Von Willebrand Factor, Recombinant

von Willebrand factor, recombinant (rVWF) is a prescription medication indicated in adult and pediatric patients with von Willebrand disease (VWD) for: 

• On-demand treatment and control of bleeding episodes
• Perioperative management of bleeding

For adult patients only:

• Routine prophylaxis to reduce the frequency of bleeding episodes.

Von Willebrand factor, recombinant is available under the following different brand names: Vonvendi

Common side effects of von Willebrand factor, recombinant include:

• headache 
• nausea
• vomiting
• dizziness
• generalized pruritus

Serious side effects of von Willebrand factor, recombinant include:

• thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke)
• hypersensitivity and infusion-related reactions (including anaphylaxis)
• development of neutralizing antibodies to VWF and/or factor VIII 

Rare side effects of von Willebrand factor, recombinant include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

 Adult and pediatric dosage

Injection, lyophilized powder for reconstitution

• 650 or 1300 IU von Willebrand factor: ristocetin cofactor (vWF: RCo) per vial
• Each vial is labeled with precise IU, which is based on the current World Health Organization standard for von Willebrand factor concentrate

von Willebrand Disease, Bleeding Episodes

Adult and pediatric dosage

• Control bleeding episodes
• Minor hemorrhage
  • Minor (e.g., readily managed epistaxis, oral bleeding, menorrhagia)
  • Initial dose: 40-50 IU/kg
  • Subsequent dose: 40-50 IU/kg every 8-24 hours as clinically required
• Major hemorrhage
  • Major (e.g., severe or refractory epistaxis, menorrhagia, gastrointestinal (GI) bleeding, central nervous system (CNS) trauma, hemarthrosis, traumatic hemorrhage, required or potentially indicated red blood cells (RBC) transfusion, intracranial hemorrhage)
  • Initial dose: 40-80 IU/kg
  • Subsequent dose: 40-60 IU/kg every 8-24 hours as clinically required for approximately 2-3 days
  • Maintain trough levels of vWF: RCo more than 50% for as long as deemed necessary
• Calculating the dose of recombinant factor VIII if needed
  • Initial dose of VWF should achieve more than 60% of vWF levels (based on vWF: RCo more than 0.6 IU/mL), and an infusion of recombinant factor VIII (rFVIII) should achieve factor VIII levels more than 40% (FVIII: C more than 0.4 IU/mL)
  • Administer rVWF with rFVIII if required, to control bleeding
  • Dosing should be at a ratio of 1.3:1 (ie, 30% more rVWF than rFVIII, based on the approximate mean recoveries to 1.5 and 2 IU/dL for rVWF and rFVIII, respectively)
  • Administer complete dose of rVWF followed by rFVIII within 10 minutes
  • rVWF dose = dose (IU/kg) x weight (kg)
  • rFVIII dose = rVWF dose divided by 1.3
• Perioperative bleeding
  • Elective surgical procedures
    • rVWF dose may be given 12-24 hours before surgery to allow the endogenous factor VIII levels to increase to at least 30 IU/dL (minor surgery) or 60 IU/dL (major surgery)
    • If FVIII: C levels are at or above the recommended minimum target levels, administer rVWF alone (without factor VIII treatment) within 1 hour before the procedure
    • If FVIII: C level is below the recommended minimum target level, administer complete rVWF dose followed by recombinant factor VIII within 10 min
    • When possible, measure incremental recovery (IR) before surgery
    • Calculation of IR: Measure baseline plasma VWF: RCo, infuse 50 IU/kg dose, and measure VWF: RCo 30 min after dose
  • Emergency surgery
    • In emergency surgery, a 12-24-hour preoperative dose in subjects requiring emergency surgery
    • Assess baseline VWF: RCo and FVIII:C levels within 3 hours before initiating the surgical procedure if it is feasible
    • Loading dose (1-hour preoperative dose): Calculate as the difference in the target peak and baseline plasma VWF: RCo levels divided by the IR
    • If baseline VWF: RCo and FVIII:C is not available, loading dose (1-hour preoperative dose) of rVWF 40-60 IU/kg VWF: RCo
    • Additionally, recombinant factor VIII at a dose of 30-45 IU/kg may be infused sequentially, preferably within 10 min after rVWF infusion in patients whose factor VIII plasma levels already are (or are highly likely to be) less than 40 to 50 IU/dL (minor surgery) or 80-100 IU/dL (major surgery)
  • Calculation of rvWF dose
    • Difference plasma VWF: RCo: Target peak plasma VWF: RCo – baseline plasma VWF: RCo
    • Difference plasma VWF: RCo x body weight [BW] (kg) divided by incremental recovery as measured in the subject (if IR is not available, assume IR of 2.0 IU/dL per IU/kg)
    • Also see prescribing information for further information
  • Recommended BW-based dosing in the absence of baseline FVIII: C, VWF: RCo, and incremental recovery
    • VWF: RCo: 25-30 IU/kg (minor); 50±10 IU/kg (major)
    • FVIII:C: 20-25 IU/kg (minor); 40-50 IU/kg (major)
    • Frequency dosing range between two times a day and every 48 hours
  • Recommended target peak plasma levels for the perioperative management of bleeding
    • VWF: RCo target peak plasma level: 50-60 IU/dL (minor); 100 IU/dL (major)
    • FVIII: C target peak plasma level: 40-50 IU/dL (minor); 80-100 IU/dL (major)
    • Monitor VWF: RCo and FVIII: C plasma levels starting 12-24 hours after surgery and at least every 24hours in the perioperative period
    • Individualize intra- and postoperative maintenance regimen according to the pharmacokinetic results and intensity and duration of the hemostatic challenge
  • Recommended target trough plasma levels and minimum duration of treatment
    • VWF: RCo target through plasma level (72 hours and less post-surgery): 30 IU/dL and more (minor); more than 50 IU/dL (major)
    • VWF: RCo target trough plasma level (more than 72 hours post-surgery): more than 30 IU/dL (major)
    • FVIII: C target tough plasma level (72 hours and less post-surgery): more than 30 IU/dL (minor); more than 50 IU/dL (major)
    • FVIII: C target trough plasma level (more than 72 hours post-surgery): more than 30 IU/dL (major)
    • Minimum duration of treatment: 48 hours (minor surgery); 72 hours (major surgery)
    • Frequency of dosing: Every 12-24 hours to every other day

von Willebrand Disease, Routine Prophylaxis

Adult dosage

• Initial: 40-60 international units/kg IV 2x per week
• Treat breakthrough bleeding as per dosing guidelines for minor and major bleeding episodes

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

Drug interactions overview

• Recombinant factor VIII (rFVIII)
  • Monitor plasma levels for FVIII: C activity in a patient requiring frequent doses of recombinant VWF in combination with rFVIII
  • Sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events (TEE) complications

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Contraindications

• Life-threatening hypersensitivity reaction to any component of the product (e.g., tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, hamster or mouse proteins)

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using von Willebrand factor, recombinant?”

Long-Term Effects

• See “What Are Side Effects Associated with Using von Willebrand factor, recombinant?”

Cautions

• Thromboembolic reactions
  • Can cause TEE (e.g., disseminated intravascular coagulation [DIC], venous thrombosis, pulmonary embolism [PE], myocardial infarction [MI], stroke)
  • Patients with known risk factors for thrombosis (eg, low ADAMTS13 levels) are at higher risk
  • Monitor for signs and symptoms of thrombosis (eg, pain, swelling, discoloration, dyspnea, cough, hemoptysis, syncope)
  • Evaluate plasma levels of VWF: RCo and factor VIII activity to avoid sustained excessive VWF and/or factor VIII activity levels
  • Start TEE prophylaxis according to current clinical practice and standard of care
• Hypersensitivity reactions
  • Can cause hypersensitivity reactions and infusion-related reactions
  • Reactions may include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, wheezing, and/or acute respiratory distress may include anaphylactic shock
  • Immediately discontinue and provide appropriate supportive care if a severe allergic reaction occurs
  • Patients may develop hypersensitivity reactions to nonhuman mammalian proteins found in the product (i.e., trace amounts of mouse immunoglobulin G [MuIgG] and hamster proteins of 2 ng/IU and lower)
• Neutralizing antibodies
  • Neutralizing antibodies to VWF and/or factor VIII reported
  • If 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
  • If inhibitors are present, consider other therapeutic options and direct patients to physicians with experience in the care of VWD or hemophilia A
  • Therapy may not be effective in patients with high levels of inhibitors to VWF or factor VIII, and infusion of this protein may lead to severe hypersensitivity reactions
  • Evaluate patients with anaphylactic reactions for the presence of inhibitors

Pregnancy and Lactation

There are no studies of use in pregnant women

Lactation

• There is no information regarding the presence of rVWF in human milk, its effects on the breastfed infant, or milk production
• Consider the developmental and health benefits of breastfeeding, along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from the therapy or from the underlying maternal condition