WILATE is indicated in children and adults with von Willebrand disease for:

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

WILATE is indicated in adolescents and adults with hemophilia A for:

• Routine prophylaxis to reduce the frequency of bleeding episodes
• On-demand treatment and control of bleeding episodes

For Intravenous Use after Reconstitution

2.1 Dose

• Initiate treatment under the supervision of a physician experienced in the treatment of coagulation disorders.
• Each vial of WILATE contains the labeled amount in International Units (IU) of von Willebrand factor (VWF) activity as measured with the Ristocetin cofactor assay (VWF:RCo), and coagulation factor VIII (FVIII) activity measured with the chromogenic substrate assay.
• The number of units of VWF:RCo and FVIII activities administered is expressed in IU, which is related to the current WHO standards for VWF and FVIII products. VWF:RCo and FVIII activities in plasma are expressed either as a percentage (relative to normal human plasma) or in IU (relative to the International Standards for VWF:RCo and FVIII activities in plasma). One IU of VWF:RCo activity is equivalent to the quantity of VWF:RCo in one mL of normal human plasma. One IU of FVIII activity is defined by the quantity of Factor VIII in one mL of normal human pooled plasma. The ratio between VWF:RCo and FVIII activities in WILATE is approximately 1:1.

VWD

• Calculate the required dosage of VWF:RCo, based on the empirical finding that 1 IU VWF:RCo per kg body weight raises the plasma VWF activity by approximately 2% of normal activity or 2 IU/dL, using the following formula:

• Adjust the dosage and frequency of administration according to the clinical effectiveness in the individual patient.

Dosing for Hemorrhages

A guide for dosing in the treatment of major and minor hemorrhages is provided in Table 1 .

Table 1 Dosing for Treatment of Minor and Major Hemorrhages in all VWD types

Type of Hemorrhages	VWF:RCo and FVIII Activity Trough Levels (% of normal)	Loading Dosage (IU VWF:RCo/kg body weight)	Maintenance Dosage (IU VWF:RCo/kg body weight)	Frequency of Doses (hours)	Duration of Therapy (days)
Minor	>30	20-40	20-30	Repeat as needed 12-24	Up to 3 days
Major	>50	40-60	20-40	Repeat as needed 12-24	Up to 5-7 days

• Adjust the dose according to the extent and location of bleeding and the patient’s clinical condition. In VWD type 3 patients, those with gastro-intestinal (GI) bleedings may require higher doses.
• Repeat doses as needed based upon repeat monitoring of appropriate clinical and laboratory measures.
• Perform appropriate laboratory tests on the patient’s plasma at suitable intervals to assure that adequate VWF:RCo and FVIII activity levels have been reached and are maintained.

Dosing for Surgeries

A guide for dosing in minor and major surgeries is provided in Table 2 .

Table 2 Dosing for Treatment in Minor and Major Surgeries in all VWD Types

Type of Surgery	Loading Dosage (IU VWF:RCo/kg body weight) (within 3 hours before surgery)	VWF:RCo Peak Levels (% of normal)	Maintenance Dosage (IU VWF:RCo/kg body weight)	VWF:RCo Trough Levels (% of normal)	Frequency of Doses (hours)	Duration of Therapy (days)
Minor (including tooth extraction)	30-60	50	15-30 or half the loading dose	>30	12-24	Until wound healing achieved, up to 3 days
Major	40-60	100	20-40 or half the loading dose	>50	12-24 (at least 2 doses within first 24 hours after the start of surgery)	Until wound healing achieved, up to 6 days or more

In order to decrease the risk of perioperative thrombosis, FVIII activity levels should not exceed 250%.

Whereas table 2 provides a dosing range that is expected to provide the desired peak levels of VWF:RCo, the following is an example on how to calculate the loading dose based on a patient’s individual IVR which is to be determined pre-surgery.

• Prior to surgery, measure incremental in vivo recovery (IVR) and assess baseline plasma VWF:RCo activity. The IVR for VWF:RCo provides the IU/dL rise per IU/kg body weight infused and can be measured and calculated as follows:
• Measure plasma VWF:RCo at baseline
• Infuse 60 IU VWF:RCo/kg of WILATE intravenously at time 0
• Measure plasma VWF:RCo at 30 minutes after the infusion

IVR = (Plasma VWF:RCo 30 min – Plasma VWF:RCo baseline )/60IU kg

• Calculation of the loading dose requires four values: the target peak plasma VWF:RCo level, the baseline VWF:RCo level, body weight (BW) in kilograms, and IVR. If the actual IVR calculation exceeds 2.5, use 2.5 to calculate the recommended loading dosing to avoid under-dosing. If IVR is not available, a standardized dose can be calculated based on an assumed VWF:RCo IVR of 2.0 U/dL per IU/kg of WILATE administered.

Example:

Assumption: Baseline VWF:RCo value = 10 IU/dL, and VWF:RCo target level = 100 IU/dL = Δ 90 IU/dL

Assumption: Patient’s weight = 75 kg, patient’s IVR = 1.8 (IU/dL)/(IU/kg)

When possible post surgery, perform appropriate laboratory tests on the patient’s plasma once a day after surgery to assure that adequate VWF:RCo and FVIII activity levels have been reached and are maintained. In order to decrease the risk of perioperative thrombosis, FVIII activity levels should not exceed 250%. [ 2 ]

Hemophilia A

• Calculation of the required dose of Factor VIII is based on the empirical finding that 1 IU Factor VIII per kg body weight raises the plasma Factor VIII activity by approximately 2% of normal activity or 2 IU/dL when assessed using the one stage clotting assay. Use the following formula to determine the required dose:

• Dose and duration of therapy depend on the patient’s weight, type and severity of hemorrhage, FVIII level, and presence of inhibitors.

Titrate dose and frequency to the patient’s clinical response, individual needs, severity of deficiency, severity of hemorrhage, desired FVIII level, and presence of inhibitor, and the patient’s clinical condition. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to WILATE.

Routine Prophylaxis

A guide for dosing WILATE for routine prophylaxis to reduce the frequency of bleeding is provided in Table 3 . Exact dosing should be defined by the patient’s clinical status and response.

Table 3 Dosing for Routine Prophylaxis

Patients	Recommended Dosage (IU/kg body weight)	Frequency of Infusions
Adolescents and adults	20-40 IU/kg	Every 2 to 3 days

Dosing for Hemorrhages

A guide for dosing in the treatment of hemorrhages is provided in Table 4 .

Table 4 Dosing for Treatment of Hemorrhages

Type of Hemorrhages	Recommended dosage (IU/kg body weight)	Frequency of Doses (hours)	Duration of Therapy (days)
Minor	30-40	Repeat every 12-24 hours	At least 1 day, until the hemorrhage has resolved
Moderate	30-40	Repeat every 12-24 hours	3 to 4 days or more, until the hemorrhage has resolved
Major	35-50	Repeat every 12-24 hours	3 to 4 days or more, until the hemorrhage has resolved
Life-threatening	35-50	Repeat every 8-24 hours	Until threat has resolved

• Monitoring parameters
• Monitor plasma FVIII levels periodically to evaluate individual patient response to the dosage regimen.
• If dosing studies have determined that a particular patient exhibits a lower/higher than expected response and shorter/longer half-life, adjust the dose and the frequency of dosing accordingly
• Failure to achieve the expected FVIII:C level or to control bleeding after an appropriately calculated dosage may be indicative of the development of an inhibitor (an antibody to FVIII:C). Quantitate the inhibitor level by appropriate laboratory procedures and document its presence. Treatment with WILATE in such cases must be individualized.

2.2 Preparation and Reconstitution

• WILATE is provided with a Mix2Vial TM transfer device for reconstitution of the freeze-dried powder in diluent, a 10 mL syringe, an infusion set and two alcohol swabs.
• Reconstitute the powder only directly before injection. Because WILATE contains no preservatives, use the solution immediately after reconstitution.

Instructions for Reconstitution:

	1) Warm the concentrate (WILATE) and Diluent in the closed vials up to room temperature. If a water bath is used for warming, avoid water contact with the rubber stoppers or the caps of the vials. The temperature of the water bath should not exceed +37°C (98°F). 2) Remove the caps from the concentrate (WILATE) vial and the diluent vial and clean the rubber stoppers with an alcohol swab.
	3) Peel away the lid of the outer package of the Mix2Vial™ transfer set. To maintain sterility, leave the Mix2Vial™ device in the clear outer packaging. Place the diluent vial on a level surface and hold the vial firmly. Take the Mix2Vial™ in its outer package and invert it over the diluent vial. Push the blue plastic cannula of the Mix2Vial™ firmly through the rubber stopper of the diluent vial (Fig. 1). While holding onto the diluent vial, remove the outer package from the Mix2Vial™, leaving the Mix2Vial™ attached firmly to the diluent vial (Fig. 2).
	4) With the concentrate (WILATE) vial held firmly on a level surface, quickly invert the diluent vial with the Mix2Vial™ attached and push the transparent plastic cannula end of the Mix2Vial™ firmly through the stopper of the concentrate (WILATE) vial (Fig. 3). The diluent will be drawn into the concentrate (WILATE) vial by the vacuum. With both vials still attached, immediately start swirling the concentrate (WILATE) vial to ensure the powder is fully saturated. A slight whirlpool is formed by swirling. In order to avoid foaming, please do not shake the vial.
	5) After 30 seconds, firmly hold both the transparent and blue parts of the Mix2Vial™. Unscrew the Mix2Vial™ into two separate pieces (Fig. 4) and discard the empty diluent vial and the blue part of the Mix2Vial™. Continue swirling until the powder in the WILATE vial has completely dissolved. This process may take several minutes. The final solution is clear or slightly opalescent, colorless or slightly yellow. If the concentrate fails to dissolve completely or an aggregate is formed, do not use the preparation.

WILATE is available as a sterile, lyophilized powder for reconstitution for intravenous injection, provided in the following nominal strengths per single-use vial:

• 500 IU VWF:RCo and 500 IU FVIII activities in 5 mL
• 1000 IU VWF:RCo and 1000 IU FVIII activities in 10 mL

WILATE is contraindicated in patients with known hypersensitivity reactions, including anaphylactic or severe systemic reactions, to human plasma-derived products, any ingredient in the formulation [see Description (11) ] , or components of the container.

The most common adverse reactions to treatment with WILATE (≥ 1%) in patients with VWD were hypersensitivity reactions, urticaria, and dizziness. The most common adverse reactions to treatment with WILATE (≥ 1%) in previously treated patients with hemophilia A was pyrexia (fever).

Seroconversions for antibodies to parvovirus B19 not accompanied by clinical signs of disease have been observed.

The most serious adverse reactions to treatment with WILATE in patients with VWD and hemophilia A are hypersensitivity reactions [see Warnings and Precautions ( 5.1 )].

WILATE is a human plasma-derived, sterile, purified, double virus inactivated von Willebrand Factor/Coagulation Factor VIII Complex. WILATE is supplied as a lyophilized powder for reconstitution for intravenous injection. The diluent for reconstitution of the lyophilized powder is Water for Injection with 0.1% Polysorbate 80.

WILATE contains no preservative. No albumin is added as a stabilizer. WILATE is labeled with the actual VWF:RCo and FVIII activities in IU per vial. The VWF activity (VWF:RCo) is determined using a manual agglutination method referenced to the current “WHO International Standard for von Willebrand Factor Concentrate”. The FVIII activity is determined using a chromogenic substrate assay referenced to the current “WHO International Standard for Human Coagulation Factor VIII Concentrate”. The assay methodologies are according to European Pharmacopoeia (Ph.Eur.). The resulting specific activity of WILATE is ≥ 60 IU VWF:RCo and ≥ 60 IU FVIII activities per mg of total protein.

The nominal composition of WILATE is as follows:

Von Willebrand Factor/Coagulation Factor VIII complex is the active ingredient in WILATE. It is derived from large pools of human plasma collected in U.S. plasma donation centers. All plasma donations are tested for viral markers in compliance with requirements of EU CPMP and FDA guidance. In addition, the limit for the titer of human parvovirus B19 DNA in the manufacturing pool is set not to exceed 10 4 IU/mL.

The product is manufactured from cryoprecipitate, which is reconstituted in a buffer and treated with aluminum hydroxide followed by two different chromatography steps, ultra- and diafiltration, and sterile filtration. The manufacturing process includes two virus inactivation steps, namely, treatment with an organic solvent/detergent (S/D) mixture, composed of tri-n-butyl phosphate (TNBP) and Octoxynol-9, and a terminal dry heat (TDH) treatment of the lyophilized product in final container [at +100°C (212°F) for 120 minutes at a specified residual moisture level of 0.7-1.6%]. In addition, the ion-exchange chromatography step utilized during WILATE manufacturing also removes some viruses [ 8 ]. The mean cumulative virus reduction factors of these steps are summarized in Table 5 .

Table 5 Virus Reduction During WILATE Manufacturing

na: not applicable

nd: not done (S/D reagents present)

HIV-1: Human Immunodeficiency Virus - 1

SBV: Sindbis Virus

BVDV: Bovine Viral Diarrhea Virus

PRV: Pseudorabies Virus

REO 3: Reovirus Type 3

HAV: Hepatitis A Virus

PPV: Porcine Parvovirus

VWD

Treatment of Bleeding Episodes

Clinical efficacy of WILATE in the control of bleeding in subjects with VWD was determined in four prospective, open-label, non-controlled clinical studies (excluding PK study). For inclusion in the studies, subjects had to have inherited VWD (any type) that did not respond to desmopressin acetate. Subjects aged ≥12 to ≤65 years were eligible to enter three of the four studies, and subjects aged ≥6 to ≤85 years were eligible for one study. Exclusion criteria included the administration of other plasma-derived or blood products or desmopressin acetate 15 days before study entry, administration of acetylsalicylic acid 7 days before study entry, symptomatic infection, past or present inhibitor activity (3 studies), and severe liver or kidney disease (3 studies). A total of 70 VWD subjects with a mean age of 37 years (range 5–77 years) were enrolled in the studies, of whom 37 were type 3 and 30 were male. The total number of exposure days to WILATE for all investigations across the four studies ranged from 202 to 4917 days. Treated BEs were analyzed for efficacy using a set of objective criteria in addition to a subjective 4-point hemostatic efficacy scale (excellent, good, moderate and none) which was determined at the discretion of the investigator. In assessing efficacy using the objective criteria, treatment of a bleeding episode was classified as a success when none of the criteria listed below were met:

• the episode was additionally treated with another VWF-containing product (excluding whole blood)
• the subject received a blood transfusion during the episode
• follow-up treatment with a daily dosage of WILATE that was greater than or equal to 50% (≥ 50%) above the initial dose (for bleeding episodes with more than 1 day of treatment)
• treatment duration of more than 4 days (> 4 days) in cases of severe bleeding (other than gastrointestinal)
• treatment duration of more than 3 days (> 3 days) in cases of moderate bleeding (other than gastrointestinal)
• treatment duration of more than 2 days (> 2 days) in cases of minor bleeding (other than gastrointestinal)
• the last efficacy rating of the bleeding episode was 'moderate' or 'none'

BEs treated with WILATE are summarized for all subjects (n=45) and subjects aged 5–16 years (n=11) in Table 9 . Among the 70 VWD subjects administered WILATE in clinical studies (excluding the PK study), 45 received on demand treatment for 1068 BEs. Using the above objective criteria, corresponding efficacy for each bleeding event was rated as being successful in 84% of the episodes. In these 45 subjects with BEs, 93% of the successfully treated BEs occurred in VWD type 3 subjects (n=25). In 11 pediatric subjects aged 5–16 years, efficacy was rated as being successful in 87.6% of BEs.

Table 9 Proportion of Successful Treatments of Bleeding Episodes with WILATE

*A “bleeding episode” may involve bleeding at multiple sites in this analysis.

Dosing information for 972 successfully treated “bleeding episodes” (1423 infusions), and 211 successfully treated bleeding episodes (289 infusions) in subjects aged 5–16 years, for regional bleeding is summarized in Table 10 . For the purpose of assigning success/failure to regional bleeding that occurred at the same time, bleeding at different sites over the same time span was counted as separate BEs. Thus, the number of these “episodes” is different from that in the overall evaluation for success/failure of WILATE in the treatment of BEs in Table 9 . The majority of BEs were treated for 1-3 days. In subjects with GI bleeds, the duration for product use to control bleeding was longer (up to 7 days).

Table 10 Administered Dosages (VWF:RCo in IU/kg) in Bleeding Episodes* Successfully Treated with WILATE: Mean ± SD (Range)

*For the purpose of this analysis, bleeding at each site is counted as a separate “episode”.

**“Other” includes mostly muscle bleeds, hematuria, ecchymosis, hematoma and other miscellaneous sites of bleeding.

Prevention of Bleeding in Surgery (Perioperative Management)

A prospective, open-label, single-arm, uncontrolled, multi-center clinical study was conducted to investigate the safety and hemostatic efficacy of WILATE in 28 subjects (19 female and 9 male) who underwent 30 surgeries. Two female subjects underwent 2 surgeries each. Subjects ranged in age from 12 to 74 years (median = 36). Three subjects were between 12 and 17 years old and 4 were 65 years or older. Six subjects had type 1 VWD, 1 had type 2A, 1 type 2B, and 20 had type 3 VWD. One type 1 and one type 3 subject had 2 surgeries each.

Twenty-one surgeries were classified as major (e.g. orthopedic joint replacement, cesarean section and vaginal deliveries, laminectomy, tonsillectomy, appendectomy, 3 rd molar extractions) and 9 were classified as minor (e.g. menisectomy, teeth extractions other than 3 rd molars, septoplasty, biopsy). Seven surgeries (3 major, 4 minor) were performed in type 1 VWD subjects, 2 surgeries (1 major, 1 minor) were performed in type 2 (A/B) VWD subjects, and 21 surgeries (17 major, 4 minor) were performed in type 3 VWD subjects. The types of surgery for the 9 minor procedures were: dental (n=5, 55.6%); orthopedic (n=2, 22.2%); ophthalmologic (n=1, 11.1%); and ear, nose and throat (n=1, 11.1%). The types of surgery for the 21 major procedures were: orthopedic (n=8, 38.1%); obstetric/gynecological (n=5, 23.8%); gastrointestinal (n=4, 19.0%); dental (n=2, 9.5%); and ear, nose and throat (n=2, 9.5%). The type of surgery according to VWD type were: VWD type 1 (n=7) – dental (n=4, 57.1%), orthopedic (n=2, 28.6%), and ear, nose and throat (n=1, 14.3%); VWD type 2 (A/B) (n=2) – orthopedic (n=1, 50%), and obstetric/gynecological (n=1, 50%); VWD type 3 (n=21) – orthopedic (n=7, 33.3%), gastrointestinal (n=4, 19.0%), obstetric/gynecological (n=4, 19.0%), dental (n=3, 14.3%), ear, nose and throat (n=2, 9.5%), and ophthalmologic (n=1, 4.8%).

Dosing was individualized based on in-vivo recovery results performed before surgery. Mean total loading dose per infusion was 51.4 IU/kg (median 52.1 IU/kg; range 27-77 IU/kg). Major surgeries required a mean loading dose of 54.7 IU/kg (median 55.5 IU/kg; range 36-69 IU/kg) in comparison with a mean loading dose of 41.9 IU/kg (median 37.5 IU/kg; range 27−77 IU/kg) for minor surgeries. Mean total maintenance dose per infusion was 28.5 IU/kg (median 28.5 IU/kg; range 8-63 IU/kg). Major surgeries required a mean maintenance infusion of 29.6 IU/kg (median 30 IU/kg; range 8-63 IU/kg) in comparison with a mean maintenance infusion of 21.6 IU/kg (median 20.6 IU/kg; range 14-38 IU/kg) for minor surgeries.

Efficacy of WILATE in surgical procedures was assessed by the surgeon at the conclusion of surgery and by the investigator-hematologist at 24 hours following completion of the final maintenance dose. Efficacy of WILATE was assessed using a stringent and objective 4-point ordinal efficacy scale (excellent, good, moderate, or none) based on estimated expected versus actual blood loss, transfusion requirements and post-operative bleeding and oozing. A rating of excellent or good was required to declare the outcome a success. An independent data monitoring committee (IDMC) additionally conducted an independent post hoc adjudication of intra- and post-operative assessments made by the surgeon/investigator-hematologist. In situations where the IDMC’s assessment differed from that of the surgeon and/or investigator-hematologist, the IDMC assessment took priority.

The overall efficacy of WILATE treatment for surgical procedures in this study was 96.7%. Treatment with WILATE was successful in all minor surgeries and in 95.2% of major surgeries ( Table 11 ). It was also successful in all surgical procedures in VWD type 3 and type 2 subjects and in 85.7% of procedures in VWD type 1 subjects ( Table 12 ). One failure was reported in a VWD type 1 subject undergoing lumbar laminectomy (major surgery) who experienced slightly greater blood loss (25 mL) than the expected maximum (20 mL).

Table 11 Hemostatic Efficacy Assessment by Severity of Surgery as Adjudicated by the IDMC (n=30)

CI = confidence interval; IDMC = Independent Data Monitoring Committee; n = number of surgeries; rate = overall success rate.

Table 12 Hemostatic Efficacy Assessment by Type of VWD as Adjudicated by the IDMC (n=30)

CI = confidence interval; IDMC = Independent Data Monitoring Committee; n = number of surgeries; rate = overall success rate; VWD = von Willebrand Disease.

In this study, actual blood loss (median) was lower than the expected maximal estimated blood loss in all types of surgeries. The actual blood loss was also lower than the average predicted blood loss in minor surgeries and equal in major surgeries ( Table 13 ).

Table 13 Expected and Actual Estimated Blood Loss during Surgery

Intra-operative transfusion was predicted in 5 subjects, but actually given in only 2. One subject received platelets intra-operatively for previously existing thrombocytopenia and one subject who underwent abdominal hysterectomy received one infusion of rejuvenated (in biochemical solution) packed red blood cells intra-operatively which was planned pre-surgery.

Three subjects received transfusions following surgery due to anemia and low hemoglobin values seen post-operatively.

Hemophilia A

Routine prophylaxis

The efficacy of WILATE in routine prophylaxis was evaluated in a prospective, open-label, multicenter clinical study in which adult subjects and pediatric subjects aged 12-15 years were treated during 6 months of prophylaxis with 20-40 IU/kg WILATE, mean dose 32 IU/kg. Within the group of 55 subjects, of which 50 adults and 5 pediatric subjects, there were 30 (54.6%) subjects with 0 bleeding episodes, 12 (21.8%) subjects with 1 bleeding episode, 4 (7.3%) subjects with 2 bleeding episodes, 4 (7.3%) subjects with 3 bleeding episodes, and 5 (9%) subjects with 5 or more bleeding episodes. Annualized bleeding rates for all bleeding episodes, treated and untreated, are summarized in Table 14 .

Table 14 Annualized Bleeding Rate in Adult and Pediatric Subjects under Prophylaxis

Treatment of bleeding episodes

The study presented above also provided data on the efficacy of WILATE in the treatment of bleeding episodes. The break-through bleeds were treated with WILATE doses adjusted to the severity of the bleed. Treatment efficacy was assessed by the patient (together with the investigator in case of on-site treatment) using the predefined criteria using an ordinal scale of excellent (abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection), good (definite pain relief and/or improvement in signs of bleeding within approximately 8–12 hours after an injection, requiring up to two injections for complete resolution), moderate (probable or slight beneficial effect within approximately 12 hours after the first injection, requiring more than two injections for complete resolution), or none (no improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution).

In the per protocol population (n=52), 57 bleeding episodes were treated with WILATE, of which 15 (26.3%) bleeding episodes were minor (e.g. early onset muscle and joint bleeds with no visible symptoms, such as little or no change in the range of motion of affected joint, mild restriction of mobility and activity, scrapes, superficial cuts, bruises, superficial mouth bleeds, and most nose bleeds), 32 (56.1%) were moderate (e.g. advanced soft tissue and muscle bleeds into the limbs, bleeding into the joint space, such as the elbow, knee, ankle, wrist, shoulder, hip, foot, or finger), 10 (17.5%) were major (e.g. complicated joint bleeds, bleeds of the pelvic muscles, eyes), and 0 (0%) were life-threatening (e.g. bleedings in the abdomen, digestive system or chest, central nervous system bleeds, bleedings in the area of the neck or throat or pharynx, or other major trauma). Forty-one bleeds (71.9%) were spontaneous and 16 (28.1%) were traumatic. Thirty-six bleeding episodes (63.2%) were managed with one WILATE injection, 12 (21.1%) were managed with two injections, 7 (12.3%) were managed with 3 injections, and 2 (3.6%) required more than 3 injections. The mean dose of WILATE per injection was 34 IU/kg. Treatment efficacy was judged as excellent for 16 (28.1%) bleeding episodes, good for 32 (56.1%) bleeding episodes and moderate for 9 (15.8%) bleeding episodes. Therefore, 84.2% of all bleeding episodes were treated successfully. The one bleeding episode in one subject younger than 16 years (bleeding in finger) was treated with a single injection of 62.81 IU/kg of WILATE with excellent efficacy (successful treatment).

Further efficacy data in the treatment of bleeding episodes is available from a pooled analysis of 37 subjects with hemophilia A included in 3 additional clinical studies. These subjects had at least 150 exposure days at the time of enrollment into the study and had been treated for at least 50 exposure days and 6 months in the study. The analysis encompassed 986 bleeding episodes, of which 936 (94.9%) were treated successfully.

1. Mannucci P.M.: Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002;88:378-379
2. Nichols WL, Hultin MB, et al. von Willebrand Disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14: 171-232
3. Mollison.P.L., Engelfriet C.P., Contreras M.: Some unfavourable effects of transfusion; in Klein H.G., Anstee D.J. (eds): Mollison's Blood Transfusion in Clinical Medicine. Blackwell Publishing, 2005, pp 666-700
4. Mannucci P.M., Federici A.B.: Antibodies to von Willebrand factor in von Willebrand disease; in Aledort L.M. (ed): Inhibitors to Coagulation Factors. New York, Plenum Press, 1995, pp 87-92
5. Kasper, C.K., Kipnis, S.A. Hepatitis and Clotting Factor Concentrates. JAMA 1972; 221:510
6. Biggs, R. Jaundice and Antibodies Directed Against Factors VIII and IX in Patients Treated for Haemophilia or Christmas Disease in the United Kingdom. Br J Haematol 1974; 26:313-329
7. Azzi A., Morfini M., Mannucci P.M.: The transfusion-associated transmission of parvovirus B19. Transfus.Med.Rev. 1999;13:194-204
8. Stadler M., et al. Characterisation of a novel high-purity, double virus inactivated von Willebrand Factor and Factor VIII concentrate (Wilate). Biologicals 2006; 34:281-288
9. Mannucci P.M.: Treatment of von Willebrand's disease. New England Journal of Medicine 2004;351:683-694

How Supplied

• WILATE is supplied in packages comprising of a single-dose vial of powder and a vial of diluent (Water for Injection with 0.1% Polysorbate 80), together with a Mix2Vial TM transfer device, a 10-mL syringe, an infusion set and two alcohol swabs.

• Each vial of WILATE contains the labeled amount of IU of VWF:RCo activity as measured using a manual agglutination method, and IU of FVIII activity measured with a chromogenic substrate assay.
• Components used in the packaging of WILATE are not made with natural rubber latex.

Storage and Handing

• Store WILATE for up to 36 months at +2°C to +8°C (36°F to 46°F) in the original containers to protect from light from the date of manufacture. Within this period, WILATE may be stored for a period of up to 6 months at room temperature (maximum of +25°C or 77°F). The starting date of room temperature storage should be clearly recorded on the product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earliest. Do not freeze.
• Do not use after the expiration date.
• Reconstitute the WILATE powder only directly before injection. Use the solution immediately after reconstitution and discard any remaining solution.

• Advise the patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic symptoms occur, advise patients to discontinue the administration immediately and contact their physician to administer appropriate emergency treatment [ see Warnings and Precautions ( 5.1 ) ].
• Inform patients that undergoing multiple treatments with WILATE may increase the risk of thrombotic events thereby requiring frequent monitoring of plasma VWF:RCo and FVIII activities. [ see Warnings and Precautions ( 5.2 ) ].
• Inform patients that there is a potential of developing inhibitors to VWF, leading to an inadequate clinical response. Thus, if the expected VWF activity plasma levels are not attained, or if bleeding is not controlled with an adequate dose or repeated dosing, contact the treating physician.[ 3 ] [ see Warnings and Precautions ( 5.3 ) ].
• Inform patients that despite procedures for screening donors and plasma as well as those for inactivation or removal of infectious agents, the possibility of transmitting infective agents with plasma-derived products cannot be totally excluded [ see Warnings and Precautions ( 5.4 ) ].

Manufactured by:

Octapharma Pharmazeutika Produktionsges.m.b.H.

Oberlaaer Strasse 235

A-1100 Vienna, Austria

U.S. License No. 1646

Distributed by:

Octapharma USA Inc.

121 River Street, 12th floor

Hoboken, NJ 07030

FDA-Approved Patient Labeling

Patient Information

WILATE

von Willebrand Factor/Coagulation Factor VIII Complex (Human)

Please read this Patient Information carefully before using WILATE and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is WILATE ?

WILATE is an injectable medicine that is used to treat bleeding in adults and children with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

WILATE is also used for the prevention of excessive bleeding during and after surgery in adults and children with VWD.

WILATE is further used routinely for the prevention of bleeding in adults and adolescents with hemophilia A and also to treat bleeding in these patients.

Who should not use WILATE ?

You should not use WILATE if you are allergic to von Willebrand Factor or Factor VIII or any of the other ingredients of WILATE.

What should I tell my healthcare provider before using WILATE ?

Talk to your healthcare provider about any medical conditions that you have or have had.

Tell your healthcare provider about all of the prescription and non-prescription medicines you take, including over-the-counter medicines, dietary supplements, or herbal medicines.

Tell your healthcare provider if you are pregnant or nursing because WILATE might not be right for you.

How should I use WILATE ?

You get WILATE as an infusion into your vein after reconstitution of the lyophilized powder by mixing it with the supplied 5 or 10 milliliter sterile solvent (Water for Injection with 0.1% Polysorbate) with the supplied transfer device (see instruction for reconstitution and injection of WILATE).

Your healthcare provider will instruct you on how to do reconstitutions and infusions using sterile technique on your own or with the help of a family member, and they may watch you give yourself the first dose of WILATE.

You must carefully follow your healthcare provider’s instructions regarding the dose and schedule for infusing WILATE so that your treatment will work the best that it can for you.

WILATE comes in different dosage strengths. The actual number of international units (IU) of von Willebrand Factor and Factor VIII in the vial will be imprinted on the label and box. Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider.

Contact your healthcare provider right away if bleeding is not controlled after using WILATE.

Talk to your healthcare provider before travelling. Plan to bring enough WILATE for your treatment during this time.

If you forget to use WILATE, do not inject a double dose to make up for the forgotten dose. Proceed with the next infusion as scheduled.

Do not stop using WILATE without consulting with your healthcare provider.

What are the possible side-effects of WILATE ?

Allergic reactions may occur. Call your healthcare provider or emergency department right away if you have any of the following symptoms: difficulty breathing, chest tightness, swelling of the face, rash or hives.

Because it is made from human blood, there is the risk that WILATE can potentially transmit disease or cause allergic reactions. Tell your healthcare provider if you have low-grade fever, rash, joint pain, nausea, vomiting, feeling tired, and yellowing of the skin.

Common side effects of WILATE are hypersensitivity reactions including urticaria (rash) dizziness, and testing positive for a common virus (parvovirus B19).

These are not all of the possible side effects from WILATE. Ask your healthcare provider for more information. You are encouraged to report side effects to Octapharma USA Inc. at 1-866-766-4860 or FDA at 1-800-FDA-1088.

Talk to your healthcare provider about any side-effect that bothers you or that does not go away.

How should I store WILATE ?

Keep WILATE in its original box to protect it from exposure to light. Do not freeze WILATE .

You can store WILATE for up to 36 months at +2°C to +8°C (36°F to 46°F) from date of manufacture. Within this period, WILATE may be stored for a period of up to 6 months at room temperature (maximum of +25°C or 77°F). Note on the carton the date which the product was removed from the refrigerator.

After storage at room temperature, the product must be used or discarded, and it must not be put back into the refrigerator.

Do not use WILATE after the expiration date printed on the vial.

Do not use WILATE if the reconstituted solution is cloudy, contains particles, or is not colorless.

Use WILATE immediately after mixing.

Dispose all materials, including any unused WILATE , in an appropriate container.

What else should I know about WILATE ?

Do not use WILATE for a medical condition for which it was not prescribed. Do not share WILATE with other people, even if they have the same diagnosis and symptoms that you have.

Resources at Octapharma available to patients

For more product information on WILATE, please visit www.wilateusa.com

For more information on patient assistance programs that are available to you, please contact the Octapharma Patient Support Center at 1-800-554-4440.

Manufactured by

Octapharma Pharmazeutika Produktionsges.m.b.H., Oberlaaer Strasse 235, A-1100 Vienna, Austria

U.S. License No. 1646

Distributed by

Octapharma USA, Inc., 121 River Street, 12 th floor, Hoboken, NJ 07030

wilate® is a registered trademark of Octapharma.

WILATE

von Willebrand Factor/Coagulation Factor VIII Complex (Human)

WILATE is supplied as a powder. Before it can be infused in your vein (intravenous injection), you must mix the powder with the supplied liquid diluent.

Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center.

Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using WILATE. If you are unsure of the procedures, please call you healthcare provider before using WILATE. Your healthcare provider will prescribe the dose that you should take.

Preparation and Reconstitution

• WILATE is provided with a Mix2Vial TM transfer device for reconstitution of the WILATE powder in diluent.
• Reconstitute the powder only directly before injection.
• Because WILATE contains no preservatives, use the solution immediately after reconstitution.

	1) Warm the WILATE and diluent vials in the closed vials up to room temperature. If a water bath is used for warming, avoid water contact with the rubber stoppers or the caps of the vials. The temperature of the water bath should not exceed +37°C (98°F). 2) Remove the caps from the WILATE vial and the diluent vial and clean the rubber stoppers with an alcohol swab.
	3) Peel away the lid of the outer package of the Mix2Vial™ transfer set. To maintain sterility, leave the Mix2Vial™ device in the clear outer packaging. Place the diluent vial on a level surface and hold the vial firmly. Take the Mix2Vial™ in its outer package and invert it over the diluent vial. Push the blue plastic cannula of the Mix2Vial™ firmly through the rubber stopper of the diluent vial (Fig. 1). While holding onto the diluent vial, remove the outer package from the Mix2Vial™, leaving the Mix2Vial™ attached firmly to the diluent vial (Fig. 2).
	4) With the WILATE vial held firmly on a level surface, quickly invert the diluent vial with the Mix2Vial™ attached and push the transparent plastic cannula end of the Mix2Vial™ firmly through the stopper of the WILATE vial (Fig. 3). The diluent will be drawn into the WILATE vial by the vacuum. With both vials still attached, immediately start swirling the concentrate (WILATE) vial to ensure the powder is fully saturated. A slight whirlpool is formed by swirling. In order to avoid foaming, please do not shake the vial.
	5) After 30 second, firmly hold both the transparent and blue parts of the Mix2Vial™. Unscrew the Mix2Vial™ into two separate pieces (Fig. 4) and discard the empty diluent vial and the blue part of the Mix2Vial™. Continue swirling until the powder in the WILATE vial has completely dissolved. This process may take several minutes. The final solution is clear or slightly opalescent, colorless or slightly yellow. If the concentrate fails to dissolve completely or an aggregate is formed, do not use the preparation.

Administration

For intravenous use after reconstitution only.

1. Inspect final solution visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2. Do not mix WILATE with other medicinal products or administer simultaneously with other intravenous preparation in the same infusion set.
3. With the WILATE vial still upright, attach a plastic disposable syringe to the Mix2Vial™ (transparent plastic part). Invert the system and draw the reconstituted WILATE into the syringe.
4. Once WILATE has been transferred into the syringe, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and detach the Mix2Vial™ from the syringe. Discard the Mix2Vial™ (transparent plastic part) and empty WILATE vial.
5. Clean the intended injection site with an alcohol swab.
6. Attach a suitable infusion needle to the syringe.
7. Measure the patient’s pulse rate before and during the injection. If a marked increase in the pulse rate occurs, reduce the injection speed or interrupt the administration.
8. Inject the solution intravenously at a slow speed of 2-4 mL/minute.
9. Dispose unused product or waste material in accordance with local requirements.

For more product information on WILATE, please visit www.wilateusa.com

Manufactured by

Octapharma Pharmazeutika Produktionsges.m.b.H., Oberlaaer Strasse 235, A-1100 Vienna, Austria

U.S. License No. 1646

Distributed by

Octapharma USA, Inc., 121 River Street, 12 th floor, Hoboken, NJ 07030

wilate® is a registered trademark of Octapharma.

Issued November 2019.

von Willebrand Factor/Coagulation Factor VIII Complex (Human)

Octapharma Pharmazeutika Produktionsges.m.b.H

500IU/5mL

NDC 68982-182-01

1000IU/10mL

NDC 68982-182-02