OBIZUR 500 U powder and solvent for solution for injection

Section

Change (in red)

4.2  Posology and method of administration

Treatment with OBIZUR should be under the supervision of a physician experienced in the treatment of haemophilia (See Section 4.4).

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions (See Section 4.4).

4.4. Special warnings and precautions for use

Dosing

Initial dosing below the recommended 200 U/kg has been associated with lack of efficacy (See Section 4.2).

Inhibitors

It is recommended to test for anti-rpFVIII antibodies prior to initiation of treatment with OBIZUR. Treatment may be started at physician’s discretion prior to receiving the result of this test. Treatment decisions can be further supported by monitoring factor VIII levels. Inhibitory antibodies against porcine factor VIII (measured using a modification of the Nijmegen variation of the Bethesda assay) were detected before and after exposure to OBIZUR. Lack of efficacy could be due to inhibitory antibodies to OBIZUR. Inhibitor titres of up to 29 Bethesda units were recorded at baseline yet patients responded positively to OBIZUR. It is recommended that treatment should be based on clinical judgement and not based on detection of inhibitory antibodies by the Bethesda assay.

Anamnestic reactions with rise in human factor VIII and/or porcine factor VIII inhibitors have also been reported in patients treated with OBIZUR. These anamnestic rises may result in lack of efficacy response to OBIZUR. If such inhibitory antibodies to OBIZUR are suspected and there is a lack of efficacy, consider other therapeutic options. 

Deletion of: If venous catheterisation is required, the risk of catheter‑related complications such as catheter site thrombosis should be considered.

Addition of the following subheadings:

Thromboembolic Events

High and sustained factor VIII activity in blood may predispose to thromboembolic events. Those with pre‑existing cardiovascular disease and the elderly are at particular risk.

Treatment Monitoring

Factor VIII activity determined by the chromogenic assay is generally lower than factor VIII activity determined by the one‑stage clotting assay. Measurement of factor VIII activity must always be carried out using the same assay methodology on any one patient. The one‑stage assay is recommended because it has been used in determination of the potency and the mean recovery rate of OBIZUR (See sections 4.2 and 5.2).

4.8   Undesirable effects

Summary of the safety profile:

Patients with acquired haemophilia may develop inhibitory antibodies to porcine factor VIII. Inhibitory antibodies, including anamnestic responses, may result in a lack of efficacy response to Obizur.

Tabulated list of adverse reactions:

Addition: Nineteen subjects did not have a detectable anti-porcine factor VIII inhibitor titer at baseline (< 0.6 BU/mL). Of the 19 subjects, twelve had no detectable anti-porcine factor VIII titer post-treatment, five had an increase in titer (≥ 0.6 BU/mL), and two subjects had no post-treatment samples analysed and seven subjects developed anamnestic reactions with a rise ≥ 10 BU in human factor VIII and/or recombinant factor VIII porcine sequence inhibitors.

5.1      Pharmacodynamic properties

Addition: In the clinical study of OBIZUR for acquired haemophilia, 29 adult patients were evaluable for safety. Nineteen subjects did not have a detectable anti-porcine factor VIII inhibitor titer at baseline (< 0.6 BU/mL). Of the 19 subjects, twelve had no detectable anti-porcine factor VIII titer post-treatment, five had an increase in titer (≥ 0.6 BU/mL), and two subjects had no post-treatment samples analysed and seven subjects developed anamnestic reactions with a rise ≥ 10 BU in human factor VIII and/or recombinant factor VIII porcine sequence inhibitors.

10 date of revision

26 March   10 June  2021

2. Qualitative and Quantitative Composition

Each powder vial contains nominally 500 Uunits of B domain deleted antihaemophilic Ffactor VIII (recombinant (rDNA), porcine sequence, susoctocog alfa.

OBIZUR contains approximately 500 U/ml of susoctocog alfa after reconstitution.

OBIZUR (antihaemophilic Ffactor VIII (recombinant rDNA), porcine sequence) is a purified protein that has 1448 amino acids with an approximate molecular mass of 175kDa.

It is produced by recombinant DNA  (rDNA) technology in baby hamster kidney (BHK) cells. The BHK cells are cultured in media that contains foetal bovine serum.

Excipient(s) with known effect

Each vial contains  4.4 4.6 mg (198 mM) sodium per ml of reconstituted solution.

4.2. Posology and method of administration

Addition of following:

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients.

In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Paediatric population

The safety and efficacy of OBIZUR Use in children and adolescents aged below 18 years with congenital haemophilia with inhibitors or in rare cases of acquired haemophilia is currently not approved have not yet been established. No data are available.

4.3 Contraindications

Known anaphylactic reactions Hypersensitivity to the active substance, hamster protein, or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.

Hypersensitivity

(…)The medicinal product contains trace amounts of hamster proteins.

Development of inhubitory antibodies Inhibitors

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk.

Name and batch number

It is strongly recommended that every time that OBIZUR 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 medicinal product.

Sodium content

OBIZUR contains 4.6 mg sodium in 1 mL of reconstituted solution in each vial, equivalent to 0.23% of the WHO recommended maximum daily intake of 2 g sodium for an adult.  Multiple vials must be taken per dose e.g A 70 kg patient using the recommended 200 U/kg dose would require 28 vials which results in a sodium intake of 128.8 mg per treatment.  This is equivalent to 6.44% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Each vial contains 4.4 mg (198 mM) sodium per ml of reconstituted solution.

To be taken into consideration by patients on a controlled sodium diet.

4.8          Undesirable effects

Patients with acquired haemophilia may develop inhibitory antibodies to porcine Ffactor VIII. Inhibitory antibodies, including anamnestic responses, may result in a lack of response to OBIZUR.

Tabulated list of adverse reactions:

The table presented below is according to the MedDRA system organ classification (SOC and Ppreferred Tterm Llevel). In the clinical trial study (…) subjects patients were evaluable for safety.

5.1          Pharmacodynamic properties

Other information replaced with Paediatric population

6.1       List of excipients

Powder

Polysorbate 80

Sodium chloride

Calcium chloride dihydrate

Sucrose

Trometamol hydrochloride Tris Base

Tris HCl

Tri sSodium citrate dihydrate

Solvent

Sterilised wWater for injections

6.5       Nature and contents of container

One pack of OBIZUR contains 1, 5 or 10 each of the following:

•              powder vials (type I glass) with a stopper (butyl rubber coated with FluroTec®) and a flip off seal;

•              pre filled (type I glass) syringes with a stopper (bromobutyl rubber coated with FluroTec® foil on the contact side), a bromobutyl rubber tip cap and a Luer Llock adapter

9. Data of latest renewal

10 Date of revision of the text

16^th  November 2020

16^th November 2020

2. Qualitative and Quantitative Composition

Each powder vial contains nominally 500 Uunits of B domain deleted antihaemophilic Ffactor VIII (recombinant (rDNA), porcine sequence, susoctocog alfa.

OBIZUR contains approximately 500 U/ml of susoctocog alfa after reconstitution.

OBIZUR (antihaemophilic Ffactor VIII (recombinant rDNA), porcine sequence) is a purified protein that has 1448 amino acids with an approximate molecular mass of 175kDa.

It is produced by recombinant DNA  (rDNA) technology in baby hamster kidney (BHK) cells. The BHK cells are cultured in media that contains foetal bovine serum.

Excipient(s) with known effect

Each vial contains  4.4 4.6 mg (198 mM) sodium per ml of reconstituted solution.

4.2. Posology and method of administration

Addition of following:

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients.

In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Paediatric population

The safety and efficacy of OBIZUR Use in children and adolescents aged below 18 years with congenital haemophilia with inhibitors or in rare cases of acquired haemophilia is currently not approved have not yet been established. No data are available.

4.3 Contraindications

Known anaphylactic reactions Hypersensitivity to the active substance, hamster protein, or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.

Hypersensitivity

(…)The medicinal product contains trace amounts of hamster proteins.

Development of inhubitory antibodies Inhibitors

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk.

Name and batch number

It is strongly recommended that every time that OBIZUR 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 medicinal product.

Sodium content

OBIZUR contains 4.6 mg sodium in 1 mL of reconstituted solution in each vial, equivalent to 0.23% of the WHO recommended maximum daily intake of 2 g sodium for an adult.  Multiple vials must be taken per dose e.g A 70 kg patient using the recommended 200 U/kg dose would require 28 vials which results in a sodium intake of 128.8 mg per treatment.  This is equivalent to 6.44% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Each vial contains 4.4 mg (198 mM) sodium per ml of reconstituted solution.

To be taken into consideration by patients on a controlled sodium diet.

4.8          Undesirable effects

Patients with acquired haemophilia may develop inhibitory antibodies to porcine Ffactor VIII. Inhibitory antibodies, including anamnestic responses, may result in a lack of response to OBIZUR.

Tabulated list of adverse reactions:

The table presented below is according to the MedDRA system organ classification (SOC and Ppreferred Tterm Llevel). In the clinical trial study (…) subjects patients were evaluable for safety.

5.1          Pharmacodynamic properties

Other information replaced with Paediatric population

6.1       List of excipients

Powder

Polysorbate 80

Sodium chloride

Calcium chloride dihydrate

Sucrose

Trometamol hydrochloride Tris Base

Tris HCl

Tri sSodium citrate dihydrate

Solvent

Sterilised wWater for injections

6.5       Nature and contents of container

One pack of OBIZUR contains 1, 5 or 10 each of the following:

•              powder vials (type I glass) with a stopper (butyl rubber coated with FluroTec®) and a flip off seal;

•              pre filled (type I glass) syringes with a stopper (bromobutyl rubber coated with FluroTec® foil on the contact side), a bromobutyl rubber tip cap and a Luer Llock adapter

9. Data of latest renewal

10 Date of revision of the text

16^th  November 2020

16^th November 2020

2. Qualitative and Quantitative Composition

Each powder vial contains nominally 500 Uunits of B domain deleted antihaemophilic Ffactor VIII (recombinant (rDNA), porcine sequence, susoctocog alfa.

OBIZUR contains approximately 500 U/ml of susoctocog alfa after reconstitution.

OBIZUR (antihaemophilic Ffactor VIII (recombinant rDNA), porcine sequence) is a purified protein that has 1448 amino acids with an approximate molecular mass of 175kDa.

It is produced by recombinant DNA  (rDNA) technology in baby hamster kidney (BHK) cells. The BHK cells are cultured in media that contains foetal bovine serum.

Excipient(s) with known effect

Each vial contains  4.4 4.6 mg (198 mM) sodium per ml of reconstituted solution.

4.2. Posology and method of administration

Addition of following:

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients.

In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Paediatric population

The safety and efficacy of OBIZUR Use in children and adolescents aged below 18 years with congenital haemophilia with inhibitors or in rare cases of acquired haemophilia is currently not approved have not yet been established. No data are available.

4.3 Contraindications

Known anaphylactic reactions Hypersensitivity to the active substance, hamster protein, or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.

Hypersensitivity

(…)The medicinal product contains trace amounts of hamster proteins.

Development of inhubitory antibodies Inhibitors

Cardiovascular events

In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk.

Name and batch number

It is strongly recommended that every time that OBIZUR 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 medicinal product.

Sodium content

OBIZUR contains 4.6 mg sodium in 1 mL of reconstituted solution in each vial, equivalent to 0.23% of the WHO recommended maximum daily intake of 2 g sodium for an adult.  Multiple vials must be taken per dose e.g A 70 kg patient using the recommended 200 U/kg dose would require 28 vials which results in a sodium intake of 128.8 mg per treatment.  This is equivalent to 6.44% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Each vial contains 4.4 mg (198 mM) sodium per ml of reconstituted solution.

To be taken into consideration by patients on a controlled sodium diet.

4.8          Undesirable effects

Patients with acquired haemophilia may develop inhibitory antibodies to porcine Ffactor VIII. Inhibitory antibodies, including anamnestic responses, may result in a lack of response to OBIZUR.

Tabulated list of adverse reactions:

The table presented below is according to the MedDRA system organ classification (SOC and Ppreferred Tterm Llevel). In the clinical trial study (…) subjects patients were evaluable for safety.

5.1          Pharmacodynamic properties

Other information replaced with Paediatric population

6.1       List of excipients

Powder

Polysorbate 80

Sodium chloride

Calcium chloride dihydrate

Sucrose

Trometamol hydrochloride Tris Base

Tris HCl

Tri sSodium citrate dihydrate

Solvent

Sterilised wWater for injections

6.5       Nature and contents of container

One pack of OBIZUR contains 1, 5 or 10 each of the following:

•              powder vials (type I glass) with a stopper (butyl rubber coated with FluroTec®) and a flip off seal;

•              pre filled (type I glass) syringes with a stopper (bromobutyl rubber coated with FluroTec® foil on the contact side), a bromobutyl rubber tip cap and a Luer Llock adapter

9. Data of latest renewal

10 Date of revision of the text

16^th  November 2020

16^th November 2020

Section

Changes

4.4     Special warnings and precautions for use

Addition of the following text:

Anamnestic reactions with rise in human factor VIII and/or porcine factor VIII inhibitors have also been reported in patients treated with OBIZUR. These anamnestic rises may result in lack of response to OBIZUR.  

4.8     Undesirable effects 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Website: www.hpra.ie

HPRA Pharmacovigilance

Earlsfort Terrace

Dublin 2

Ireland

Tel: +353 1 676 4971

Fax: +353 1 676 2517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

10 Date of revision of the text

17 September 2020