Consumer medicine information

Biostate

Factor VIII; von Willebrand factor

BRAND INFORMATION

Brand name

Biostate

Active ingredient

Factor VIII; von Willebrand factor

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Biostate.

What is in this leaflet

This leaflet answers some common questions about Biostate®. It does not contain complete information about Biostate®.

It does not take the place of talking to your doctor.

If you have any concerns about using this medicine, please talk to your doctor. Follow your doctor’s advice even if it is different from what this leaflet says.

Please read this leaflet carefully and keep it for future reference.

The information in this leaflet is subject to change. Please check with your Haemophilia Treatment Centre if there is any new information about this medicine that you should know since you were last treated.

What Biostate® is used for

Biostate® contains FVIII and VWF in a purified and concentrated form. Both FVIII and VWF are blood proteins that are essential for normal blood clotting.

Biostate® is used in patients with von Willebrand Disease (VWD), a bleeding disorder resulting from low levels of VWF or abnormal VWF. Individuals with VWD tend to take longer than normal to form blood clots, and tend to bleed from the skin and mucous membranes such as the nose, mouth and intestines. Because VWF provides stability for the fragile FVIII protein in the blood, patients with VWD may also have low FVIII levels.

Biostate® is also used in patients with haemophilia A, a bleeding disorder, in which there are low levels of FVIII or abnormal FVIII. Individuals with low levels or abnormal FVIII have difficulty in forming blood clots, with these clots often taking longer than normal to be made. Sometimes the individual may bleed unexpectedly into their joints, muscles or internal organs.

Ask your Haemophilia Treatment Centre if you have any questions about why Biostate® has been prescribed for you.

Before you are given Biostate®

Tell your doctor if you:

  • have allergies to any medicines
  • are taking or using any other medicines. These include medicines bought from pharmacies, supermarkets and health food stores.
  • have any other medical conditions
  • are pregnant or breast-feeding
  • become pregnant during your treatment.

If you want further information, consult your doctor or Haemophilia Treatment Centre.

About blood products

Biostate® is manufactured from human plasma (the liquid component of blood) collected by Australian Red Cross Lifeblood. When products are made from human blood and injected into you, it is possible that viruses or other substances could be present in the product and cause an illness. These could be viruses such as hepatitis, human immunodeficiency virus (HIV), or parvovirus B19 and theoretically the Creutzfeldt-Jakob Disease (CJD) agent. There could also be other infectious agents some of which may not yet have been discovered.

To reduce the risk of this happening, strict controls are applied when selecting blood donors and donations. In addition, extra steps are taken when manufacturing this product. Biostate® is specially treated to remove and kill viruses. This special treatment is considered effective against certain viruses known as enveloped viruses (such as HIV and hepatitis B and C), and also the non-enveloped virus, hepatitis A. They may be of limited value against non-enveloped viruses such as parvovirus B19. Despite these safety measures, such products may still potentially transmit disease.

Vaccines are available against some of these viruses and your doctor will be able to help you decide whether it is worthwhile having any of those vaccines.

Please discuss the risks and benefits of Biostate® with your doctor.

How to use Biostate®

The dosage and administration of Biostate® must be carefully controlled. Your doctor will be responsible for determining what dose is appropriate to your condition.

Biostate® will usually be given in a hospital. Should your doctor decide that treatment at home is appropriate, your Haemophilia Treatment Centre will provide detailed instructions on how to use Biostate®.

The following procedures are given as a guide only:

Preparing Biostate® for administration

You will need one 5 mL Water for Injections vial for each 250 IU and 500 IU (100 IU/mL) vial of Biostate®, or one 10 mL Water for Injections vial for each 500 IU (50 IU/mL) and 1000 IU vial of Biostate®.

  1. Ensure you have all the required equipment to administer Biostate®.
  2. Allow the vials of Biostate® and Water for Injections to reach room temperature prior to use, which may take up to one hour. Do not warm the Water for Injections in hot water.
  3. Remove jewellery, watches, rings, etc.
  4. Wash hands with soap and water, dry with a clean towel.
  5. Select an appropriate work area with good lighting and a surface which can be cleaned (such as a kitchen table).
  6. Using a clean cloth or paper towel, clean the preparation area with methylated spirits.
  7. Gather the equipment to be used.

Equipment

  • One carton of Biostate® containing:
    - one vial of Biostate®
    - one vial of Water for Injections
    - one Mix2Vial™ filter transfer set.
    Check the expiry date of each item. Do not use if expired.
  • two alcohol wipes
  • sharps container
  • waste container for discarding biological material
  • plastic syringe(s)
  • adhesive tape
  • cotton balls
  • intravenous injection set
  • gloves.

Instructions for Biostate® reconstitution

Follow these steps to prepare the injection.

  1. Wash hands with soap and water, dry with a clean towel.
  2. Ensure Biostate® and Water for Injections are at room temperature.
  3. Remove flip top caps from Biostate® and Water for Injections vials.
  4. Wipe the rubber stoppers of both the Biostate® and Water for Injections vials with the alcohol wipes and allow to dry for two minutes. Do not leave the alcohol wipes resting on the stoppers. Do not touch the rubber stoppers with your fingers.
  5. Open the lid of the Mix2Vial™ packaging. If the seal of the lid is not intact or you have any other concerns about the integrity of the Mix2Vial™, do not use it but return it to your Haemophilia Treatment Centre or Australian Red Cross Lifeblood. Place the Water for Injections vial on a level surface and hold the vial firmly. Take the Mix2Vial™ together with the outer package, invert it and push the blue plastic cannula of the Mix2Vial™ firmly through the rubber stopper of the Water for Injections vial. See Figure 1, (5 mL Water for Injections vial is provided for 250 IU vial and 500 IU (100 IU/mL) vial and 10 mL Water for Injections vial is provided for 500 IU (50 IU/mL) vial and 1000 IU vial).

WFI = Water for Injections

  1. While holding onto the vial of Water for Injections, carefully remove the outer package from the Mix2Vial™, being careful to leave the Mix2Vial™ firmly attached to the vial of Water for Injections, see Figure 2. Make sure that you only remove the outer package and not the Mix2Vial™.
  2. With the Biostate® vial held firmly on a level surface, invert the Water for Injections with the Mix2Vial™ attached and push the transparent plastic cannula end of the Mix2Vial™ firmly through the stopper of the Biostate® vial, see Figure 3. The water will be drawn into the vial by the vacuum contained within the Biostate® vial. If water is not drawn into the vial, it means that there is no vacuum in the vial and the seal may be faulty. Do not use the product but return it to your Haemophilia Treatment Centre or Australian Red Cross Lifeblood.
    Note: The Mix2Vial™ is intended to filter the contents of a single vial of Biostate® only. If multiple vials of Biostate® are to be given, a separate Mix2Vial™ must be used for each vial.
  3. With the Water for Injections and Biostate® vials still attached to the Mix2Vial™, gently swirl (do not shake) the Biostate® vial until all of the product is dissolved. Ensure the contents of the vial are completely dissolved. If a clot or gel forms do not use the product but return it to your Haemophilia Treatment Centre or Australian Red Cross Lifeblood.
  4. Once the contents of the Biostate® vial are completely dissolved, firmly hold both the transparent and blue parts of the Mix2Vial™. Unscrew the Mix2Vial™ into two separate pieces, see Figure 4. Discard the empty Water for Injections vial with the blue part of the Mix2Vial™ still attached into an appropriate waste container.
  5. While the Biostate® vial is upright, attach a plastic disposable syringe to the transparent part of the Mix2Vial™. Invert the system and draw the Biostate® into the syringe by pulling the plunger back slowly.
  6. Once the Biostate® 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. Do not use the Mix2Vial™ for injection.
    Note: One large syringe may be used to withdraw Biostate® from multiple vials.
  7. Discard the empty vial of Biostate® with the transparent part of the Mix2Vial™ attached, into an appropriate waste container.

Use Biostate® as soon as you can after preparation. (Make sure it is used for one person on one occasion only). The solution must not be stored for longer than 8 hours and the infusion should be completed as soon as practicable, as Biostate® does not contain an antimicrobial preservative. Any unused portion remaining in the vial must be discarded appropriately.

Do not refrigerate Biostate® once it has been prepared.

Injection administration procedure guidelines

The injection is best given by following each of the steps outlined in turn.

Should any of the symptoms listed under ‘Side effects’ develop, stop the infusion immediately and contact your Haemophilia Treatment Centre.

  1. Apply tourniquet. Select injection site.
  2. Wash hands with soap and water, dry with a clean towel.
  3. Cleanse the skin area with an alcohol wipe, allow to dry.
  4. Put on gloves.
  5. Insert intravenous needle into vein.
  6. Secure needle with adhesive tape.
  7. Attach the syringe containing Biostate® to the intravenous needle.
  8. Gently pull back the plunger until the tubing is filled with blood.
  9. Release the tourniquet.
  10. Administer the Biostate® solution slowly (usually within 5 minutes, or as tolerated).
  11. Carefully remove adhesive tape.
  12. Carefully remove the intravenous needle with syringe attached and place directly into the sharps container.
  13. Apply pressure to the injection site using a cotton ball for one to two minutes. Apply dressing if necessary.
  14. Discard all used sharps into the sharps container, and dispose of the other used equipment appropriately.
  15. Wash hands with soap and water, dry with a clean towel.

Side effects

Along with their intended effects, medicines may cause some unwanted effects, which can sometimes be serious. Furthermore, individual patients may react differently to the same dose of the same medicine. This applies to Biostate®, although severe reactions after Biostate® injection are rare. Ask your Haemophilia Treatment Centre if you need more information.

Stop using this product immediately and contact your doctor if any of the following side effects occur:

  • headache
  • pain (such as back pain, joint pains and bone pains)
  • dizziness
  • anxiety
  • reddening of the face or neck
  • chest pain
  • sweating
  • feeling sick or vomiting
  • strange taste in the mouth
  • irritation of the vein used for infusion (which may include swelling, redness or tenderness)
  • shortness of breath or difficulty breathing.

Contact your doctor immediately if you experience any of these symptoms at any time:

  • fever
  • loss of appetite
  • extreme tiredness
  • abdominal pain
  • jaundice (yellow skin and eyes)
  • dark urine
  • joint pains
  • skin rashes.

Inhibitors

Treatment with factor VIII products such as Biostate® may sometimes lead to the formation of antibodies (inhibitors) which neutralise factor VIII and reduce the effectiveness of the treatment. Your doctor will monitor you for development of these inhibitors and if they suspect that an inhibitor is present, the level of inhibitor will be measured using the appropriate laboratory tests. In some patients, inhibitors can be successfully overcome with larger doses of factor VIII, but for some patients it may be necessary to switch to a different treatment.

Overdose

Cases of overdose have been observed. No severe adverse reactions were associated with these cases. The risk of thromboembolic events cannot be excluded in cases of major overdose, especially in patients with VWD. If you have any questions, consult your doctor.

Storing Biostate®

Store at 2°C to 8°C (Refrigerate. Do not freeze). Biostate® can be stored at 25°C or below for a single period of 6 months. The product must not be returned to refrigeration after storage at 25°C or below. Protect from light.

Do not use after the expiry date.

Further information

This is not all the information that is available on Biostate®. If you have any more questions or are not sure about anything, ask your Haemophilia Treatment Centre.

Product description

What it looks like

Biostate® is a white or pale yellow powder contained in a glass vial. Biostate® is registered in four presentations. Each pack size contains:

  1. 250 IU vial of Biostate® (with a FVIII concentration of 50 IU/mL and a VWF concentration of 120 IU/mL), 5 mL vial of Water for Injections, and a special filter transfer set called a Mix2Vial™.
  2. 500 IU vial of Biostate® (with a FVIII concentration of 50 IU/mL and a VWF concentration of 120 IU/mL), 10 mL vial of Water for Injections, and a special filter transfer set called a Mix2Vial™.
  3. 500 IU vial of Biostate®, (with a FVIII concentration of 100 IU/mL and a VWF concentration of 240 IU/mL), 5 mL vial of Water for Injections, and a special filter transfer set called a Mix2Vial™.
  4. 1000 IU vial of Biostate®, (with a FVIII concentration of 100 IU/mL and a VWF concentration of 240 IU/mL), 10 mL vial of Water for Injections, and a special filter transfer set called a Mix2Vial™.

Ingredients

Biostate® contains FVIII and VWF as the active ingredients. It also contains:

  • sucrose
  • sodium citrate dihydrate
  • sodium chloride
  • trometamol
  • calcium chloride dihydrate
  • sodium octanoate
  • human albumin
  • human plasma proteins.

This product is packaged in latex free materials.

Manufacturer

Biostate® is manufactured in Australia by:

CSL Behring (Australia) Pty Ltd
ABN 48 160 734 761
189–209 Camp Road
Broadmeadows VIC 3047
Australia

Distributor

Australian Red Cross Lifeblood

Date of revision

March 2020

Australian Register Numbers

250 IU FVIII/600 IU VWF:
AUST R 73032

500 IU FVIII/1200 IU VWF:
AUST R 79993

500 IU FVIII/1200 IU VWF:
AUST R 150648

1000 IU FVIII/2400 IU VWF:
AUST R 150657

® Registered trademark of CSL Limited

™ Mix2Vial is a trademark of West Pharmaceutical Services, Inc. or a subsidiary thereof

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Biostate

Active ingredient

Factor VIII; von Willebrand factor

Schedule

Unscheduled

 

Notes

Distributed by Australian Red Cross Lifeblood

1 Name of Medicine

Human coagulation factor VIII and human von Willebrand factor complex.

6.7 Physicochemical Properties

CAS number.

9001-27-8.

2 Qualitative and Quantitative Composition

Biostate is a high purity, sterile, powder for injection containing a human coagulation factor VIII (FVIII) and human von Willebrand factor (VWF) complex. Biostate is manufactured from human plasma collected by Australian Red Cross Lifeblood. The FVIII/VWF complex in Biostate is purified from cryoprecipitate using selective precipitation and size exclusion chromatography steps.

Von Willebrand factor (VWF).

Following reconstitution, 1 mL of Biostate contains:
Biostate 50 IU FVIII/mL: approximately 120 IU of human plasma derived VWF.
Biostate 100 IU FVIII/mL: approximately 240 IU of human plasma derived VWF.
The VWF activity of Biostate is determined using a VWF to platelet glycoprotein Ib binding activity assay (VWF:Ac). The VWF activity is expressed as international units (IU) and 1 IU VWF:Ac is equivalent to 1 IU VWF ristocetin cofactor (VWF:RCo) in accordance with the WHO standard. The specific VWF activity of the product prior to the addition of human albumin as a stabiliser is approximately 100 IU of VWF/mg protein.

Factor VIII (FVIII).

Following reconstitution, 1 mL of Biostate contains:
Biostate 50 IU FVIII/mL: approximately 50 IU of human plasma-derived coagulation FVIII.
Biostate 100 IU FVIII/mL: approximately 100 IU of human plasma-derived coagulation FVIII.
The FVIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The activity of FVIII is measured as FVIII coagulation activity (FVIII:C). The specific FVIII activity of Biostate prior to the addition of human albumin as a stabiliser is approximately 50 IU of FVIII/mg protein.
Biostate contains other proteins such as fibrinogen, fibronectin, immunoglobulins (IgA, IgM, IgG) and transforming growth factor-β (TGF-β), all of which are present at significantly lower levels than in normal plasma.
Biostate is available in two different concentrations (strengths) and in four different presentations as detailed in Table 1. The amount of VWF in the final product is dependent on the method of preparation of the cryoprecipitate, and this influences the VWF:FVIII ratio.
Biostate contains VWF and FVIII in a ratio of 2.4:1.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and diluent for solution for injection.
Powder: white or pale yellow.
Diluent: clear, colourless (WFI).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The Biostate FVIII/VWF complex consists of two different noncovalently bound proteins, FVIII and VWF. FVIII is an essential cofactor in activation of factor X leading ultimately to the formation of thrombin and fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilising carrier protein for the procoagulant protein FVIII.
Von Willebrand Disease (VWD) is an autosomally inherited congenital bleeding disorder in which there is a deficiency or dysfunction of VWF. A reduction in VWF concentration in the bloodstream results in low FVIII activity and abnormal platelet function, which may result in excessive bleeding. The VWF activity in Biostate exists in a 2.4:1 ratio with FVIII:C activity. Biostate has been demonstrated to contain the high molecular weight (HMW) multimers of VWF. HMW multimers are considered to be important for correcting the haemostatic defect in patients with VWD as they are important for platelet adhesion.
Haemophilia A is an X-linked recessive blood coagulation disorder. It is caused by reduced FVIII activity, through either insufficient or abnormal synthesis of the FVIII protein, which is required for the formation of blood clots. Activated FVIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Clinical trials.

A total of 221 subjects were exposed in the prospective clinical studies, including 147 subjects with haemophilia A and 74 subjects with VWD. Among these exposed subjects, 5 subjects with haemophilia A and 3 subjects with VWD were adolescents, (aged 12 to < 18 years), 36 subjects with haemophilia A (1 with high titre FVIII inhibitors was < 1 year old) and 18 subjects with VWD were paediatrics aged < 12 years.
In addition, efficacy and safety data in VWD subjects were collected in 2 published investigator-led studies that included 43 adult VWD subjects (Shortt 2007) and 43 adolescents and children (Howman 2011). Fifteen paediatric haemophilia A subjects, with FVIII inhibitors, treated for immune tolerance induction are reported in a published investigator-led retrospective chart review (Robertson 2014).

Von Willebrand disease.

Efficacy in the control of nonsurgical and surgical bleeding was assessed in 3 open-label non-controlled trials. A 4-point rating scale was used in all trials: none = no control of bleeding; moderate = moderate control of bleeding, other treatment also required; good = slight oozing, partial but adequate control of bleeding; excellent = haemostasis achieved.
In the first trial, with a focus on non-surgical bleeds (NSB), the haemostatic efficacy for 98.2% of 407 evaluable NSB were assessed by the investigator as excellent or good and 1.7% as moderate. During the study 8 subjects experienced 125 major NSBs, of which 7 were mucosal bleeds. The investigator's overall assessment was excellent for 1 and moderate for the other 6 major mucosal bleeds which were uterine bleeds; although for 4 of the later 6 bleeds the investigator had assessed efficacy as good on at least 1 day. Eight subjects in this trial were treated on demand for 12 months before being switched to a prophylaxis regimen. The total number of NSB events decreased from 306 (ranging from 18 to 82 per subject, on-demand) to 10 in 5 of the subjects during prophylaxis. The haemostatic efficacy of all events treated with Biostate was assessed by the investigator as excellent.
In the second trial the focus was on surgery. In 9 subjects undergoing 10 major surgical procedures, the efficacy was excellent or good in 10 (100%). In 11 patients undergoing 15 minor surgical procedures, haemostatic efficacy was excellent in 14 (93%) and good in 1 (7%). The mean dose to achieve haemostasis was 27 IU FVIII:C/kg/day for a median 2 days in non-surgical bleeding, 33 IU FVIII:C/kg/day for a median 2 days in minor surgery and 41 IU FVIII:C/kg/day for a median 7.5 days in major surgery.
In the third trial 12 paediatric subjects treated on demand experienced 96 NSB events which included 26 major events, 13 of which were mucosal bleeds. Haemostatic efficacy was assessed as excellent (45%) and good (55%) by the investigator for all of the NSB events evaluated. Three subjects in this group underwent 8 minor surgical procedures (all were dental). For a group of 4 paediatric subjects receiving prophylaxis treatment, 73 NSB events required treatment, however the haemostatic efficacy for these events was assessed by the investigator as excellent for 81% and good for the remaining 19% of events.
In a retrospective review of surgical bleeding in 43 adult patients undergoing 58 procedures, the haemostatic efficacy was excellent or good in 100% of procedures. Efficacy in the VWD type 3 patients (n = 5) was rated as excellent in 55%. The mean dose to achieve haemostasis was 29 IU FVIII:C/kg/day for a mean 2 days (range 1-4) in minor dental procedures and 5 days (range 1-13) in major surgery. There was some concomitant use of tranexamic acid and desmopressin.
In a second retrospective review in children and adolescents, 42 surgical events were treated: 10 major events in 10 subjects and 32 minor surgical events in 21 subjects. Four episodes of post-surgical bleeding events were also treated in 4 subjects, who had not received the product to prevent bleeding during the procedure. A total of 72 NSB events were treated: 46 mucocutaneous in 11 subjects and 26 musculoskeletal or soft tissue bleedings in 13 subjects. Only tranexamic acid was used as an adjunctive therapy in these subjects.
The haemostatic efficacy for all surgical events was excellent or good in approximately 90% of events (90% major and 91% of minor surgical events). Haemostatic efficacy for all NSB events was rated as excellent or good in 94% of events, and within type 3 VWD subjects in 98% of NSB events.
The mean daily dose was 51 IU FVIII/kg (range 13-151) for major surgery with a median treatment duration of 7 days (range 1-24) and 45 IU FVIII/kg (range 14-76) for minor surgery with a median treatment duration of 3 days (range 1-8). For NSB events, the mean daily dose was 45 IU FVIII/kg (range 16-192) with a median treatment duration of 1 day (range 1-13).
Efficacy and safety in acquired VWD has not been established.
Adverse reactions encountered during the clinical trials in VWD patients are included, see Section 4.8 Adverse Effects (Undesirable Effects).

Haemophilia A.

Efficacy in haemophilia A was assessed in 2 open-label, non-controlled trials.
In the first study in adult and adolescent subjects with haemophilia A, 81 subjects were treated with 77 subjects completing 6 months of treatment. Patients were treated either on demand (including the prevention of bleeding in relation to surgery) or as prophylaxis. Of 656 evaluable bleeding events, 96.4% were assessed as excellent or good, 3.5% as moderate and 0.2% as none (one event, no efficacy).
During the study, a total of 37 surgical events occurred in 20 subjects; 12 events were major and 25 minor. Investigator's assessment of haemostatic efficacy at discharge was reported as excellent for 8 major and 10 minor surgical events, and as good for 2 major surgical events.
In the second study in paediatric subjects < 12 years of age, 35 subjects were treated either on-demand or as prophylaxis, with 21 subjects completing at least 50 exposure days. In the on-demand group, all 318 evaluable bleeding events were assessed as excellent or good (24.2 and 75.8% respectively), including 98 (30.6%) major bleeds, 7 of which were mucosal. In the prophylaxis group 99.4% of the evaluable bleeding events (172) were assessed as excellent or good (1 event was moderate). Of the 85 major bleeding events (49.1%), none were mucosal. Five subjects in the prophylaxis group did not experience any bleeding event during treatment.
A total of 5 surgeries, 2 major and 3 minor, occurred during the study. The investigator's assessment of these events was reported as excellent for 2 (minor) surgeries and good for the remaining 3 surgeries.
The retrospective chart review of haemophilia A subjects with FVIII inhibitors describes exposure to high doses of Biostate.
Adverse reactions encountered during the clinical trials in haemophilia A patients are included, see Section 4.8 Adverse Effects (Undesirable Effects).
Efficacy and safety have not been studied in previously untreated patients.

5.2 Pharmacokinetic Properties

Von Willebrand factor.

The pharmacokinetics (PK) of the product have been evaluated in VWD patients in the nonbleeding state.
Based on a PK study with 12 subjects with VWD, the PK characteristics for VWF:RCo, VWF antigen (VWF:Ag) and VWF collagen binding (VWF:CB) in Table 5 were observed following a single intravenous infusion of 80 IU VWF:RCo/kg.
Peak plasma levels of VWF usually occur within a mean time of 18 minutes (median 15 minutes) after injection.
Similar results for both VWF and FVIII PK parameters were found when assessed after 6 months of treatment.
A population PK analysis which included PK data from both the adult subjects and a trial in paediatric subjects, indicated that dosing both populations on a 80 IU/kg basis provides similar concentrations for each of the VWF markers measured and found only body weight influences the PK of Biostate which supports the dosing of Biostate on an IU/kg basis.

Factor VIII.

The pharmacokinetics of the product have been evaluated in haemophilia A patients in the non-bleeding state.
Based on a PK study with 16 subjects with haemophilia A, the PK characteristics for FVIII:C in Table 6 were observed following a single intravenous infusion of 50 IU/kg.
Peak plasma levels of FVIII usually occur within a mean time of 49 minutes (median 30 minutes) after injection.
Similar PK results, including FVIII half-life, were found when PK parameters were assessed 6 months after the initial PK study. VWF PK parameters were not measured in the initial assessment or the repeat assessment after 6 months.

Paediatric population.

There were small differences in PK parameters, reduced exposure and increased clearance, observed between the paediatric age groups (< 6 years and 6-12 years) in both VWD and haemophilia A studies. The differences when compared with inherent subject variability are not expected to be clinically important.
The PK data in paediatric subjects are comparable to those observed in adult subjects.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with Biostate.

Carcinogenicity.

No carcinogenicity studies have been conducted with Biostate.

4 Clinical Particulars

4.1 Therapeutic Indications

Biostate is indicated for:
the prophylaxis and treatment of nonsurgical and surgical bleeding in patients with von Willebrand disease when desmopressin (DDAVP) treatment is ineffective or contraindicated;
the prophylaxis and treatment of nonsurgical and surgical bleeding associated with FVIII deficiency due to haemophilia A.

4.3 Contraindications

Biostate is contraindicated in individuals with a history of anaphylactic or severe systemic response to coagulation FVIII and/or VWF preparations. Also it is contraindicated in individuals with a known hypersensitivity to any of the product components.

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Allergic type hypersensitivity reactions are possible. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case of shock, the current medical standards for shock treatment should be observed.

Haemophilia A.

Inhibitors.

The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the FVIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma, using appropriate biological testing. The risk of developing inhibitors is correlated to the exposure to antihaemophilic FVIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.
In general, all patients treated with coagulation FVIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected FVIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for FVIII inhibitor presence should be performed. In patients with high levels of inhibitor, FVIII therapy may not be effective and other therapeutic options should be considered. The management of such patients should be directed by physicians with experience in the care of haemophilia A patients and those with FVIII inhibitors.

Von Willebrand disease.

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors. Therefore, patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous thromboembolism should be instituted for patients at risk according to the current medical standards.
When using a FVIII containing VWF product, continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII containing VWF products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels which may increase the risk of thrombotic events, and antithrombotic measures should be considered.
Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, therapy may not only be ineffective but also lead to anaphylactoid reactions and other therapeutic options should be considered.

Pathogen safety.

This product is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically Creutzfeldt-Jakob Disease (CJD) agents that can cause disease.
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/ removal of viruses.
The manufacturing process includes solvent detergent (tri-n-butyl phosphate and polysorbate 80) and dry heat treatment (80°C for 72 hours) as dedicated virus inactivation steps to reduce the theoretical risk of virus transmission. The solvent detergent, dry heat treatment, and partitioning steps used in the manufacture of Biostate have been demonstrated to be effective virus inactivation/removal steps in vitro for the relevant viruses, human immunodeficiency virus (HIV) and hepatitis A virus (HAV), and also with models for hepatitis B virus (HBV) and hepatitis C virus (HCV). The manufacturing process also contributes to inactivation/removal of human parvovirus B19 (B19).
Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the nonenveloped virus HAV. The measures taken may be of limited value against nonenveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be serious for pregnant women and for individuals with immunodeficiency or increased erythropoiesis.
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/ repeated receipt of human plasma-derived products.
It is strongly recommended that every time that Biostate is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Use in the elderly.

The safety of this product for use in the elderly population has not been established in appropriate studies.

Paediatric use.

The listed warnings and precautions apply both to adults and paediatrics.

Effects on laboratory tests.

FVIII and/or VWF are endogenous plasma proteins therefore no specific effects on laboratory tests are anticipated.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction of VWF and FVIII with other medicinal products has not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal reproduction studies have not been conducted with Biostate.

Von Willebrand disease.

Experience in the treatment of pregnant or breast feeding women is not available. Biostate should be administered to pregnant or breast feeding VWF deficient women only if clearly indicated, taking into consideration that delivery confers an increased risk of haemorrhagic events in these patients.

Haemophilia A.

Based on the rare occurrence of haemophilia A in women, experience regarding the treatment during pregnancy and breast feeding is not available.
Therefore, Biostate should be used during pregnancy and breast feeding only if clearly indicated.
See Use in pregnancy.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions presented in Table 4 are based on experience from clinical trials and postmarketing experience from patients with haemophilia A and VWD.
The following standard categories of frequency are used where data are available: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000; not known: frequency cannot be estimated from the available data.

Description of selected adverse reactions.

FVIII inhibition.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to FVIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response.

VWF inhibition.

Patients with VWD, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and may occur concomitantly to anaphylactic reactions. Therefore, patients experiencing an anaphylactic reaction should be evaluated for the presence of an inhibitor.

Hypersensitivity (allergic reactions).

Includes angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing have been observed on occasion, and may in some cases progress to severe anaphylaxis (including shock).

Thromboembolic events.

In patients with VWD, there is a risk of occurrence of thromboembolic events, particularly in patients with known clinical or laboratory risk factors. In patients receiving FVIII containing VWF products, sustained excessive FVIII:C plasma levels may increase the risk of thromboembolic events.
For safety with respect to transmissible agents, see Section 4.4 Special Warnings and Precautions for Use.

Paediatric population.

Frequency, type and severity of adverse reactions in the haemophilia A paediatric population is expected to be the same as in that observed in the adult population.
Frequency, type and severity of adverse reactions in the von Willebrand paediatric population is expected to be the same as in that observed in the adult population.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit/ risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

It is recommended that prescribed doses of Biostate should be expressed as International Units written in full.
The dosage recommendations provided are general guidelines for therapy. The exact loading and maintenance doses and dosing intervals should be based on the patient's clinical condition and response to therapy. Laboratory tests should be performed to ensure that the desired plasma FVIII and VWF concentrations are achieved.
The active ingredients, VWF and FVIII are present in a ratio of 2.4:1.

Von Willebrand disease population.

Provided in Table 2 are VWD dosage guidelines for patients with severe VWD (< 10% normal VWF). In patients with less severe VWF deficiency, doses may need to be adjusted down to achieve the desired serum plasma concentrations. It is recommended that plasma VWF and FVIII concentrations are determined at suitable time intervals.
In young patients or patients with gastrointestinal bleeds or menorrhagia, shorter dose intervals or higher doses may be necessary. The clinical status of the individual patient, as well as their VWF:RCo and FVIII:C plasma levels, should be taken into consideration in determining the dose and duration of treatment.

Paediatric VWD population.

Based on results from a clinical trial in paediatric patients under 12 years of age to achieve haemostasis, a prophylactic dose range of 40-80 IU VWF:Ac/kg body weight (equivalent to VWF:RCo) 1 to 3 times a week should be considered.

Haemophilia A population.

Provided in Table 3 are dosage guidelines for patients with Haemophilia A.

Paediatric haemophilia A population.

Dosing in haemophilia A in children (< 12 years of age) and adolescents (12 to < 18 years of age) is based on body weight and is therefore generally based on the same guidelines as for adults. In some cases shorter dose intervals or higher doses may be necessary. The frequency of administration should always be oriented to the clinical effectiveness in the individual case.

Continuous infusion.

Studies using continuous infusion have not been carried out in patients. However, it is suggested that this method is suitable for covering surgical procedures. The product required should be reconstituted to the same volume and in the same diluent as for bolus infusion, and administered using an infusion pump suitable for this volume. Reconstitution should be done under aseptic conditions, and sterile integrity of the delivery device should be maintained.

Monitoring advice.

It is recommended that plasma FVIII:C and/or VWF:RCo concentrations be determined in patient's plasma at suitable intervals and during the treatment of severe bleeding episodes.

Reconstitution.

1. Ensure that the Biostate and water for injections vials are at room temperature (20°C to 30°C). Remove the flip-top caps from the Biostate and water for injections vials. Apply an appropriate disinfectant to both rubber stoppers and allow to dry. Remove the lid of the Mix2Vial packaging. If the seal of the lid is not intact or there are any concerns about the integrity of the Mix2Vial, do not use it but return it to Australian Red Cross Lifeblood.
2. Place the water for injections vial upright on a level surface. Pick up the Mix2Vial in its outer package and invert it. Holding the water for injections vial securely, push the blue end of the Mix2Vial vertically down through the water for injections vial stopper.
3. Carefully remove the Mix2Vial outer package. Ensure the Mix2Vial remains attached to the water for injections vial.
4. Place the product vial upright on a level surface, invert the water for injections vial with the Mix2Vial attached. Holding the product vial securely push the clear end of the Mix2Vial vertically down through the product vial stopper. The water for injections will be drawn out of its vial and into the product vial by the vacuum within the product vial. In the unlikely event that the vial does not contain a vacuum, do not use the product, but return it to Australian Red Cross Lifeblood.
5. Leaving the system connected, gently swirl to ensure that the product is fully dissolved. Unscrew the Mix2Vial into two separate pieces. Discard the water for injections vial and the blue end of the Mix2Vial.
6. Keeping the product vial upright, attach the syringe to the clear end of the Mix2Vial. Invert the system and draw the reconstituted product into the syringe. When the product has been transferred, discard the Mix2Vial and product vial.

Note.

The Mix2Vial is intended to filter the contents of a single vial of Biostate only. If multiple vials of Biostate are to be administered, a separate Mix2Vial must be used for each vial.
Do not refrigerate Biostate once it has been reconstituted.
Biostate is a white or pale yellow powder contained in a glass vial. Upon reconstitution it forms a colourless to slightly yellow solution with a clear to opalescent appearance. After filtering/ withdrawal, the reconstituted product should be inspected visually for particulate matter and discolouration prior to administration. Do not use visibly cloudy solutions or solutions still containing flakes or particles. If a clot or gel forms, do not use the product but return it to Australian Red Cross Lifeblood.

Note.

Whilst the physicochemical stability of the active ingredients has been demonstrated for 8 hours following reconstitution at room temperature (below 25°C), Biostate does not contain an antimicrobial preservative. Therefore, it is recommended that the reconstituted product should be used as soon as practicable.
Use in one patient on one occasion only.

Administration.

Biostate is intended for intravenous administration.
1. With the Biostate vial upright, attach a plastic disposable syringe to the Mix2Vial (transparent plastic part). Invert the system and draw the reconstituted Biostate into the syringe by pulling the plunger back slowly. One large syringe may be used to pool several vials of reconstituted Biostate.
2. Once the Biostate 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 Biostate vial in an appropriate waste container. Fit the syringe to a suitable injection needle to administer the reconstituted Biostate. Do not use the Mix2Vial for injection.
3. Give the dose slowly by the intravenous route (usually within 5 to 6 minutes, or as tolerated by the patient). The injection/ infusion rate should not exceed 6 mL per minute and the patient should be observed carefully during administration. If there is any reaction that might be related to the administration of Biostate, the rate of injection should be decreased or if needed, the application should be stopped (see Section 4.4 Special Warnings and Precautions for Use).
4. When the contents of more than one vial are to be given, it will be convenient to pool the total amount prior to administration (e.g. in a large syringe or sterile bag). This must be done aseptically.
5. To reduce microbiological hazard, use as soon as practicable after reconstitution/ preparation. For use in surgery, the conditions described under Continuous infusion can apply. This product is for single use only and any unused portion remaining in the vial must be discarded appropriately.
6. The solution must not be added or mixed with any other fluids to be given, including whole blood.
Medical personnel, family carers and patients should be adequately trained in the techniques for the preparation and the administration of Biostate. A detailed and comprehensive Consumer Medicine Information document is available but this instruction must not take the place of professional medical advice and supervised training in the administration of Biostate.

Spillage and breakages.

Should a break in the container or spillage occur, due precautions should be taken to avoid contamination of cuts and abrasions, as well as to avoid inhalation or swallowing of the spillage. Adequate disinfection can be obtained with the application of 1% sodium hypochlorite for 15 minutes. Commercial bleaches may be diluted appropriately to obtain this concentration.

4.7 Effects on Ability to Drive and Use Machines

No effects on ability to drive and use machines have been observed.

4.9 Overdose

Cases of overdose (twice the amount of the recommended dose) have been observed in clinical trials. No severe adverse reactions were associated with these cases. The risk of thromboembolic events cannot be excluded in case of major overdose, especially in patients with VWD.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

Unscheduled.

6 Pharmaceutical Particulars

6.1 List of Excipients

Human plasma proteins; albumin stabiliser (≥ 99% pure); sucrose; sodium citrate dihydrate; sodium chloride; trometamol; calcium chloride dihydrate; sodium octanoate.

6.2 Incompatibilities

Compatibility studies have not been conducted, therefore Biostate must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the carton packaging.

Reconstituted product.

Whilst the physico-chemical stability of the active ingredients has been demonstrated for 8 hours following reconstitution at room temperature (below 25°C), Biostate does not contain an antimicrobial preservative. Therefore, it is recommended that the reconstituted product should be used as soon as practicable.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze.) Biostate can be stored below 25°C for a single period of 6 months. The product must not be returned to refrigeration after storage below 25°C. Protect from light. Do not use after the expiry date.

6.5 Nature and Contents of Container

Each presentation includes Biostate powder for injection and WFI in clear glass vials with latex free rubber closures closed with an aluminium seal and a plastic flip-top cap.
Each presentation is supplied with a Mix2Vial filter transfer set.
250 IU FVIII/600 IU VWF vial of Biostate (50 IU FVIII/mL, 120 IU VWF/mL), 5 mL vial of water for injections.
500 IU FVIII/1200 IU VWF vial of Biostate (50 IU FVIII/mL, 120 IU VWF/mL), 10 mL vial of water for injections.
500 IU FVIII/1200 IU VWF vial of Biostate (100 IU FVIII/mL, 240 IU VWF/mL), 5 mL vial of water for injections.
1000 IU FVIII/2400 IU VWF vial of Biostate (100 IU FVIII/mL, 240 IU VWF/mL), 10 mL vial of water for injections.
Not all registered presentations may be supplied.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes