2.1 Recommended Dosage

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 clinical judgement and based on the subject's weight, type and severity of the bleeding episodes/surgical intervention and based on monitoring of appropriate clinical and laboratory measures.
• For patients experiencing bleeding, hemostasis cannot be ensured until factor VIII coagulation activity (FVIII:C) has reached 40 IU/deciliter (dL) (i.e., 40% of normal activity). 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 in order to achieve a hemostatic plasma level of FVIII:C. However, if an immediate rise in FVIII:C is not necessary or if the baseline FVIII:C level is sufficient to ensure hemostasis, administer VONVENDI without rFVIII.
• Depending on the patient's baseline FVIII:C level, a single infusion of VONVENDI is expected, in a majority of patients, to lead to an increase in endogenous FVIII:C activity above 40% within 6 hours.
• When repeated infusions are required, monitor factor VIII levels to determine if rFVIII is required with subsequent infusions.

2.2 Preparation and Reconstitution

• 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.

2.3 Administration

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.

5.1 Embolism and Thrombosis

Thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels [see Description (11)]. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and have prophylaxis measures against thromboembolism instituted according to current recommendations 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.

Of the 100 subjects treated with VONVENDI in clinical trials, one subject was diagnosed with deep vein thrombosis, which was revealed by imaging conducted as a part of the hospital's standard of care for high-risk patients, 3 days after total hip replacement surgery while receiving VONVENDI.

5.2 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. 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.

5.3 Neutralizing Antibodies

Neutralizing antibodies (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.

5.4 Monitoring Laboratory Tests

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.

6.1 Clinical Trials Experience

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 profile of VONVENDI was evaluated in five prospective, multicenter trials; four were conducted in subjects with VWD (n=100) and one was conducted in subjects with hemophilia A (n=12). The adverse drug reaction (ADR) terms listed below (Table 5) were assessed by the sponsor/company as having a plausible causal relationship to the study medication in three clinical trials (n=80) during which VONVENDI was used for PK assessment, on-demand treatment and perioperative management of bleeding episodes in patients undergoing surgery.

Single patient treated with Vonvendi in a clinical trial developed infusion-related reaction. This patient was previously exposed to Vonvendi without any symptoms. He developed chest discomfort and increased heart rate 3 minutes after the infusion was started. The patient was treated with supportive care and symptoms were resolved in 3 hours.

In the completed prophylaxis clinical study, twenty-two adult subjects of age 18 years and older receiving on-demand therapy or prophylactic therapy with plasma derived VWF prior to study entry received prophylactic treatment with VONVENDI during the study. The adverse drug reaction (ADR) terms are listed below (Table 6).

6.2 Postmarketing Experience

The following adverse drug reactions (ADR) 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.

Postmarketing ADRs reported in association with VONVENDI treatment include infusion-related reactions (IRR) which may be clinically manifested by symptoms such as tachycardia, flushing, rash, dyspnea, and blurred vision. In the postmarketing cases reported, the symptoms resolved, and the patients fully recovered within 4 hours after stopping the infusion.

Anaphylactic reaction has been reported with use of Vonvendi in the postmarketing setting.

6.3 Immunogenicity

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 100 subjects who received VONVENDI in the clinical trials, one subject 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 subjects included in the 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.

8.1 Pregnancy

8.2 Lactation

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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use

Clinical trials of VONVENDI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects.

12.1 Mechanism of Action

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.2

12.2 Pharmacodynamics

The PD of VWF following prophylactic treatment with VONVENDI were investigated in a clinical trial. In Prior OD adult subjects with Type 3 VWD, a single infusion of VONVENDI led to an increase of FVIII:C with peak levels observed approximately 24 hours post-infusion (mean [SD] dose: 50.2 [3.33] 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 4.0) IU/dL (baseline after wash-out, N=10) to 10.5 (6.0 to 31.0) IU/dL (Month 12, N=8). The pre-dose FVIII:C (median [range] ≥10.5 [1.0 to 148] IU/dL) were observed over the prophylactic visits at Months 1, 2, 3, 6, 9 and 12. At Month 12, the mean (SD) Cmax and AUC(0-96 hours) of FVIII:C were 106 (37.2) IU/dL and 5962 (2671) IU*h/dL (N=8), respectively.

12.3 Pharmacokinetics

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

Table 8 below summarizes the PK parameters of VONVENDI after infusions of 50 IU/kg (PK50) or 80 IU/kg VWF:RCo (PK80) VONVENDI.

The PK of VWF following prophylactic treatment with VONVENDI were investigated in a clinical trial. Steady state PK parameters of VWF:RCo are presented in Table 9 for subjects with Type 3 VWD who were previously treated on-demand (OD) with any VWF product prior to study entry (Prior OD group) and subjects 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

On-Demand Treatment and Control of Bleeding Episodes

Hemostatic efficacy of VONVENDI was assessed in a multicenter, open-label trial investigating different dosing strategies with and without rFVIII for on-demand treatment and control of bleeding episodes in adults (age 18 years and older) diagnosed with von Willebrand disease. In this trial, all subjects requiring rFVIII received ADVATE [Antihemophilic factor (recombinant)].

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, based on FVIII:C levels. The aim of the initial dose of VONVENDI with ADVATE was to achieve target plasma levels of greater than 60 IU/dL (60%) VWF:RCo and greater than 40 IU/dL (40%) of FVIII:C.

A total of 193 bleeding episodes were reported in 22/37 subjects exposed to VONVENDI for on-demand treatment. Demographic and baseline characteristics are listed in Table 10.

The primary efficacy endpoint was the number of subjects 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 in a subject treated with VONVENDI (with or without ADVATE) during the trial period. The efficacy rating was assessed 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 11.

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 subjects with GI bleeds (n=2), and subjects in whom the number of infusions to control a bleeding episode was estimated retrospectively (n=2). The rate of subjects (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 were controlled with an efficacy rating of excellent (96.9%) or good (3.1%). Control of bleeding episodes was consistent across all degrees of severity.

For an overview of hemostatic efficacy by bleeding severity and number of infusions required to treat a bleeding episode, refer to Table 12.

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. In relation to bleeding severity, the median cumulative dose to treat a bleeding episode was 43.3 (range, 25.2 to 158.2) IU/kg for minor bleeding episodes (n=122), 52.7 (range, 23.8 to 184.9) IU/kg for moderate bleeding episodes (n=61), 100 (range, 57.5 to 135) IU/kg for major bleeding episodes (n=7).

Table 13 summarizes data obtained for number of infusions and efficacy rating per bleeding episode by location.

Perioperative Management of Bleeding

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 (age 18 years and older) diagnosed with severe VWD and the subjects were followed for 14 days after surgery.

A total of 15 VWD subjects completed the trial and 93% of the subjects were less than 65 years old (range, 20 to 70 years), of whom 53.3% were females and 53% (8/15) were type 3 VWD patients. Out of 15 subjects, 10 subjects underwent major surgeries and five subjects underwent minor surgeries.

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 subjects 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 subjects' 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, subjects 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 Incremental recovery were used to guide the initial and subsequent doses.

Six of the 10 subjects undergoing major surgery received protocol-specified loading dose. It should be noted that the protocol-specified loading dose was based on VWF:RCo levels assessed prior to the 12 to 24 hour preoperative dose. Four of 10 subjects undergoing major surgery and four out of five subjects undergoing minor surgery received a loading dose of VONVENDI based on VWF:RCo assessed prior to loading dose and after administration of the 12 to 24 hour preoperative dose. Unlike the protocol-specified loading dose based on the levels assessed prior to the preoperative dose between 12 to 24 hours of the surgery, the loading doses in these eight subjects were calculated based on VWF:RCo levels after a preoperative dose, and were therefore lower doses than protocol-specified loading dose. No differences in safety or efficacy were noted between the two groups.

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 73.3% of surgeries and good for 26.7% of surgeries.

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

Dosing was individualized based on incremental recovery 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 subjects 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).

Routine Prophylaxis to Reduce the Frequency of Bleeding Episodes in Patients with Severe Type 3 VWD Receiving On-Demand Therapy

VONVENDI was studied in a prospective, single arm, open-label, international multicenter study to evaluate efficacy, safety, PK and pharmacodynamics (PD) of prophylactic treatment in reducing the frequency of bleeding episodes in adult subjects (age 18 years and older) diagnosed with VWD.

Subjects were enrolled into two treatment arms based on the treatment they received for management of bleeding prior to study entry consisting of a Prior OD group in which subjects received on-demand (OD) treatment only and the Switch group in which subjects had received prophylactic treatment with plasma derived VWF (pdVWF). Efficacy was assessed based on the median annualized bleeding rate for all bleeds, spontaneous bleeds and joint bleeds and was based on descriptive statistics.

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

Median age of subjects in the study was 34 years (18 - 77 years), 54.5% were male and 96% of subjects were white and 86.4% were non-Hispanic or Latino. Of the 12 subjects 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 subjects in the Switch group, one had severe Type 1, one had severe Type 2 VWD, and eight had severe Type 3 VWD.

Subjects in the Prior OD group began treatment at 50 ± 10 IU/kg per infusion twice weekly. One subject in the Prior OD group required dose adjustments for management of breakthrough bleeding. The majority of subjects (9/10) with Type 3 VWD in the Prior OD group received twice weekly dosing with Vonvendi and had a median maximum dose of 55.9 (IU/kg).

The study did not adequately demonstrate efficacy of Vonvendi as prophylactic treatment to reduce bleeding events in subjects with Type 3 VWD receiving prophylactic therapy prior to study entry (Switch group).

The efficacy parameters of Vonvendi as prophylactic treatment in subjects with Type 3 VWD receiving on-demand treatment prior to study entry is provided in Table 16. The median percentage change of ABRs from historical to on-study were: for all bleeds -54.7%, for spontaneous bleeds -75.9%, and for joint bleeds -100.0%.

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.