Product information- biostate

Biostate®
Australia
NAME OF THE MEDICINE
Human coagulation factor VIII and human von Willebrand factor complex, powder for DESCRIPTION
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 the Australian Red Cross Blood Service. It is intended for intravenous administration. The FVIII/VWF complex in Biostate® is purified from cryoprecipitate using selective precipitation and size exclusion chromatography steps. The Biostate® manufacturing process includes solvent detergent (tributyl phosphate and polysorbate 80) and dry heat treatment (80°C for 72 hours) steps to reduce the potential for 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 model viruses for hepatitis B virus (HBV) and hepatitis C virus (HCV). The manufacturing process also contributes to inactivation/removal of human Von Willebrand Factor
Following reconstitution, 1 mL of Biostate® contains: • Biostate® 50 IU FVIII/mL: approximately 100 IU of human plasma derived VWF • Biostate® 100 IU FVIII/mL: approximately 200 IU of human plasma derived VWF. The VWF:RCo activity is determined using the WHO standard for VWF. The specific VWF activity of Biostate® prior to the addition of human albumin as a stabiliser is approximately Factor VIII
Following reconstitution, 1 mL of Biostate® contains: • Biostate® 50 IU FVIII/mL: approximately 50 IU of human plasma derived coagulation • Biostate® 100 IU FVIII/mL: approximately 100 IU of human plasma derived The FVIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific FVIII activity of Biostate® prior to the addition of human albumin as a stabiliser is approximately 70 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 three different presentations as detailed in Tab le 1. The amount of VWF:RCo in the final product is
dependent on the method of preparation of the cryoprecipitate, and this influences the VWF:RCo:FVIII ratio. Biostate® contains VWF:RCo and FVIII in a ratio of 2:1. Tab le 1: Biostate® Composition*
Concentration
50 IU FVIII/mL / 100 IU VWF/mL
100 IU FVIII/mL / 200 IU
Presentation
250 IU FVIII/
500 IU FVIII/
1000 IU FVIII/
500 IU VWF
1000 IU VWF
2000 IU VWF
Active ingredients IU/vial
Excipients mg/vial
Reconstitution Volume (mL)
VWF:RCo – VWF ristocetin cofactor activity. PHARMACOLOGY
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. The activity of FVIII is measured as FVIII coagulation activity (FVIII:C). VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilising carrier protein for the procoagulant protein FVIII. The activity of VWF is measured as von Willebrand factor ristocetin cofactor activity 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 as the platelets are prevented from adhering to sub-endothelial tissue. As a result, excessive bleeding may occur. The VWF:RCo activity in Biostate® exists in a 2:1 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. FVIII is a cofactor for activated factor IX, and accelerates the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen Pharmacokinetics
Von Willebrand Factor
The pharmacokinetics of the product have been evaluated in VWD patients in the non- Based on a pharmacokinetic study with 14 subjects with VWD, the following pharmacokinetic characteristics for VWF:RCo, VWF:Ag, and VWF:CB were observed following a single intravenous infusion of 80 IU VWF:RCo/kg. Table 2: Pharmacokinetics data for VWF:RCo, VWF:Ag, and VWF:CB
Parameter
a median AUC = area under the curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; SD = standard deviation; Tmax = time the maximum concentration occurs; Vss = volume of distribution at steady state; VWF:Ag = von Willebrand factor: Antigen; VWF:CB = von Willebrand factor: Collagen Binding; VWF:RCo = von Willebrand factor: Ristocetin Cofactor. Peak plasma levels of VWF usually occur within a mean time of 18 minutes (median Similar results for both VWF and FVIII PK parameters were found when assessed after 6 Factor VIII
The pharmacokinetics of the product have been evaluated in haemophilia A patients in the non- Based on a pharmacokinetic study with 16 subjects with haemophilia A, the following pharmacokinetic characteristics for FVIII:C were observed following a single intravenous Table 3: Pharmacokinetics data for FVIII:C
Parameter
AUC = area under the curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; IU = International Unit; MRT = mean residence time; N = number of subjects; SD = standard deviation; Tmax = time the maximum concentration occurs; Vss = volume of distribution at steady state; FVIII:C = Factor VIII: Coagulant. Peak plasma levels of FVIII usually occur within a mean time of 49 minutes (median Similar pharmacokinetic 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
No pharmacokinetic data are available in patients younger than 12 years. CLINICAL TRIALS
A total of 168 subjects were exposed in the prospective clinical studies, including 111 subjects with haemophilia A and 57 subjects with VWD. Among these exposed subjects, 5 subjects with haemophilia A and 3 subjects with VWD were adolescents, i.e. aged 12 – <18 years, and 1 subject with VWD was a 3-year-old child. In addition, efficacy and safety data in VWD subjects were collected in 2 published investigator-led studies that included 43 adult VWD subjects (Shortt study) and 43 adolescents and children (Howman study). Von Willebrand disease
Efficacy in the control of non-surgical and surgical bleeding was assessed in two open-label non-controlled trials. A 4-point rating scale was used in both 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 98.3% of 405 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 four of the later 6 bleeds the investigator had assessed efficacy as good on at least 1 day. In the second trial the focus was on surgery. In 9 patients 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 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 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 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 The mean daily dose was 51 IU FVIII/kg (range: 13–151 IU FVIII/kg) for major surgery with a median treatment duration of 7 days (range: 1–24 days) and 45 IU FVIII/kg (range: 14– 76 IU FVIII/kg) for minor surgery with a median treatment duration of 3 days (range: 1–8 days). For NSB events, the mean daily dose was 45 IU FVIII/kg (range: 16–192 IU FVIII/kg) with a median treatment duration of 1 day (range: 1–13 days). Efficacy and safety in acquired VWD has not been established. Adverse reactions encountered during the clinical trials in VWD patients are included under ADVERSE EFFECTS.
Haemophilia A
In an open study in adult 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. Adverse reactions encountered during the clinical trials in haemophilia A patients are included under ADVERSE EFFECTS.
Efficacy and safety have not been studied in previously untreated patients. INDICATIONS
• the treatment of bleeding episodes including surgical bleeding in patients with von Willebrand disease when desmopressin (DDAVP) treatment is ineffective or • the treatment and prophylaxis of bleeding associated with FVIII deficiency due to 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 its components. PRECAUTIONS
Biostate® should be used with caution in patients with a known allergy to FVIII and/or VWF concentrates, or human albumin. Allergic, anaphylactic reactions or fever are rarely observed in patients receiving FVIII preparations. If any adverse event occurs while Biostate® is being administered, the rate of injection should be slowed or stopped to alleviate symptoms. Patients should be informed of the early signs of hypersensitivity reactions such as allergic skin reactions including hives, generalised urticaria, tightness of the chest, wheezing, flushing, hypotension and anaphylaxis. If these symptoms occur they should be advised to seek medical opinion. In case of shock, the current medical standards for treatment of shock should be The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. These inhibitors are immunoglobulins (usually IgG) directed against the FVIII procoagulant activity. The inhibitor level in the plasma is measured by the Bethesda assay (as Bethesda Units (BU) per mL). The risk of developing inhibitors is correlated to the exposure to 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. Patients with VWD, especially type 3 patients, may very rarely develop inhibitors to VWF. If such inhibitors occur, the condition would manifest itself as an inadequate clinical response such as bleeding not being controlled with an appropriate dose or the expected VWF:RCo activity plasma levels not being attained. Such antibodies may occur in close association with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor. Thromboembolic events have been rarely reported in VWD patients receiving coagulation factor replacement therapy, especially in the setting of known risk factors for thrombosis and may be related to the generation of supranormal FVIII levels. In these patients, caution should be exercised and antithrombotic measures 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. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain viral markers. In addition, virus removal and inactivation steps are included in the manufacturing process. The current procedures applied in the manufacture of this product are effective against enveloped viruses such as HIV, HBV and HCV viruses, and the non-enveloped virus HAV. They are also known to contribute to the inactivation/removal of the non-enveloped virus, Despite these safety measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such Vaccination (e.g. hepatitis A and hepatitis B) should be considered where appropriate, for patients in receipt of medicinal products manufactured from human plasma. Effects on fertility
No reproductive toxicity studies have been conducted with Biostate®. Use in pregnancy and lactation
The safety of this product for use in human pregnancy or during lactation has not been Paediatric use
The use of Biostate® in the paediatric population has not been established in clinical studies. Use in the elderly
The safety of this product for use in the elderly population has not been established in Carcinogenicity and genotoxicity
No carcinogenicity or genotoxicity studies have been conducted with Biostate®. Effect on laboratory tests
FVIII and/or VWF are endogenous plasma proteins; no specific effects on laboratory tests are INTERACTIONS WITH OTHER MEDICINES
The interaction of Biostate® with other medicines has not been established in specific studies. ADVERSE EFFECTS
The following tabulated adverse reactions are based on experience from scientific literature, clinical trials and postmarketing experience from patients with haemophilia A and VWD. The following standard categories of frequency are used where data are available: frequency cannot be estimated from the available data Tab le 4: Frequency of Adverse Reactions
Frequency in
Frequency in clinical
MedDRA SOC
Adverse Reaction*
Postmarketing
Surveillance
Hypersensitivity (including tachycardia, chest pain, *Adverse events assessed as related to administration of the FVIII/VWF product. 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. In such cases, it is recommended that a specialised haemophilia centre be contacted. There is no experience from clinical trials in previously untreated patients (PUPs). Therefore, no valid figures on the incidence of clinically relevant specific inhibitors are currently available. 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. In all such cases, it is recommended that a specialised haemophilia centre be contacted. Hypersensitivity (allergic reactions): Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest (including chest pain and chest discomfort), back pain, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis (including 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 PRECAUTIONS.
Paediatric population
There are insufficient data to estimate the frequency, type and severity of adverse reactions in DOSAGE AND ADMINISTRATION
The dosage recommendations in Tab le 5 (VWD) and Tab le 6 (Haemophilia A) 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:RCo and FVIII are present in a ratio of 2:1. Tab le 5: VWD Dosage Guidelines*
Dose (IU/kg)
Target FVIII/VWF (%)
Indication
Dose Frequency
VWF/FVIII trough levels of >30% until VWF/FVIII trough levels of >30% until VWF/FVIII trough levels of >50% until * For patients with severely reduced VWF levels, e.g. <10% of normal.
Note: Doses may need to be adjusted down in patients with less severe VWF deficiencies to ensure that the
desired plasma concentrations of VWF and FVIII are achieved. It is recommended that plasma VWF and FVIII
concentrations are determined at suitable time intervals.
Tab le 6: Haemophilia A Dosage Guidelines
Treatment Day(s)
Target FVIII (%)
Indication
Dose Frequency
or Duration
Note: The ‘pre-op’ dose is the loading dose prior to surgery, day 1 is the day of surgery and trough levels need
to be maintained above target on day of surgery, and subsequently. For extensive dental clearance or surgery
higher levels may be necessary for longer periods of time. The use of an antifibrinolytic agent in support of
factor replacement is strongly recommended after dental extractions.
Continuous Infusion
No studies using continuous infusion were 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 concentrations be determined in patient’s plasma at suitable intervals and during the treatment of severe haemorrhage. Reconstitution
• Before reconstitution allow the vials of Biostate® and Water for Injections to reach a • Remove the caps from the top of the Biostate® and Water for Injections vials. • Apply a suitable antiseptic to the exposed part of the rubber stoppers of both Biostate® and Water for Injections and allow to dry. • Open the outer package of the Mix2Vial™ filter transfer set by peeling away the lid. 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 the Australian Red Cross Blood Service.
Place the Water for Injections on a level surface and hold the vial firmly. Take the Mix2Vial™ together with its outer package and invert it. Push the blue plastic cannula of the Mix2Vial™ firmly through the rubber stopper of the Water for Injections. • While holding onto the vial of Water for Injections, carefully remove the outer package from the Mix2Vial™, being careful to leave the Mix2Vial™ attached firmly to the Water for Injections vial. Ensure that only the package and not the Mix2Vial™ is • 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 Biostate® stopper. The water will be drawn into the vial by the vacuum within. In the unlikely event that the vial does not contain a
vacuum, do not use the product, but return it to the Australian Red Cross Blood
Service.
• With the Water for Injections and Biostate® vials still attached, gently swirl the product vial to ensure the product is fully dissolved. Avoid excessive frothing. A clear or slightly opalescent solution is usually obtained within 2 to 5 minutes. The solution should be used as described in Administration.
• 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, and discard the empty Water for Injections vial and the blue part of the Mix2Vial™ in an appropriate waste container. 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 Do not refrigerate Biostate® once it has been reconstituted. Administration
Whilst the physico-chemical stability of the active ingredients has been demonstrated
for 4 hours following reconstitution at room temperature (below 25°C), the product does
not contain an antimicrobial preservative. Therefore it is recommended that the
reconstituted product should be used as soon as practicable. Any unused solution should
be discarded appropriately. Use in one patient on one occasion only. If a clot or gel
forms, do not use the product but return it to the Australian Red Cross Blood Service.
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 (usually within 5 minutes, or as tolerated by the patient) by the intravenous route. When the contents of more than one vial are to be given, it will be convenient to pool the total amount prior to administration in a large syringe or sterile 4. 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. 5. The solution must not be added or mixed with any other fluids to be given, including 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 OVERDOSAGE
No symptoms of overdose with human plasma coagulation FVIII/VWF concentrates are PRESENTATION AND STORAGE CONDITIONS
Biostate® powder for injection is packaged as: • 250 IU FVIII/500 IU VWF vial of Biostate® (50 IU FVIII/mL, 100 IU VWF/mL), 5 mL vial of Water for Injections, and one Mix2Vial™ filter transfer set • 500 IU FVIII/1000 IU VWF vial of Biostate® (50 IU FVIII/mL, 100 IU VWF/mL), 10 mL vial of Water for Injections, and one Mix2Vial™ filter transfer set • 500 IU FVIII/1000 IU VWF vial of Biostate® (100 IU FVIII/mL, 200 IU VWF/mL), 5 mL vial of Water for Injections, and one Mix2Vial™ filter transfer set 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. NAME AND ADDRESS OF THE SPONSOR
Distributed by: Australian Red Cross Blood Service POISON SCHEDULE OF THE MEDICINE
Date of first inclusion in the Australian Register of Therapeutic Goods (the
Date of most recent amendment: 26 November 2013
® Biostate is a registered trademark of CSL Limited ™ Mix2Vial is a trademark of West Pharmaceuticals, Inc. or a subsidiary thereof For Medical/Technical Enquiries:
For Customer Service Enquiries:
[email protected]

Source: http://www.cslbehring.com.au/docs/132/95/Biostate%20AU%20PI%2017.00%20(supplied)_2.pdf