Biostate

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Dried factor VIII fraction 500 IU; von Willebrand's factor : Ristocetin cofactor 1000 IU
Available from:
CSL Behring (NZ) Ltd
INN (International Name):
Dried factor VIII fraction 500 IU
Dosage:
500 IU
Pharmaceutical form:
Injection with diluent
Composition:
Active: Dried factor VIII fraction 500 IU von Willebrand's factor : Ristocetin cofactor 1000 IU Excipient: Albumin Calcium chloride dihydrate Plasma protein Sodium chloride Sodium citrate dihydrate Sodium octanoate Sucrose Trometamol Water for injection
Units in package:
Combination pack, Powder + Diluent + Reconstitution device, 1 dose unit
Class:
General sale
Prescription type:
General sale
Manufactured by:
CSL Behring (Australia) Pty Ltd
Therapeutic indications:
Biostate® is indicated for: · the prophylaxis and treatment of non-surgical and surgical bleeding in patients with von Willebrand disease when desmopressin (DDAVP) treatment is ineffective or contraindicated
Product summary:
Package - Contents - Shelf Life: Combination pack, Powder + Diluent + Reconstitution device - 1 dose units - 36 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. one excursion of up to 6 months at 25°C allowed - Vial, glass, Lyophilised powder, 500/1000 IU of FVIII/VWF - 1 dose units - 36 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light. one excursion of up to 6 months at 25°C allowed - Vial, glass, Diluent - 5 mL - 60 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-8436
Authorization date:
2009-09-21

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 1 of 20

1 PRODUCT NAME

Biostate

250 IU FVIII/500 IU VWF powder and diluent (5 mL) for solution for injection

Biostate

500 IU FVIII/1000 IU VWF powder and diluent (5 mL) for solution for injection

Biostate

500 IU FVIII/1000 IU VWF powder and diluent (10 mL) for solution for injection

Biostate

1000 IU FVIII/2000 IU VWF powder and diluent (10 mL) for solution for injection

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 donated by New Zealand’s voluntary non-remunerated

donors. The FVIII/VWF complex in Biostate

is purified from cryoprecipitate using selective

precipitation and size exclusion chromatography steps. It 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

250 IU FVIII/500 IU VWF powder and diluent for solution for injection

One vial of powder contains nominally:

250 IU human coagulation factor VIII (FVIII).

500 IU human von Willebrand factor (VWF).

After reconstitution with the 5 mL water for injections provided, the solution contains 50 IU/mL of

FVIII and 100 IU/mL of VWF.

Biostate

500 IU FVIII/1000 IU VWF powder and diluent for solution for injection

One vial of powder contains nominally:

500 IU human coagulation factor VIII (FVIII).

1000 IU human von Willebrand factor (VWF).

After reconstitution with the 10 mL water for injections provided, the solution contains 50 IU/mL of

FVIII and 100 IU/mL of VWF.

Biostate

500 IU FVIII/1000 IU VWF powder and diluent for solution for injection

One vial of powder contains nominally:

500 IU human coagulation factor VIII (FVIII).

1000 IU human von Willebrand factor (VWF).

After reconstitution with the 5 mL water for injections provided, the solution contains 100 IU/mL of

FVIII and 200 IU/mL of VWF.

Biostate

1000 IU FVIII/2000 IU VWF powder and diluent for solution for injection

One vial of powder contains nominally:

1000 IU human coagulation factor VIII (FVIII).

2000 IU human von Willebrand factor (VWF).

After reconstitution with the 10 mL water for injections provided, the solution contains 100 IU/mL of

FVIII and 200 IU/mL of VWF.

Note: Not all registered presentations may be supplied.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 2 of 20

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.

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.

Excipient with known effect:

Biostate

250IU FVIII/500 IU VWF and 500 IU FVIII/1000 IU VWF IU (5 mL WFI): each contain

up to 14.75 mg (0.64 mmol) sodium per vial, equivalent to 0.74% of the WHO recommended

maximum daily intake of 2 g sodium for an adult.

Biostate

500 IU FVIII/1000 IU VWF and 1000 IU FVIII/2000 IU VWF (10 mL WFI): each contain

up to 29.50 mg (1.28 mmol) sodium per vial, equivalent to 1.48% of the WHO recommended

maximum daily intake of 2 g sodium for an adult.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder and diluent for solution for injection.

Powder: white or pale yellow

Diluent: clear, colourless (WFI)

4 CLINICAL PARTICULARS

4.1

Therapeutic indications

Biostate

is indicated for:

the prophylaxis and treatment of non-surgical and surgical bleeding in patients with von

Willebrand disease when desmopressin (DDAVP) treatment is ineffective or contraindicated

the prophylaxis and treatment of non-surgical and surgical bleeding associated with FVIII

deficiency due to haemophilia A.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 3 of 20

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 2:1.

Von Willebrand disease population

Provided in

Table 1

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.

Table 1: VWD dosage guidelines

Indication

Dose (IU/kg)

Dose frequency

Target FVIII/VWF (%)

(IU/dL)

FVIII:C

VWF:Ac

1

Spontaneous bleeding

episodes

12.5–25

25–50

Initial

VWF peak level >50%, FVIII >30%

12.5

Subsequent

every 12–24 hours

VWF/FVIII trough levels of >30% until

bleeding stops (usually, 2–4 days)

Minor surgery

Daily

VWF/FVIII trough levels of >30% until

healing is complete (usually, 2–4 days)

Major surgery

30–40

60–80

Initial

VWF peak level >100%, FVIII >60%

15–30

30–60

Subsequent

every 12–24 hours

VWF/FVIII trough levels of >50% until

healing is complete (usually, 5–10 days)

Prophylaxis

12.5–20

25–40

1–3 times weekly

Trough >1

Equivalent to VWF:RCo

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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 4 of 20

Haemophilia A population

Provided in

Table 2

are dosage guidelines for patients with Haemophilia A.

Table 2: Haemophilia A dosage guidelines

Indication

Dose

(IU/kg)

Dose frequency

Treatment day(s)

or duration

Target FVIII (%)

(IU/dL)

Minor bleeding

episodes

10–15

12–24 hourly

1–2

Peak 20–30

Moderate to severe

bleeding episodes

e.g. haemarthroses

15–40

8–24 hourly

1–4

Peak 30–80

Life threatening

bleeding e.g.

intracranial

haemorrhage

50–60

20–25

Single dose

8–12 hourly

2–10

Peak >100

Trough 80–100

Minor surgery

20–30

20–25

20–30

Single dose

12 hourly

24 hourly

Pre-op

1–3

≥4

Peak 40–60

Trough 40–50

Trough 20–30

Major surgery

40–50

20–25

15–20

10–20

Single dose

8–12 hourly

8–12 hourly

12 hourly

Pre-op

1–3

4–6

≥7

Peak 80–100

Trough 80–100

Trough 60–80

Trough 40–60

Dentistry

e.g. invasive dental

procedures,

extractions, surgery

35–40

25–30

Single dose

12 hourly

Pre-op

1–3

Peak 70–80

Trough 50–60

Prophylaxis

25–40

3 times weekly

Ongoing

Trough 1

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.

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.

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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 5 of 20

Method of administration

For intravenous use.

Medical personnel, family carers and patients should be adequately trained in the techniques for the

preparation and the administration of Biostate

For instructions on reconstitution of the medicine before administration, see section 6.6.

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

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.

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).

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.

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.

The solution must not be added or mixed with any other fluids to be given, including whole

blood.

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.

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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 6 of 20

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 anti-haemophilic 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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 7 of 20

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 Biostate

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 non-enveloped virus HAV. The measures taken may be of limited value against non-enveloped

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.

Paediatric use

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

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 8 of 20

Use in the elderly

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

studies.

Effect on laboratory tests

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

are anticipated.

4.5

Interaction with other medicines and other forms of interaction

No interaction studies have been performed.

4.6

Fertility, pregnancy and lactation

Effects on fertility

Animal reproduction studies have not been conducted with Biostate

Use in pregnancy and lactation

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.

4.7

Effects on ability to drive and use machines

Biostate

has no influence on ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

During treatment with Biostate

the following adverse reactions may occur: hypersensitivity or

allergic reactions, thromboembolic events, pyrexia, headache, dysgeusia and abnormal liver function

test levels. Furthermore, patients may develop inhibitors to FVIII and/or VWF.

Tabulated summary of adverse reactions

The adverse reactions presented in

Table 3

are based on experience from clinical trials and

postmarketing experience from patients with haemophilia A and VWD.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 9 of 20

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.

Table 3: Frequency of adverse reactions

MedDRA SOC

Adverse reaction*

Frequency in clinical

trials

Frequency in

postmarketing

surveillance

Blood and lymphatic

system disorders

FVIII inhibition

Common

Very rare

VWF inhibition

Not known**

Very rare

Immune system disorders

Hypersensitivity (including

tachycardia, chest pain, chest

discomfort and back pain)

Common

Very rare

Nervous system disorders

Dysgeusia

Uncommon

Very rare

Vascular disorders

Thromboembolic event

Uncommon

Very rare

General disorders and

administration site

conditions

Pyrexia

Common

Very rare

Headache

Very common

Very rare

Investigations

Liver function test abnormal

Uncommon

Very rare

* Adverse events adjudicated as related to Biostate

** Observed during postmarketing surveillance, not observed in clinical trials.

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).

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 10 of 20

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.

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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked

to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

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 advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5 PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antihaemorrhagics: Blood coagulation factors, von Willebrand factor

and coagulation factor VIII in combination.

ATC code: B02BD06

The Biostate

FVIII/VWF complex consists of two different non-covalently 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 2:1 ratio with FVIII:C activity. Biostate

has been

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 11 of 20

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 efficacy and safety

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 study) and 43 adolescents and children (Howman

study). Fifteen paediatric haemophilia A subjects, with FVIII inhibitors, treated for immune tolerance

induction are reported in a published investigator-led retrospective chart review (Robertson study).

Von Willebrand Disease

Efficacy in the control of non-surgical 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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 12 of 20

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

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 in section 4.8.

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).

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 13 of 20

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 in

section 4.8.

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 non-bleeding

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 4

were observed following a single

intravenous infusion of 80 IU VWF:RCo/kg.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 14 of 20

Table 4: Pharmacokinetics data for VWF:RCo, VWF:Ag and VWF:CB

Parameter

VWF:RCo

VWF:Ag

VWF:CB

N

Mean

SD

Range

N

Mean

SD

Range

N

Mean

SD

Range

Incremental

recovery

(kg/mL)

0.017

0.002

0.01

0.02

0.018

0.002

0.01

0.02

0.020

0.004

0.02

0.02

Half-life (h)

13.7

35.1

18.3

11.4

27.0

16.0

25.1

0–72

(h.IU/mL)

17.7

8.6–38.0

37.8

13.3

22.6

64.7

24.8

14.8

41.1

MRT (h)

14.0

25.5

23.6

15.3

33.6

20.0

11.6

28.6

(IU/mL)

1.65

0.63

0.93

3.36

2.29

0.59

1.52

3.66

1.68

0.50

1.04

2.66

0.25

0.25

1.03

0.25

0.25

1.00

0.25

0.25

1.00

(IU/mL)

0.01

0.01

0.00–0.03

0.10

0.05

0.02

0.17

0.05

0.02

0.02

0.09

Total

clearance

(mL/(h.kg))

6.09

1.66

3.06

9.32

3.57

0.69

2.61

4.78

3.53

0.89

2.32

4.77

(mL/kg)

74.8

35.3

44.7

158.0

82.8

18.6

64.5

128.4

68.6

15.7

47.5

93.7

median.

AUC = area under the curve; C

= maximum plasma concentration; C

= minimum plasma concentration;

IU = International Unit; MRT = mean residence time; N = number of subjects; SD = standard deviation;

= time to maximum concentration; V

= 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 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 5

were observed following a single intravenous infusion of 50 IU/kg.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 15 of 20

Table 5: Pharmacokinetics data for FVIII:C

Parameter

FVIII:C

N

Mean

SD

Range

Incremental recovery (kg/mL)

0.021

0.006

0.011

0.032

Half-life (h)

13.40

2.53

8.78

18.51

0–48

(h.IU/mL)

13.79

3.79

7.04

21.79

MRT (h)

16.96

3.68

11.29

26.31

(IU/mL)

1.07

0.28

0.57

1.57

0.81

0.94

0.42

4.03

(IU/mL)

0.060

0.028

0.021

0.111

Total clearance (mL/(h.kg))

3.92

1.22

2.30

7.11

(mL/kg)

65.33

20.65

35.07

113.06

AUC = area under the curve; C

= maximum plasma concentration; C

= minimum plasma concentration;

IU = International Unit; MRT = mean residence time; N = number of subjects; SD = standard deviation;

= time to maximum concentration; V

= volume of distribution at steady state;

FVIII:C = factor VIII: coagulation activity.

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

The product contains FVIII and VWF as active ingredients which are derived from human plasma and

act like endogenous constituents of plasma. Preclinical studies with repeated dose applications

(chronic toxicity, carcinogenicity and mutagenicity) cannot be reasonably performed in conventional

animal models due to the development of antibodies following the application of heterologous human

proteins.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 16 of 20

6 PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Powder:

Human plasma proteins

Albumin stabiliser (≥99% pure)

Calcium chloride dihydrate

Sucrose

Sodium citrate dihydrate

Sodium chloride

Sodium octanoate

Trometamol

Diluent:

Water for Injections

6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other

medicinal products, except those mentioned in section 6.6.

6.3

Shelf life

3 years

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, which can be found on the carton packaging.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 17 of 20

6.5

Nature and contents of container and special equipment for use

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 and is supplied with a

Mix2Vial

filter transfer set.

250 IU FVIII/500 IU VWF vial of Biostate

, 5 mL vial of Water for Injections

500 IU FVIII/1000 IU VWF vial of Biostate

, 10 mL vial of Water for Injections

500 IU FVIII/1000 IU VWF vial of Biostate

, 5 mL vial of Water for Injections

1000 IU FVIII/2000 IU VWF vial of Biostate

, 10 mL vial of Water for Injections.

Not all registered presentations may be supplied.

6.6

Special precautions for disposal and other handling

Use in one patient on one occasion only.

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 the New Zealand Blood

Service.

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.

Reconstitution

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 the New Zealand Blood Service.

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. See

Figure 1

Carefully remove the Mix2Vial

outer package. Ensure the Mix2Vial

remains attached to the

Water for Injections vial. See

Figure 2

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 18 of 20

Figure 1

Figure 2

Figure 3

Figure 4

Note: WFI = Water for Injections

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. See

Figure 3

. 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 the

New Zealand Blood Service.

Leaving the system connected, gently swirl to ensure that the product is fully dissolved. Unscrew

the Mix2Vial

into two separate pieces (see

Figure 4

). Discard the Water for Injections vial and

the blue end of the Mix2Vial

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: 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.

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

requirements.

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.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 19 of 20

7 MEDICINE SCHEDULE

General Sale Medicine

8 SPONSOR

CSL Behring (NZ) Ltd

666 Great South Road

Penrose

Auckland

New Zealand

For Medical/Technical Enquiries

TOLL FREE: 0800 640 677

For Customer Service Enquiries

TOLL FREE: 0800 841 532

customerservice@cslbehring.com.au

www.cslbehring.com.au

DISTRIBUTOR

New Zealand Blood Service

71 Great South Road

Epsom

Auckland

New Zealand

9 DATE OF FIRST APPROVAL

1 March 2001

10 DATE OF REVISION OF THE TEXT

2 November 2018

SUMMARY TABLE OF CHANGES

Section Changed

Summary of new information

Conversion to new data sheet format.

Section 2

Updates to include information on actives and details on new VWF activity

assay.

Section 4.1

Editorial changes for clarity.

NEW ZEALAND DATA SHEET

Biostate NZ DS 18.00

Page 20 of 20

Section 4.2

Changes to reflect new VWF activity assay. Update to VWD dose instructions

and VWD prophylaxis dose frequency. Inclusion of VWD and haemophilia A

paediatric dose information. Update to infusion rate administration instructions.

Section 4.4

Update to reflect inclusion of paediatric clinical data.

Section 5.1

Update to VWD and haemophilia A clinical data.

Section 5.2

Update to VWD and haemophilia A PK data.

Section 6.3, 6.6

Update to post-reconstitution storage instructions and editorial changes to

reconstitution instructions.

Section 6.6

Editorial changes to reconstitution instructions.

Section 8

Addition of toll free number.

Registered trademark of CSL Limited

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

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