VONVENDI (von Willebrand Factor (Recombinant)) kit

For intravenous use after reconstitution only.

• Each vial of VONVENDI is labeled with the actual amount of rVWF activity in International Units (IU), as measured with the Ristocetin cofactor assay (VWF:RCo).
• Individualize dosage and frequency according to the patient’s weight, type, location, and severity of the bleeding episodes/surgical intervention and monitoring of appropriate clinical and laboratory measures [see Warnings and Precautions (5.2, 5.3)] .
• If the patient's baseline plasma FVIII:C level is below 40%, or is unknown, administer an approved recombinant (non-von Willebrand factor containing) factor VIII (rFVIII) with the first infusion of VONVENDI to achieve a hemostatic plasma level of FVIII:C.
• If an immediate rise in FVIII:C is not necessary, administer VONVENDI without rFVIII. Depending on the patient’s baseline FVIII:C level, a single infusion of VONVENDI is expected to increase endogenous FVIII:C activity above 40% within 6 hours.
• See rFVIII package insert for reconstitution and administration instructions.
• When repeated infusions are required, monitor factor VIII levels to determine if rFVIII is required with subsequent infusions.

On-Demand Treatment and Control of Bleeding Episodes

• The recommended dose of VONVENDI is based on the type of bleeding episodes. Dosing guidelines for treatment of minor and major bleeds in adult and pediatric patients are provided in Table 1.

• The initial dose of VONVENDI should achieve greater than 60% of von Willebrand factor (VWF) levels (based on VWF:RCo greater than 60 IU/dL) and an infusion of rFVIII should achieve factor VIII levels greater than 40% (FVIII:C greater than 40 IU/dL). In major bleeding episodes, maintain trough levels of VWF:RCo greater than 50% for as long as deemed necessary.
• Administer VONVENDI with rFVIII if the FVIII:C level is less than 40%, or is unknown, to control bleeding. The rFVIII dose should be calculated according to the difference between the patient’s baseline plasma FVIII:C level, and the desired peak FVIII:C level to achieve an appropriate plasma FVIII:C level based on the approximate mean recovery of 2 (IU/dL)/(IU/kg).
• Administer the complete dose of VONVENDI followed by rFVIII within 10 minutes.

Perioperative Management of Bleeding

Routine Prophylaxis in Adults

For initiation of prophylactic treatment, administer 40 to 60 IU of VONVENDI per kg of body weight twice weekly. Treat breakthrough bleeding as per the dosing guidelines in Table 1.

• Allow VONVENDI and Sterile Water for Injection (diluent) to reach room temperature.
• If the patient requires more than one vial of VONVENDI per injection, reconstitute each vial according to the following instructions.
• Some flakes or particles may remain in the reconstituted vial. The filter included in the Mix2Vial device will remove extraneous flakes or particles, and 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.

For intravenous administration only.

• Administer VONVENDI immediately after reconstitution. If not, store at room temperature not to exceed 25°C (77°F) for up to 3 hours. Discard after 3 hours.
• No more than two vials of VONVENDI may be pooled into a single syringe. Pooling of more than two vials into a syringe may result in formation of filaments, which requires discarding of the solution in the syringe. If a patient is to receive more than one vial of VONVENDI, leave syringe attached to the vial or cover syringe tip with a suitable sterile cap until ready to infuse to reduce risk of contamination.
• Use plastic syringes with this product because proteins in the product tend to stick to the surface of glass syringes.
• Do not mix VONVENDI with other medicinal products.

Thromboembolic events have occurred with VONVENDI [see Adverse Reactions (6.1)]. These events can include disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. Patients with known risk factors for thrombosis, including low ADAMTS13 levels, are at a higher risk [see Description (11)]. Monitor patients for signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope. Institute prophylaxis measures against thromboembolism according to current clinical practice and standard of care.

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

Hypersensitivity reactions and infusion-related reactions have occurred with VONVENDI [see Adverse Reactions (6.1) . 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. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of VONVENDI and provide appropriate supportive care.

VONVENDI contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster proteins less than or equal to 2 ng/IU VONVENDI. Patients treated with this product may develop hypersensitivity reactions to non-human mammalian proteins.

Neutralizing antibodies to VWF and/or factor VIII can occur with VONVENDI. 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.

Monitor plasma levels of VWF:RCo and factor VIII activities in patients receiving VONVENDI to avoid sustained excessive VWF and/or factor VIII activity levels, which may increase the risk of thrombotic events, particularly in patients with known clinical or laboratory risk factors.

Monitor for development of VWF and/or factor VIII inhibitors when suspected. Perform appropriate inhibitor assays to determine if VWF and/or factor VIII inhibitors are present if bleeding is not controlled with the expected dose of VONVENDI.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data described in this section reflects exposure of VONVENDI in six clinical studies (Study 1, Study 2, Study 3, Study 4, Study 5 and Study 6) in patients with von Willebrand Disease (VWD). A total of 103 adult and 29 pediatric patients received intravenous infusion of VONVENDI with or without rFVIII with a median dose of 311 IU/kg per patient (range of 2 to 29593 IU/kg). The patients were followed for up to 4.6 years.

The most common adverse reactions observed in greater than or equal to 2% of patients in clinical trials with VONVENDI (n=132) were headache, vomiting, nausea, dizziness and generalized pruritus.

Table 5 lists the adverse reactions reported with VONVENDI from pooled safety population from six clinical studies.

The following adverse reactions have been identified during post-approval use of VONVENDI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity including anaphylactic reaction; Infusion related reaction.

Risk Summary

There is no information regarding the presence of VONVENDI in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VONVENDI and any potential adverse effects on the breastfed infant from VONVENDI or from the underlying maternal condition.

The safety and effectiveness of VONVENDI for on-demand treatment of bleeding episodes and perioperative management of bleeding have been established in pediatric patients. The use of VONVENDI was supported by evidence from Study 3 and Study 6 which included 26 pediatric patients 1 to 16 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)].

Clinical studies with VONVENDI included 4 (3%) patients aged 65 years and above. No overall differences in safety or effectiveness were observed between these and younger patients.

In VWD patients, VONVENDI acts 1) to promote hemostasis by mediating platelet adhesion to damaged vascular sub-endothelial matrix (e.g., collagen) and platelet aggregation, and 2) as a carrier protein for factor VIII, protecting it from rapid proteolysis. 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 receptors.¹ The binding capacity and affinity of VONVENDI to factor VIII in plasma is comparable to that of endogenous VWF, allowing for VONVENDI to reduce factor VIII clearance.

The PD of VWF following prophylactic treatment with VONVENDI in adults were investigated in a clinical trial (Study 5). In Prior OD adult patients, a single infusion of VONVENDI led to an increase of FVIII:C with peak levels observed approximately 24 hours post-infusion (mean [SD] dose: 50.1 [3.03] IU/kg). After 1-year repeat infusions of 50 ± 10 IU/kg VONVENDI twice weekly, the median (range) pre-dose FVIII:C increased from 2.0 (2.0 to 45.0) IU/dL (baseline after wash-out, N=12) to 11.0 (6.0 to 81.0) IU/dL (Month 12, N=9). The pre-dose FVIII:C (median [range] ≥11.0 [10.0 to 81.0] IU/dL) were observed over the prophylactic visits at Months 1, 2, 3, 6, 9 and 12. At Month 12, the median [range] C_max and AUC_{(0-96 hours)} of FVIII:C were 97.0 [63.0, 169.0] IU/dL and 5752 [2870, 11400] IU*h/dL (N=9), respectively.

The PD of VWF in 20 pediatric patients (aged less than 17 years) receiving on-demand therapy for bleeding episodes and treatment for surgical bleeds were evaluated using sparse sampling across three age groups (less than 6 years old, 6 years to less than 12 years old, and 12 years to less than 17 years old). Following a single infusion of VONVENDI at 50 (±5) IU/kg in pediatric patients, the median baseline corrected C_max and AUC_0-96 of FVIII:C were 64.5 IU/dL and 3379 IU*h/dL.

The PK profile of VONVENDI was determined based on data analyses from two clinical trials in adults (Studies 1 and 2) by assessment of VWF:RCo, VWF:Ag, and VWF:CB following a single dose. Patients were evaluated in the non-bleeding state.

Table 7 below summarizes the PK parameters of VONVENDI after infusions of 50 IU/kg (PK₅₀) or 80 IU/kg VWF:RCo (PK₈₀) VONVENDI in adult patients.

The PK of VWF following prophylactic treatment with VONVENDI in adults were investigated in a clinical trial (Study 5). Steady state PK parameters of VWF:RCo are presented in Table 8 for patients who were previously treated on-demand (OD) with any VWF product prior to study entry (Prior OD group) and patients who were previously treated prophylactically with a plasma derived VWF product (Switch group) prior to study enrollment. The pharmacokinetics of VWF following single and multiple dosing (at Month 12) were similar in the Prior OD group. The PK of VWF following multiple dosing (at 12 months) were similar between Prior OD and Switch groups.

The pharmacokinetics of VWF in pediatric patients with VWD were estimated based on PK modeling using sparse PK samples collected during a pediatric clinical trial (Study 3) across three age groups (less than 6 years old [N=5], 6 years to less than 12 years old [N=10], and 12 years to less than 17 years old [N=6]) receiving 50 ± 5 IU/kg rVWF:RCo VONVENDI (Table 9).

The immunogenicity of VONVENDI was assessed in clinical trials by assessing the development of neutralizing antibodies against VWF and FVIII, as well as binding antibodies against VWF, Furin, Chinese hamster ovary (CHO) protein and mouse IgG. Of the 132 patients who received VONVENDI in the clinical trials, one patient who was treated with VONVENDI perioperatively developed treatment-emergent binding antibodies against VWF following a surgery, for whom no adverse events or lack of hemostatic efficacy was reported. No binding antibodies against potential impurities such as rFurin, CHO-protein or mouse IgG developed after treatment with VONVENDI.

Two patients included in the surgery study had pre-existing high-titer specific binding antibodies against VWF. The high-titer binding anti-VWF antibodies were associated with a significantly decreased VWF:Ag activity post-infusion of either plasma derived VWF (pdVWF) or rVWF and consequently, the decreased activity of VWF:RCo, VWF:CB and FVIII:C. This finding indicates the potential clinical significance of pre-existing binding (non-neutralizing) antibodies: VWD patients previously treated with pdVWF concentrates may be at risk to express a pre-existing binding antibody against VWF prior to first exposure to rVWF which could potentially result in a decreased hemostatic response to rVWF. Such patients could be managed clinically by administration of higher doses of rVWF based on the PK data for each individual patient.

In vitro and in vivo genotoxicity studies indicated no mutagenic potential for VONVENDI. Long-term animal studies to assess the carcinogenic potential of VONVENDI were not performed. Animal studies evaluating the developmental and reproductive toxicity of VONVENDI were not conducted.

The efficacy of VONVENDI was evaluated in Study 1 (NCT00816660), Study 2 (NCT01410227), Study 3 (NCT02932618), Study 4 (NCT02283268), Study 5 (NCT02973087), and Study 6 (NCT03879135), as described below.

Study 1

This was a multicenter, single-blind, randomized, controlled, dose escalation study to evaluate the pharmacokinetics (PK), safety and tolerability of VONVENDI in patients with severe von Willebrand disease (VWD). The study enrolled patients with type 3 or severe type 1 VWD (VWF:RCo ≤10% and FVIII<20%), and who had a history of ≥25 days of exposure to VWF/FVIII factor concentrates.

A total of 31 patients received a single infusion of VONVENDI and rFVIII in a ratio of 1.3:1. VONVENDI was administered at a dose of either 2, 7.5, 20, or 50 IU/kg. The major outcome measures were PK parameters as described in section 12 above [see Clinical pharmacology (12.3)].

On-Demand Treatment and Control of Bleeding Episodes

Study 2 (Adults)

Hemostatic efficacy of VONVENDI was assessed in a multicenter, open-label trial investigating different dosing strategies with and without rFVIII (ADVATE) for on-demand treatment and control of bleeding episodes in adults diagnosed with von Willebrand disease. The study enrolled 37 patients who received treatment for on-demand treatment and control of bleeding episodes.

The demographic of the population were as follows: median age of 37 years (range 18 to 64), 20 patients (54%) were female, 32 patients (86%) were White, 5 patients (14%) were Asian and 2 patients (5%) were of Hispanic or Latino ethnicity. The types of VWD were as follows: Type 1 (n=2; 5%), Type 2A (n=5; 14%), Type 2N (n=1; 3%). and Type 3 (n=29; 78%).

Bleeding episodes were treated initially with an infusion of VONVENDI and ADVATE at a ratio of 1.3:1 respectively (i.e., 30% more VONVENDI than ADVATE), and subsequently with VONVENDI with or without ADVATE. ADVATE was given based on FVIII:C levels with a goal to achieve target plasma levels of greater than 40 IU/dL (40%) of FVIII:C.

A total of 192 bleeding episodes were treated with VONVENDI in 22/37 adult patients. The median cumulative dose of VONVENDI administered per bleeding episode (with or without ADVATE) was 48.2 IU/kg (90% CI, 43.9 to 50.2) IU/kg. The median number of VONVENDI infusions was 2 for major/severe (range: 1 to 3), 1 for moderate (range: 1 to 4), and 1 for minor bleeding episodes (range: 1 to 3). The median cumulative dose based on bleeding severity was 100 IU/kg (range, 57.5 to 135 IU/kg) for major (n=7), 52.7 IU/kg (range, 23.8 to 184.9 IU/kg) for moderate (n=61), and 43.3 IU/kg (range: 25.2 to 158.2 IU/kg) for minor bleeding episodes (n=122).

The primary efficacy endpoint was the number of patients with treatment success for control of bleeding episodes. Treatment success was defined as a mean efficacy rating score of less than 2.5 for all bleeding episodes treated with VONVENDI (with or without ADVATE) during the trial period, using a pre-specified 4-point rating scale comparing the prospectively estimated number of infusions needed to treat the bleeding episodes as assessed by the investigator to the actual number of infusions administered. The definitions for each of the 4-point rating scales are provided in Table 10.

Secondary efficacy measures were the number of treated bleeding episodes with an efficacy rating of “excellent” or “good”, the number of infusions and number of units of VONVENDI, administered with or without ADVATE, per bleeding episode.

The primary efficacy assessment excluded patients with GI bleeds (n=2), and patients in whom the number of infusions required per bleeding episode was estimated retrospectively (n=2). The rate of patients (n=18) with treatment success was 100% (95% CI, 81.5 to 100). Sensitivity analyses of treatment success for bleeding episodes including GI bleeds and those bleeding episodes for which the investigator had to make retrospective assessment of the number of infusions required (n=22: 17 with type 3 VWD, 4 with type 2A VWD and 1 with type 2N VWD) confirmed the primary analysis, with a 100% treatment success rate for each scenario.

All bleeding episodes treated with VONVENDI and ADVATE or VONVENDI alone received an efficacy rating of excellent (97%) or good (3%). This was consistent across all degrees of severity.

Table 11 summarizes data obtained for number of infusions and efficacy rating per bleeding episode by location. Bleeding episodes of “Other” location (n=37) are not included in the table.

Study 3 (Pediatrics)

Hemostatic efficacy of VONVENDI with or without ADVATE for on-demand treatment of non-surgical bleeding episodes was assessed in a multicenter, open-label trial in pediatric patients diagnosed with severe VWD. The study enrolled 18 patients who received treatment for on-demand bleeding episodes, including 3 patients who were 17 years old. The patients were followed for a duration of at least 12 months.

The demographics of the population were as follows: the median age was 11 years (range 1 to 17 years), 11 patients (61%) were female, 15 patients (94%) were White, 1 patient (6%) was of multiple races, and 1 patient (6%) was Hispanic or Latino. The types of VWD were as follows: Type 1 (n=2; 11%), Type 2A (n=3; 17%), Type 2B (n=2; 11%), and Type 3 (n=11; 61%).

A total of 28 bleeding episodes in 7 patients were treated with an initial dose of 40 to 60 IU/kg VONVENDI (median dose of 48 IU/kg; range 18 to 63 IU/kg) along with 30 to 45 IU/kg ADVATE (median dose of 33 IU/kg; range 9 to 45 IU/kg). A total of 76 bleeding episodes in 15 patients received an initial dose of 40 to 60 IU/kg VONVENDI (median dose 49 IU/kg; range 18 to 86 IU/kg) without ADVATE due to baseline FVIII level of at least 30%. In 8 patients, at least one additional dose of VONVENDI without ADVATE was administered in 18 bleeding episodes every 8 to 24 hours to maintain VWF:RCo and FVIII levels.

The primary efficacy endpoint was the number of patients with treatment success. Treatment success was defined as a mean efficacy rating score of less than 2.5 for all bleeding episodes using the pre-specified 4-point efficacy rating scale. Secondary efficacy outcome measures were assessed for each bleeding episode and included the number of treated nonsurgical bleeding episodes with an efficacy rating of “excellent” or “good”, the number of infusions, and VONVENDI and ADVATE consumption.

Table 12 summarizes efficacy rating and VONVENDI consumption by bleeding episode severity.

Table 13 summarizes efficacy rating by location of the bleeding episode.

Perioperative Management of Bleeding

Study 4 (Adults)

Hemostatic efficacy of VONVENDI was assessed in a prospective, open-label, multicenter trial to evaluate efficacy and safety of VONVENDI with or without ADVATE in elective surgical procedures in adults diagnosed with severe VWD and the patients were followed for 14 days after surgery. A total of 15 VWD patients completed the trial. Out of 15 patients, 10 underwent major surgeries and five underwent minor surgeries.

The demographics of the population were as follows: Median age was 40 (range, 20 to 70 years), 8 patients (53%) were female, 12 patients (80%) were White, 3 patients (20%) were Asian and 1 patient (7%) was Hispanic or Latino. The types of VWD were as follows: Type 1 (n=3; 20%), Type 2A (n=2; 13%), Type 2B (n=1; 7%), Type 2M (n=1; 7%) and Type 3 (n=8; 53%).

Major surgeries included orthopedic surgeries: total hip replacement, total knee replacement, knee endoprosthesis, ankle prosthesis, anterior cruciate ligament surgery and meniscectomy. Other major surgeries included laparoscopic cholecystectomy, laparoscopic cystectomy and complex dental extractions. Minor surgeries/procedures included nasopharyngoscopy, dental extractions, colonoscopy and radioisotope synovectomy.

All patients were administered a 12 to 24 hour preoperative dose of 40 to 60 IU/kg of VONVENDI to increase the factor VIII levels to target levels. Within 3 hours prior to surgery, the patients’ FVIII:C levels were assessed to ensure that target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries was achieved. Within 1 hour prior to surgery, patients received a dose of VONVENDI. ADVATE (recombinant Factor VIII) was administered based on FVIII:C levels performed 3 hours prior to surgery. VWF and factor VIII IR were used to guide the initial and subsequent doses.

The primary outcome measure was the overall hemostatic efficacy assessed 24 hours after the last perioperative VONVENDI infusion or at completion of study visit whichever occurred earlier using a 4-point ordinal efficacy scale outlined in Table 14 (“excellent”, “good”, “moderate” and “none”) based on estimated expected versus actual blood loss, transfusion requirements and postoperative bleeding and oozing. A rating of excellent or good was required to declare the outcome a success.

Overall hemostatic efficacy for major and minor surgeries was 100% (15/15) with a 90% confidence interval of 81.9% to 100%. It was excellent for 60% of surgeries and good for 40% of surgeries.

Intraoperative hemostatic efficacy was a secondary endpoint. For major and minor surgeries, it was 100% with a 90% confidence interval of 81.9% to 100%. It was excellent for 73% of surgeries and good for 27% of surgeries.

For details regarding hemostatic efficacy for minor and major surgery, see Table 15.

Dosing was individualized based on IR results performed before surgery.

Mean total 12 to 24 preoperative dose was 50.9 IU/kg (median 55.0 IU/kg; range, 36.1 to 59.9 IU/kg).

Mean total loading dose (1 hour preoperative dose) per infusion was 38.6 IU/kg (median 35.8 IU/kg; range, 8.0 to 82.7 IU/kg). Major surgeries required a mean loading dose of 42.8 IU/kg (median 37.6 IU/kg; range, 15.7 to 82.7 IU/kg) in comparison with a mean loading dose of 30.2 IU/kg (median 34.2 IU/kg; range, 8.0 to 46.4 IU/kg) for minor surgeries.

For patients treated with VONVENDI (with or without ADVATE), the median total postoperative dose within the first 7 days after surgery was 114.2 IU/kg with a range of 23.8 to 318.9 IU/kg (n=13) and 76.2 IU/kg with a range of 23.8 to 214.4 IU/kg for the next 7 postoperative days (n=8).

Study 3 (Pediatrics)

The multicenter, open-label pediatric trial (Study 3) also assessed the efficacy of VONVENDI with or without ADVATE in the management of surgical bleeding from elective and emergency surgeries in pediatric patients diagnosed with severe von Willebrand disease. A total of 4 patients completed the study. Four minor (three elective and one emergency) surgeries were treated with VONVENDI in these four patients, aged 6 to 12 years.

Of the 4 patients who underwent surgeries, 2 were 12 to <17 years, and 2 were 6 to <12 years, and no subjects were <6 years. Three were male subjects with one female undergoing emergency surgery. All patients were White and /non-Hispanic or Latino and 1 had Type 1 VWD and 3 had Type 3 VWD.

Minor surgeries included second stage buccal mucosa hypospadias reconstruction, tunneled central venous catheter with subcutaneous port removal (emergency surgery), and circumcision.

The mean dose of VONVENDI administered preoperatively and postoperatively during the 4 surgeries was 94 IU/kg (mean, 1.8 preoperative infusions) and 117 IU/kg (mean, 2.3 postoperative infusions), respectively. A total of 5 infusions of ADVATE were administered for one surgery in one patient. This patient received one preoperative infusion and 4 postoperative infusions.

All 4 surgeries had overall and intraoperative hemostatic efficacy ratings of “Excellent” (95% CI [39.8, 100.0]). The blood loss rating (actual versus predicted blood loss) was “Excellent” for all 4 surgeries.

Routine Prophylaxis to Reduce the Frequency of Bleeding Episodes

Study 5 (Adults)

VONVENDI was assessed in a prospective, single arm, open-label, international multicenter study (Study 5) to evaluate efficacy, safety, PK and PD of prophylactic treatment in reducing the frequency of bleeding episodes in adult patients (age 18 years and older) diagnosed with VWD. Patients were enrolled into two treatment arms based on the treatment they received for management of bleeding prior to study entry consisting of a Prior on-demand (OD) group in which patients received on-demand treatment only and the Switch group in which patients had received prophylactic treatment with pdVWF. Efficacy was assessed based on the annualized bleeding rate for all bleeds, spontaneous bleeds and joint bleeds and was based on descriptive statistics.

The study enrolled 23 patients who received prophylactic treatment. Twenty-two efficacy evaluable patients received a median of 92.5 doses, 12 of these patients had previously received on demand treatment (Prior OD group) and 10 patients previously received prophylactic treatment with pdVWF (Switch group) prior to enrolling into this study. Nine patients in the Prior OD group and 8 patients in the Switch group completed the study which required 12 months of treatment.

The demographic of the population is as follows: Median age of patients in the study was 34 years (18 - 77 years), 12 patients (55%) were male, 21 patients (95%) were White and 19 patients (86%) were non-Hispanic or Latino. Of the 12 patients in the Prior OD group, one had severe Type 1, one had severe Type 2 VWD, and ten had severe Type 3 VWD. Of the 10 patients in the Switch group, one had severe Type 1, one had severe Type 2 VWD, and eight had severe Type 3 VWD.

Patients in the Prior OD group began treatment at 50 ± 10 IU/kg per infusion twice weekly and in the Switch group, the initial VONVENDI prophylactic treatment was based on matching (±10%) VWF content of the patient’s prior pdVWF prophylaxis regimen. The initial prophylactic regimen for 80% of Switch patients was also twice weekly, except for 2 patients; one started with a once weekly regimen of 80 IU/kg/infusion and the other started with 3-times-per-week regimen of 60 IU/kg/infusion. Dose adjustments up to 80 IU/kg per infusion and/or higher frequency up to 3 infusions per week were allowed in cases of breakthrough bleeding episodes.

The mean (SD) [range] average weight-adjusted VONVENDI prophylaxis dose per infusion was 52.2 (3.8) [44.8, 58.8] IU/kg for Prior OD patients and 52.2 (16.2) [24.4, 79.4] IU/kg for Switch patients. The mean (SD) number of prophylaxis infusions per week were 1.88 (0.7) for Prior OD and 1.85 (0.4) for Switch patients.

For the Prior OD group, treatment success was defined as at least 25% reduction in the ABR for spontaneous bleeding episodes requiring factor treatment from the patient’s historical to the on-study period (reduction success). A total of 11/12 (91.7%) Prior OD patients achieved ABR reduction success.

For the Switch group, treatment success was defined as achieving an on-study ABR for spontaneous bleeding episodes requiring factor treatment that was no greater than the patient’s historical ABR for treated bleeding episodes (preservation success). A total of 9/10 (90%) Switch patients achieved preservation success.

The efficacy parameters of VONVENDI as prophylactic treatment in adult patients are provided in Table 16.

How Supplied

VONVENDI is packaged with Sterile Water for Injection (sWFI), one Mix2Vial reconstitution device, one full prescribing physician insert, and one patient insert.

VONVENDI is available in single-dose vials that contain the following product strengths:

The actual von Willebrand factor activity in international units is printed on the label of each VONVENDI vial and carton.

Components are not made with natural rubber latex.

Storage and Handling

• Store at refrigerated temperature 2°C to 8°C (36°F to 46°F) or room temperature not to exceed 30°C (86°F).
• Do not freeze.
• Store in the original box and protect from extreme exposure to light.
• Do not use beyond the expiration date printed on the VONVENDI vial label or carton.
• Do not use if the solution in the syringe is cloudy or contains flakes or particles after filtration from the vial into the syringe.
• Use reconstituted product immediately or within 3 hours after reconstitution.
• Discard any unused reconstituted product after 3 hours.