von Willebrand factor is recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes and perioperative management of bleeding in adults with von Willebrand disease as well as for routine prophylaxis to reduce the frequency of bleeding episodes in adults with severe Type 3 von Willebrand disease receiving on-demand therapy. During clinical trials, all bleeding episodes (n = 193) treated with von Willebrand factor alone or von Willebrand factor and factor VIII were controlled with an efficacy rating of excellent (96.9%) or good (3.1%). Most bleeds (81.8%) were resolved with a single infusion. During perioperative management, overall hemostatic efficacy 24 hours after the last perioperative infusion or at completion of study visit, whichever occurred earlier, for both major and minor surgeries was 100% (excellent 60% and good 40%). In subjects with Type 3 von Willebrand disease receiving on-demand treatment (n = 10), the median percentage change of annualized bleeding rates from historical to on-study were -54.7% for all bleeds, -75.9% for spontaneous bleeds, and -100% for joint bleeds. Thrombotic events can occur in patients receiving von Willebrand factor; monitor vWF:RCo and factor VIII activities.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-von Willebrand factor activity is expressed in International Units, as measured with the Ristocetin cofactor assay (vFW:RCo).
-The actual potency per vial of von Willebrand factor is stated on each vial.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Use plastic syringes with von Willebrand factor; proteins contained in the product may adhere to the surface of glass syringes.
-Do not mix von Willebrand factor with other medicinal products.
Intravenous Administration
Reconstitution
-Allow vials of concentrate and provided diluent to reach room temperature.
-Peel back the cover of the Mix2Vial transfer device and leave in the packaging.
-Place diluent vial on a flat surface and hold tightly; push the blue plastic cannula of the Mix2Vial firmly through the center of the stopper of the diluent vial. Carefully remove the clear package leaving the Mix2Vial firmly attached to the diluent vial.
-Hold the concentrate vial firmly on a level surface. Invert the diluent vial with Mix2Vial attached, and push the transparent plastic cannula end of the Mix2Vial firmly through the center of the stopper of the concentrate vial. The diluent will be drawn into the concentrate vial by vacuum.
-Gently swirl the vials, or allow the reconstituted product to sit for 5 minutes then gently swirl to ensure powder is fully dissolved. Do not shake.
-Unscrew the Mix2Vial into 2 separate pieces, and discard the empty diluent vial and the blue part of the Mix2Vial.
-Draw air into an empty, sterile disposable plastic syringe. The amount of air should be equal to the amount of reconstituted concentrate to be withdrawn from the vial.
-While the concentrate vial is upright, attach the syringe to the clear plastic connector by turning syringe clockwise, and inject air into the vial. Keep plunger pressed, and invert the system so the vial is on top. Draw the solution into the syringe by pulling back slowly on the plunger. Do not push and pull the solution back and forth between the syringe and vial.
-Detach the syringe from the Mix2Vial.
-Some flakes or particles may remain in the reconstituted vial; however, the filter included in the Mix2Vial device will remove foreign flakes or particles. The resulting solution in the syringe should be clear and colorless. Do not use the solution in the syringe if it is cloudy or contains flakes or particles after filtration from the vial into the syringe.
-The contents of up to 2 vials of von Willebrand factor may be drawn into a single syringe. When pushing air into the second vial of solution to be pooled into the syringe, position the vial and connect syringe so that the vial is on top.
-Storage: Administer immediately after reconstitution. May store at room temperature not to exceed 25 degrees C (77 degrees F) for up to 3 hours. Do not refrigerate.
Intermittent IV infusion
-Attach the syringe to a suitable infusion needle.
-Infuse at a maximum rate of 4 mL/minute. If tachycardia occurs, reduce the administration rate or interrupt administration.
-If the dose requires multiple syringes, attach and administer each additional syringe 1 at a time.
-If recombinant factor VIII is needed, administer the complete dose of von Willebrand factor followed by recombinant factor VIII within 10 minutes.
Antibody formation inhibiting von Willebrand factor or factor VIII may occur with the administration of von Willebrand factor replacement. If expected plasma concentrations of vWF activity (vWF:RCo) are not achieved, perform an appropriate assay to determine if inhibitors are present. In patients with high concentrations of inhibitors to vWF or factor VIII, von Willebrand factor therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Of 100 subjects receiving von Willebrand factor during clinical trials, 1 subject treated with von Willebrand factor perioperatively developed treatment-emergent binding antibodies against von Willebrand factor after surgery, with no adverse events or lack of hemostatic efficacy reported.
Dizziness (3.75%), vertigo (2.5%), dysgeusia (1.25%), and tremor (1.25%) were reported from completed clinical trials in pharmacokinetics, on-demand, and surgery patients with von Willebrand disease (n = 80). Headache (18.2%) was reported from completed prophylaxis clinical trials (n =22).
Hypertension (1.25%), sinus tachycardia (1.25%), heart rate increase (1.25%), and electrocardiogram T wave inversions (1.25%) were reported from completed clinical trials in pharmacokinetics, on-demand, and surgery patients with von Willebrand disease (n = 80). Supraventricular tachycardia (SVT) and ventricular extrasystoles were each reported in 4.5% of patients from completed prophylaxis clinical trials (n = 22). A single subject treated with von Willebrand factor for perioperative management of bleeding developed proximal deep vein thrombosis postoperatively. Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur in patients treated with von Willebrand factor. Institute prophylactic measures and monitor for early signs and symptoms of thrombosis (e.g., pain, swelling, discoloration, dyspnea, cough, hemoptysis, syncope).
An injection site reaction (infusion site paresthesias) was reported in 1 patient (1.25%) from completed clinical trials in pharmacokinetics, on-demand, and surgery patients with von Willebrand disease (n = 80). Injection site irritation (4.5%), purpura (4.5%), pruritic rash (4.5%), and arthralgia (13.6%) were reported from completed prophylaxis clinical trials (n = 22).
Hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, are possible with von Willebrand factor. These reactions can include anaphylactic shock, angioedema, generalized urticaria, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, chest tightness, wheezing, and acute respiratory distress. Discontinue von Willebrand factor immediately and provide appropriate supportive care if signs and symptoms of allergic reactions occur. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors. Generalized pruritus (2.5%), chest discomfort (1.25%), flushing (1.25%), nausea (3.75%), and vomiting (3.75%) were reported from completed clinical trials in pharmacokinetics, on-demand, and surgery patients with von Willebrand disease (n = 80). Infusion-related reactions, manifesting as tachycardia, flushing, rash, dyspnea, and blurred vision, have been reported in postmarketing experience with von Willebrand factor. During clinical trials, a single patient, who had previously received von Willebrand factor without any adverse sequelae, developed chest discomfort and increased heart rate 3 minutes after infusion initiation. The patient was treated with supportive care and symptoms resolved within 3 hours. In postmarketing cases reported, infusion-related reaction symptoms resolved, and the patients fully recovered within 4 hours of drug discontinuation.
Elevated hepatic enzymes, including increased ALT (9.1%) and increased AST (4.5%), and diarrhea (4.5%) were reported from completed prophylaxis clinical trials in patients with von Willebrand disease (n = 22).
Recombinant von Willebrand factor is contraindicated in patients who have had life-threatening hypersensitivity reactions to von Willebrand factor or any constituents of the product. Recombinant von Willebrand factor contains trace amounts of hamster and mouse proteins and is contraindicated in patients who have hamster protein hypersensitivity or murine protein hypersensitivity. Patients treated with this product may develop hypersensitivity reactions to nonhuman mammalian proteins. Recombinant von Willebrand factor is also contraindicated in patients who have a mannitol hypersensitivity or polysorbate 80 hypersensitivity, as it contains these excipients.
Neutralizing antibodies to von Willebrand factor and/or factor VIII may occur during therapy with von Willebrand factor. If plasma von Willebrand factor activity concentrations are not achieved, perform an appropriate assay to determine if von Willebrand factor inhibitors or factor VIII inhibitors are present. If inhibitors are present, consider other therapeutic options and direct the patient to a physician with experience in the care of either von Willebrand's disease or hemophilia A. In patients with high concentrations of inhibitors to factor VIII or von Willebrand factor, therapy with von Willebrand factor may be ineffective, and further infusion of the product may result in severe hypersensitivity reactions. Inhibitor antibodies can occur concomitantly with anaphylactic reactions; evaluate patients with anaphylactic reactions for the presence of inhibitors.
Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur in patients receiving von Willebrand factor, especially in patients with known risk factors for thromboembolic disease, including low ADAMTS13 concentrations. Institute prophylactic measures and monitor for early signs and symptoms of thrombosis (e.g., pain, swelling, discoloration, dyspnea, cough, hemoptysis, syncope). Monitor plasma concentrations of vWF:RCo and factor VIII activities to avoid sustained excessive activity concentrations, which may increase the risk of thrombotic events, especially in those with known risk factors.
It is unknown if von Willebrand factor can cause fetal harm when administered during pregnancy or if it can affect reproductive ability. There are no adequate or well-controlled studies in pregnant women, and animal reproductive studies have not been conducted with von Willebrand factor. Administer von Willebrand factor to a pregnant woman only if clearly needed.
There are no data on the presence of von Willebrand factor in human breast milk, its effects on the breast-fed infant, or its effects on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for von Willebrand factor and any potential adverse effects on the breast-fed infant from von Willebrand factor or the underlying maternal condition.
General dosing information:
-Individualize dose and frequency based on type and severity of bleed, the patient's clinical status, and the vWF activity concentration.
-For patients experiencing bleeding, hemostasis cannot be achieved unless the factor VIII activity (FVIII:C) is 40% of normal. If baseline FVIII:C is less than 40% or is unknown, administer recombinant factor VIII with the first infusion of von Willebrand factor. Calculate the recombinant factor VIII dose according to the difference between the patient's baseline FVIII:C concentration and the desired peak FVIII:C concentration to achieve an appropriate FVIII:C concentration based on the approximate mean recovery of 2 International Units/dL per International Units/kg.
-If an immediate rise in FVIII:C is not necessary or if baseline FVIII:C is sufficient to ensure hemostasis, administer von Willebrand factor without recombinant factor VIII.
-Depending on the patient's baseline FVIII:C, a single infusion of von Willebrand factor is expected to increase endogenous FVIII:C above 40% within 6 hours.
-When repeated infusions are required, monitor factor VIII concentrations to determine if recombinant factor VIII is required with subsequent von Willebrand factor infusions.
For the on-demand treatment and control of hemorrhage in patients with von Willebrand's disease:
NOTE: The initial dose should achieve more than 60% of vWF concentrations (based on vFW:RCo more than 60 International Units/dL), and an infusion of recombinant factor VIII should achieve factor VIII concentrations more than 40% (FVIII:C more than 40 International Units/dL).
-for the treatment of minor bleeding including readily managed epistaxis, oral bleeding, or menorrhagia:
Intravenous dosage:
Adults: 40 to 50 International Units/kg IV followed by 40 to 50 International Units/kg IV every 8 to 24 hours as clinically required.
-for the treatment of major bleeding including severe or refractory epistaxis, menorrhagia, GI bleeding, CNS trauma, hemarthrosis, or traumatic hemorrhage:
NOTE: For major bleeding, if FVIII: C activity is unknown, administer factor VIII to achieve a target peak FVIII:C activity of 80 to 100 International Units/dL.
Intravenous dosage:
Adults: 50 to 80 International Units/kg IV followed by 40 to 60 International Units/kg IV every 8 to 24 hours for approximately 2 to 3 days, as clinically required. Maintain vWF:RCo trough concentrations more than 50% for as long as necessary.
For the perioperative management of surgical bleeding (surgical bleeding prophylaxis) in patients with von Willebrand disease:
Intravenous dosage:
Adults: Calculate the recombinant von Willebrand factor (rVWF) loading dose to be administered IV 1 hour before surgery. The loading dose is calculated using the formula: Loading dose = [(Target VWF:RCo - Baseline VWF:RCo) x Weight] / IR. Baseline FVIII:C and VWF:RCo concentrations should be assessed within 3 hours of the procedure. When possible, determine the incremental recovery (IR) prior to the procedure. If the IR is unavailable, assume an IR of 2 International Units/dL per International Units/kg. To determine the IR, measure the baseline plasma VWF:RCo, infuse rVWF 50 International Units/kg IV, and measure plasma VWF:RCo 30 minutes after the infusion. The IR is calculated by using the formula: IR = (Plasma VWF:RCo at 30 minutes - Plasma VWF:RCo at baseline) / 50 International Units/kg. Additionally, recombinant factor VIII at a dose of 30 to 45 International Units/kg IV may be infused sequentially, preferably within 10 minutes after the rVWF infusion, in patients whose factor VIII plasma levels are (or are highly likely to be) less than 40 to 50 International Units/dL for minor surgery or 80 to 100 International Units/dL for major surgery.
TARGET PEAK CONCENTRATIONS: The recommended VWF:RCo target peak plasma level for minor and major surgery is 50 to 60 International Units/dL and 100 International Units/dL, respectively. The recommended FVIII:C target peak plasma level for minor and major surgery is 40 to 50 International Units/dL and 80 to 100 International Units/dL, respectively.
ALTERNATIVE DOSING IF BASELINE FVIII:C, VWF:RCo, and IR ARE UNAVAILALBE: The following doses are expected to attain desired target concentrations of VWF:RCo and FVIII:C. For minor surgery, give 25 to 30 International Units/kg IV of rVWF (plus 20 to 25 International Units/kg IV of recombinant Factor VIII) 1 hour before the procedure. For major surgery, give 40 to 60 International Units/kg IV of rVWF (plus 40 to 50 International Units/kg IV of recombinant factor VIII) 1 hour before the procedure.
12- to 24-HOUR PREOPERATIVE DOSE FOR ELECTIVE PROCEDURES: A preoperative dose may be administered 12 to 24 hours prior to surgery so that endogenous VIII levels are at least 30 International Units/dL (minor surgery) or 60 International Units/dL (major surgery) before the 1-hour preoperative dose of rVWF. Measure the FVIII:C concentration to determine need of 12 to 24 hour preoperative dose. Assess baseline VWF:RCo concentrations within 3 hours of the 12 to 24 hour preoperative dose.
POST-PROCEDURE: Monitor VWF:RCo and FVIII:C plasma levels starting 12 to 24 hours after surgery and at least every 24 hours in the perioperative period. Additional recombinant factor VIII may be required to attain the recommended FVIII:C target peak plasma levels. The frequency of further rVWF dosing should be individualized according to the pharmacokinetic results and intensity and duration of the hemostatic challenge and should range between twice daily and every 48 hours. The minimum duration of treatment for minor and major surgery is 48 hours and 72 hours, respectively.
For routine bleeding prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy:
Intravenous dosage:
Adults: 40 to 60 International Units/kg/dose IV twice weekly. Adjust dose if breakthrough bleeding occurs in joints or if severe bleeding occurs. Treat breakthrough bleeding. Max: 60 International Units/kg/dose IV twice weekly.
Maximum Dosage Limits:
-Adults
80 International Units/kg/dose IV.
-Geriatric
80 International Units/kg/dose IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with von Willebrand Factor products.
Recombinant von Willebrand factor promotes hemostasis in patients with von Willebrand disease by mediating platelet aggregation and platelet adhesion to damaged vascular sub-endothelial matrix (e.g., collagen). The adhesive activity of von Willebrand factor is dependent upon the size of its multimers; large multimers are the most effective in supporting interactions with collagen and platelet receptors. Recombinant von Willebrand factor contains ultra-large multimers in addition to all of the multimers found in plasma since it is not exposed to proteolysis during the manufacturing process. Additionally, von Willebrand factor is a carrier protein for factor VIII, protecting it from rapid proteolysis. The binding of recombinant von Willebrand factor to factor VIII is comparable to that of endogenous von Willebrand factor.
Recombinant von Willebrand factor is administered intravenously. Pharmacokinetic (PK) parameters were assessed after a single infusion of von Willebrand factor 50 International Units/kg or 80 International Units/kg in patients in the non-bleeding state. Sustained increase of factor VIII activity was seen by 6 hours after a single von Willebrand factor infusion. Mean PK parameters after administration of 50 International Units/kg with recombinant factor VIII were as follows: half-life = 19.3 hours; clearance (CL) = 0.04 dL/kg/hour; AUC = 1,541.4 hours x International Units/dL; incremental recovery (IR) = 1.7 International Units/dL per International Units/kg. Mean PK parameters after administration of 50 International Units/kg were as follows: half-life = 22.6 hours; CL = 0.02 dL/kg/hour; AUC = 2,105.4 hours x International Units/dL; IR = 1.9 International Units/dL per International Units/kg. Mean PK parameters after administration of 80 International Units/kg were as follows: half-life = 19.1 hours; CL = 0.03 dL/kg/hour; AUC = 2,939 hours x International Units/dL; IR = 2 International Units/dL per International Units/kg. Steady-state PK assessment of vWF:RCo at month 12 in patients previously treated on-demand with any von Willebrand product were as follows: half-life = 16.5 hours; clearance (CL) = 0.04 dL/kg/hour; AUC = 1,199 hours x International Units/dL; incremental recovery (IR) = 1.8 International Units/dL per International Units/kg. In those treated prophylactically with plasma-derived von Willebrand factor, PK parameters were as follows: half-life = 14.1 hours; clearance (CL) = 0.04 dL/kg/hour; AUC = 1,662 hours x International Units/dL; incremental recovery (IR) = 1.8 International Units/dL per International Units/kg. In clinical trials, peak FVIII:C concentrations were observed approximately 24 hours after a single infusion (mean dose: 50.2 International Units/kg). After 1 year of twice weekly infusions, pre-dose FVIII:C increased from 2 to 10.5 International Units/dL. The mean Cmax and AUC of FVIII:C were 106 International Units/dL and 5,962 hours x International/dL, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: none