von Willebrand Factor (Recombinant)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Vonvendi: 650 units (1 ea); 1300 units (1 ea) [contains mouse (murine) and/or hamster protein, polysorbate 80]

Pharmacology

Mechanism of Action

von Willebrand Factor (recombinant) promotes platelet aggregation and adhesion to damaged vascular endothelium and acts as a stabilizing carrier protein for factor VIII.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

19.1 to 22.6 hours

Use: Labeled Indications

von Willebrand disease: Treatment (on demand) and control of bleeding episodes and perioperative management of bleeding in adults with von Willebrand disease (VWD).

Contraindications

Life-threatening hypersensitivity reactions to von Willebrand factor (recombinant), hamster or mouse proteins, or any component of the formulation

Dosage and Administration

Dosing: Adult

von Willebrand disease: IV: Note: Individualize dosage and frequency based on patient weight, type and severity of the bleeding episodes/surgical intervention, and monitoring of appropriate clinical and laboratory measures. If baseline factor VIII coagulation (FVIII:C) activity is <40% or is unknown, administer factor VIII with the first infusion of VWF (recombinant) to ensure hemostasis. If an immediate rise in FVIII:C activity is not necessary or if the baseline FVIII:C activity is sufficient to ensure hemostasis, VWF (recombinant) may be administered without factor VIII. When repeated VWF (recombinant) infusions are required, monitor FVIII:C activity to determine if factor VIII is also required. If target laboratory measures of VWF or FVIII activity (VWF:RCo and FVIII:C) are not attained or if bleeding persists, evaluate for the presence of VWF or factor VIII inhibitors.

On-demand treatment and control of bleeding episodes: Note: The initial dose of VWF (recombinant) should achieve >60% of VWF levels (based on VWF:RCo >60 units/dL), and a factor VIII infusion should achieve FVIII:C activity >40% (>40 units/dL). For major bleeding, if FVIII:C activity is unknown, administer factor VIII to achieve a target peak FVIII:C activity of 80 to 100 units/dL.

Minor hemorrhage (eg, epistaxis [readily managed], menorrhagia, oral bleeding): Initial: 40 to 50 units/kg; maintenance dose: 40 to 50 units/kg every 8 to 24 hours (as clinically required); adjust dose based on location and extent of bleeding.

Major hemorrhage (eg, CNS trauma, epistaxis [severe or refractory], GI bleeding, hemarthrosis, menorrhagia, traumatic hemorrhage): Initial: 50 to 80 units/kg; maintenance dose: 40 to 60 units/kg every 8 to 24 hours for ~2 to 3 days (as clinically required); adjust dose based on location and extent of bleeding. Maintain trough levels of VWF:RCo >50% as long as deemed necessary.

Perioperative management of bleeding:

Elective surgery: May assess FVIII:C and VWF:RCo activity 12 to 24 hours before surgery and administer VWF (recombinant) at that time to allow endogenous FVIII:C activity to increase to ≥30 units/dL for minor surgery or ≥60 units/dL for major surgery. Also assess FVIII:C activity within 3 hours prior to surgery. If FVIII:C activity is ≥30 units/dL (minor surgery) or ≥60 units/dL (major surgery), administer VWF (recombinant) alone within 1 hour prior to surgery. If the FVIII:C activity is below the recommended target levels, administer VWF (recombinant) followed by factor VIII within 10 minutes. Refer to calculation and table below for dose determination.

Emergency surgery: Baseline VWF:RCo and FVIII:C activity should be assessed within 3 hours prior to initiating the surgical procedure if feasible. The loading dose (1 hour preoperative dose) can be calculated as the difference in the target peak and baseline plasma VWF:RCo activity divided by the incremental recovery (IR). If the IR is not available, assume an IR of 2 units/dL per units/kg.

If baseline VWF:RCo and FVIII:C activity is not available, administer loading dose (1 hour preoperative dose) of VWF (recombinant) 40 to 60 units/kg. Factor VIII may be infused sequentially, preferably within 10 minutes after the VWF (recombinant) infusion in patients whose FVIII:C activity already are (or are highly likely to be) <40 to 50 units/dL (minor surgery) or <80 to 100 units/dL (major surgery).

Calculation of VWF (recombinant) dose to be given within 1 hour prior to surgery:

[Target peak plasma VWF:RCo activity – baseline plasma VWF:RCo activity] x BW (kg)/IR

Baseline plasma VWF:RCo = VWF:RCo activity assessed within 3 hours prior to administration of 12 to 24 hours preoperative dose of VWF (recombinant) or if no dose is administered 12 to 24 hours preoperatively, use the VWF:RCo activity prior to surgery. For patients who received an initial VWF (recombinant) dose 12 to 24 hours prior to surgery, the VWF:RCo activity attained prior to this dose may also be used to calculate the 1 hour pre-operative VWF (recombinant) dose. If baseline VWF:RCo activity is not available, administer a weight-based loading dose of 40 to 60 units/kg.

IR = may assume an IR of 2 units/dL per units/kg or calculate (if possible) as follows:

Measure baseline VWF:RCo, then administer VWF (recombinant) 50 units/kg and measure VWF:RCo 30 minutes after infusion and use the formula to calculate IR:

IR = VWF:RCo at 30 minutes (units/dL) – VWF:RCo at baseline (units/dL)/Dose (units/kg)

Table has been converted to the following text.

Recommended VWF:RCo and FVIII:C target peak plasma activity and body weight-based dosing for perioperative management of bleeding:

Body weight dosing may be used in the absence of baseline FVIII:C and VWF:RCO activity, and IR:

Minor surgery:

VWF:RCo dose of 25 to 30 units/kg, VWF:RCo target peak plasma activity of 50 to 60 units/dL

FVIII:C dose of 20 to 25 units/kg, FVIII:C target peak plasma activity of 40 to 50 units/dL

Major surgery:

VWF:RCo dose of 40 to 60 units/kg, VWF:RCo target peak plasma activity of 100 units/dL

FVIII:C dose of 40 to 50 units/kg, FVIII:C target peak plasma activity of 80 to 100 units/dL

Table has been converted to the following text.

Recommended VWF:RCo and FVIII:C target trough plasma activity and minimum duration of treatment for subsequent maintenance doses:

Minor surgery: Minimum duration of therapy is 48 hours:

VWF:RCo target trough plasma activity up to 72 hours post-surgery: ≥30 units/dL; redose every 12 to 24 hours to every other day

FVIII:C target trough plasma activity up to 72 hours post-surgery: >30 units/dL; redose every 12 to 24 hours to every other day

Major surgery: Minimum duration of therapy is 72 hours:

VWF:RCo target trough plasma activity up to 72 hours post-surgery: >50 units/dL; redose every 12 to 24 hours to every other day

VWF:RCo target trough plasma activity after 72 hours post-surgery: >30 units/dL; redose every 12 to 24 hours to every other day

FVIII:C target trough plasma activity up to 72 hours post-surgery: >50 units/dL; redose every 12 to 24 hours to every other day

FVIII:C target trough plasma activity after 72 hours post-surgery: >30 units/dL; redose every 12 to 24 hours to every other day

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Allow vial and diluent to warm to room temperature before reconstitution. After adding diluent, gently swirl vial or allow reconstituted product to sit for 5 minutes, and then gently swirl to ensure complete dissolution; do not shake. If the dose requires more than one vial, reconstitute each vial separately. Use plastic syringes; proteins in the product stick to the surface of glass syringes. Do not mix with any other medicinal products. See manufacturer’s product labeling for details.

Administration

IV: Infuse slowly (maximum rate: 4 mL/minute). If tachycardia occurs, slow infusion rate or interrupt administration. If also administering factor VIII, administer the complete dose of VWF (recombinant) followed by factor VIII within 10 minutes.

Storage

Intact vials may be stored refrigerated (2°C to 8°C [36°F to 46°F]) or at room temperature (≤30°C [≤86°F]) in original box; do not freeze. Protect from extreme exposure to light. Use reconstituted solution immediately; or may store at room temperature ≤25°C (≤77°F) for up to 3 hours. Do not refrigerate after reconstitution.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

1% to 10%:

Cardiovascular: Chest discomfort (1%), deep vein thrombosis (1%), hypertension (1%), inversion T wave on ECG (1%), tachycardia (1%)

Central nervous system: Dizziness (4%), vertigo (3%)

Dermatologic: Pruritus (3%)

Endocrine & metabolic: Hot flash (1%)

Gastrointestinal: Nausea (4%), vomiting (4%), dysgeusia (1%)

Immunologic: Antibody development (1%)

Local: Infusion site reaction (paresthesia; 1%)

Neuromuscular & skeletal: Tremor (1%)

Frequency not defined: Hypersensitivity: Hypersensitivity reaction

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, infusion related reaction

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Neutralizing antibodies (inhibitors) to von Willebrand factor (VWF) and/or factor VIII may occur. In patients who have high levels of inhibitors to VWF or factor VIII, therapy may not be effective and VWF (recombinant) use may lead severe hypersensitivity reactions; these patients should be managed by an experienced health care provider and alternatives to therapy should be considered. Any patient who has an inadequate response to therapy or a severe adverse reaction should be evaluated for the presence of inhibitors.
• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, may occur; discontinue if hypersensitivity reactions occur and administer appropriate treatment. Discontinue immediately if signs/symptoms of severe allergic reactions occur. Patients experiencing anaphylactic reactions should be evaluated for the presence of inhibitors.
• Thrombotic events: Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke may occur, especially in patients with known risk factors for thrombosis (including low ADAMTS13 levels). Risk is increased in patients requiring frequent doses of VWF (recombinant) in combination with factor VIII (recombinant), which may cause a sustained excessive rise in FVIII:C activity; monitor for signs and symptoms of thrombosis.

Dosage form specific issues:

• Mouse/hamster protein: Contains trace amounts of mouse and hamster proteins; hypersensitivity reactions may occur.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Monitoring Parameters

Plasma activity of VWF:RCo and FVIII:C (prior to, during, and after treatment; refer to manufacturer's labeling for details); development of VWF and/or factor VIII inhibitors; signs of bleeding; signs/symptoms of hypersensitivity reactions or thrombosis

Pregnancy

Pregnancy Considerations

Pregnant patients with von Willebrand disease may have an increased risk of bleeding following abortion, antenatal procedures, delivery, and miscarriage; close surveillance is recommended. Clotting factors should be monitored at the first antenatal visit, once or twice during the third trimester, at delivery, and prior to surgical or invasive procedures. Changes in von Willebrand factor levels may vary during pregnancy, depending on type. Factor replacement may be required during pregnancy if concentrations are <0.5 IU/mL to prevent maternal bleeding during procedures (including delivery) or if a spontaneous miscarriage occurs. Hemostatic concentrations should be maintained for at least 3 to 5 days following procedures or postpartum. Other agents may be preferred for the treatment of von Willebrand disease in pregnancy; however, when replacement therapy is needed, a recombinant product or a product made from a safe plasma source with viral testing that contains both factor VIII and von Willebrand factor is recommended (AGOG 580 2013; NHF 2018; RCOG [Pavord 2017]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience change in taste. Have patient report immediately to prescriber signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), dizziness, passing out, severe headache, vision changes, hot flashes, burning or numbness feeling, severe nausea, severe vomiting, severe loss of strength and energy, agitation, blurred vision, fast heartbeat, or twitching (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.