2.1 Dosage in von Willebrand Disease

The ratio between VWF:RCo and FVIII activities in Wilate is approximately 1:1.

The dosage should be adjusted according to the extent and location of the bleeding. In VWD type 3 patients, especially in those with gastro-intestinal (GI) bleedings, higher doses may be required.

2.2 Dosing Schedule

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

The careful control of replacement therapy is especially important in life-threatening hemorrhages. When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII activity.[ 1 ]

Table 1 Guide to Wilate Dosing for Treatment of Minor and Major Hemorrhages

*This may need to be continued for up to 3 days for minor hemorrhages and 5-7 days for major hemorrhages

Repeat doses are administered for as long as needed based upon repeat monitoring of appropriate clinical and laboratory measures.

Although dose can be estimated by the guidelines above, it is highly recommended that whenever possible, appropriate laboratory tests should be performed on the patient’s plasma at suitable intervals to assure that adequate VWF:RCo and FVIII activity levels have been reached and are maintained.

In the unlikely event that a patient who is actively bleeding should miss a dose, it may be appropriate to adopt a dosage depending on the level of coagulation factors measured, extent of the bleeding, and patient's clinical condition.

2.3 Administration

Wilate is administered via intravenous infusion. 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.

Instructions for Reconstitution:

	1) Warm the Powder and Diluent in the closed vials up to room temperature. This temperature should be maintained during reconstitution. If a water bath is used for warming, care must be taken to avoid water coming into contact with the rubber stoppers (latex-free) 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, carefully remove the outer package from the Mix2Vial™, being careful to leave 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.
	5) With both vials still attached, gently swirl the product vial to ensure the product is fully dissolved to a clear solution. Once the contents of the Wilate vial are completely dissolved, 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™.

• The powder should be reconstituted only directly before injection. As Wilate contains no preservatives, the solution should be used immediately after reconstitution.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• The filtered solution is clear or slightly opalescent, colourless or slightly yellow. If the concentrate fails to dissolve completely or an aggregate is formed, the preparation must not be used.

Instructions for Injection:

1. 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.
2. 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.
3. Clean the intended injection site with an alcohol swab.
4. Attach a suitable infusion needle to the syringe.
5. Inject the solution intravenously at a slow speed of 2-4 mL/minute.

• As a precautionary measure, the patient’s pulse rate should be measured before and during the injection. If a marked increase in the pulse rate occurs, the injection speed must be reduced or the administration must be interrupted.
• Any unused product or waste material should be disposed of in accordance with local requirements.

Incompatibilities

Wilate must not be mixed with other medicinal products or administered simultaneously with other intravenous preparation in the same infusion set.

5.1 Hypersensitivity

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed upon use of Wilate, and may in some cases progress to severe anaphylaxis (including shock) with or without fever.[ 2 ] Closely monitor patients receiving Wilate and carefully observe for any symptoms throughout the infusion period.

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, discontinue the administration immediately and contact the physician. Since inhibitor antibodies may occur concomitantly with anaphylactic reactions, patients experiencing an anaphylactic reaction should also be evaluated for the presence of inhibitors.[ 2 ]

5.2 Thromboembolic Risk

When using a FVIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII activity.[ 1 ] Monitor plasma levels of VWF:RCo and FVIII activities in patients receiving Wilate to avoid sustained excessive VWF and FVIII activity levels, which may increase the risk of thrombotic events.

5.3 Inhibitor Formation

Patients with VWD, especially type 3 patients, may potentially develop neutralizing antibodies (inhibitors) to VWF. If a patient develops inhibitor to VWF (or FVIII), the condition will manifest itself as 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, perform an appropriate assay to determine if a VWF inhibitor is present. In patients with antibodies against VWF, VWF is not effective and infusion of this protein may lead to severe adverse events. Consider other therapeutic options for such patients. Physicians with experience in the care of patients with hemostatic disorders should direct their management.[ 3 ] In all such cases, it is recommended that a center specialized in bleeding disorders be contacted.

Since inhibitor antibodies may occur concomitantly with anaphylactic reactions, patients experiencing an anaphylactic reaction should also be evaluated for the presence of inhibitors.[ 2 ]

5.4 Infection Risk from Human Plasma

Wilate is made from human plasma. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the variant Creutzfeldt-Jakob disease (vCJD) agent. There is also the possibility that unknown infectious agents may be present in such products. The risk that such products will transmit viruses has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses during manufacture. Despite these measures, such products may still potentially transmit disease. [ 4 ]

Record the batch number of the product every time Wilate is administered to a patient, and consider appropriate vaccination (against hepatitis A and B virus) of patients in regular/repeated receipt of Wilate. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Octapharma USA, Inc., telephone # 1-866-766-4860.

5.5 Monitoring and Laboratory Tests

Monitor plasma levels of VWF:RCo and FVIII activities in patients receiving Wilate to avoid sustained excessive VWF and FVIII 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 FVIII inhibitors. Perform assays to determine if VWF and/or FVIII inhibitor(s) is present if bleeding is not controlled with the expected dose of Wilate. [ 5 ]

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 the clinical trails of another drug and may not reflect the rates observed in clinical practice.

There were 92 VWD patients who received Wilate on 5676 occasions including clinical studies that involved prophylactic use, treatment on demand, surgery, and pharmacokinetics. Their safety data showed that the most common adverse reactions were urticaria and dizziness (each with 2 patients; 2.2%). There were also four patients (4.4%) who showed seroconversion for antibodies to parvovirus B19 not accompanied by clinical signs of disease. Seroconversion has not been reported since implementation of minipool testing of plasma used for the manufacture of Wilate.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during the post approval use of Wilate. 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 product exposure.

Post-marketing adverse reactions reported in patients treated for VWD include hypersensitivity reactions, dyspnea, nausea, vomiting, and cough.

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Wilate. It is also not known whether Wilate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Wilate should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery

Wilate has not been studied in labor or delivery. It should be administered to VWF-deficient women at labor or delivery only if clearly indicated. [ 6 ]

8.3 Nursing Mothers

Wilate has not been studied in lactating women.

8.4 Pediatric Use

Eleven pediatric patients with VWD between 5 to 16 years of age (8 type 3, 1 type 2, 2 type 1) were treated with Wilate for 234 bleeding episodes (BEs) in clinical studies. These studies showed that 88% of the BEs were treated successfully in this population ( Table 7 ). No dose adjustment is needed for pediatric patients as administered dosages were similar to those used in the adult population ( Table 8 ).

8.5 Geriatric Use

Although some of the patients who participated in the Wilate studies were over 65 years of age, the number of patients was inadequate to allow subgroup analysis to support recommendations in the geriatric population.

12.1 Mechanism of Action

VWF and FVIII are normal constituents of human plasma. VWF is a multimeric protein with two key functions. It is an adhesive molecule, which mediates the binding between platelets and damaged sub-endothelial tissues. It is also a carrier protein, involved in the transport and stabilization of FVIII. Patients suffering from VWD have a deficiency or abnormality of VWF. This reduction in VWF concentration in the bloodstream result in a correspondingly low FVIII activity and an abnormal platelet function thereby resulting in excessive bleeding. [ 8 ]

The VWF in Wilate is derived from normal human plasma and is expected to behave in the same way as endogenous VWF. Thus, administration of VWF allows correction of the hemostatic abnormalities in VWD patients at two levels:

• The VWF re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds both to the vascular sub-endothelium and to the platelet membrane), providing primary hemostasis, as shown by the shortening of the bleeding time. This effect occurs immediately.
• The VWF induces correction of the associated FVIII deficiency in VWD. Administered intravenously, VWF binds endogenous FVIII (which is produced normally by the patient), and by stabilizing this factor, avoids its rapid degradation. This action is slightly delayed. However, administration of a FVIII-containing VWF preparation like Wilate rapidly restores the FVIII activity level to normal.[ 8 ]

12.2 Pharmacodynamics

There have been no specific pharmacodynamic studies on Wilate.

12.3 Pharmacokinetics

An open label, prospective, randomized, controlled, two-arm cross-over Phase 2 study with Wilate and a comparator product was conducted at 6 sites in the US. In this study, pharmacokinetic (PK) profiles of Wilate were determined by FVIII activity, VWF:RCo, VWF:Ag, and VWF:CB.

Each of twenty-two subjects with inherited VWD [Type 1, n=6; Type 2, n=9 (6 Type 2A, 1 Type 2B, and 2 Type 2M); and Type 3, n=7] received an intravenous bolus dose of Wilate containing approximately 40 IU of VWF:RCo/kg BW. Twenty subjects completed the study as per protocol. PK parameters of VWF:RCo and FVIII are summarized in Table 3 and Table 4 , respectively.

Table 3 Pharmacokinetic Parameters of VWF:RCo:mean ± SD (range)

C max = peak concentration; AUC = area under curve; CL = clearance; Vss = volume of distribution at steady state; MRT = mean residence time

The PK parameters reported in Table 3 are based on VWF:RCo values obtained using a modified Behring Coagulation System (BCS) analytical method. The modified BCS was used because of its validated lower variability compared to the standard BCS. The measured concentrations (IU VWF:RCo/mL) are higher by the modified BCS than by the standard BCS analytical method which is used in some clinical laboratories. Dose adjusted C max and AUC determined by this modified BCS method are approximately 1.5 times higher than those by the standard BCS method. No difference has been found in incremental recovery.

Table 4 Pharmacokinetic Parameters of FVIII:C: mean ± SD (range) - chromogenic

C max = peak concentration; AUC = area under curve; CL = clearance; Vss = volume of distribution at steady state; MRT = mean residence time

Effect of age and VWD type on the pharmacokinetics of Wilate:

Due to small sample size (in age or VWD type subsets) and high PK variability, it is difficult to conclude if age or type of VWD had any impact on the pharmacokinetics of Wilate.

Effect of gender on the pharmacokinetics of Wilate:

Based on PK data of Wilate from 8 males and 12 females, it appears that the females (4.35 ± 1.54 mL/hr/kg) had higher clearance of VWF:RCo than the males (3.16 ± 1.19 mL/hr/kg). The clinical significance of this finding is not known.