prescribing Information 2. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015;126(17):2038-2046. 3. Peyvandi F, Mamaev A, Wang JD, et al. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost. 2019;17(1):52-62. 4. Data on file, Shire, Plc.

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

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 80 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=80) were generalized pruritus, vomiting, nausea, dizziness, and vertigo.

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

Please see VONVENDI full Prescribing Information.