Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
OBIZUR 500 U powder and solvent for solution for injection
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each powder vial contains nominally 500 Units of B domain deleted antihaemophilic Factor VIII (recombinant), porcine sequence, susoctocog alfa.
OBIZUR contains approximately 500 U/ml susoctocog alfa after reconstitution.
The potency (U) is determined using the
OBIZUR (antihaemophilic Factor VIII (recombinant), 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 fetal bovine serum. The manufacturing process is free of human serum and human protein products and does not contain any additional animal derived materials.
Excipient(s) with known effect
Each vial contains 4.4 mg (198 mM) sodium per ml of reconstituted solution.
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
The powder is white.
The solvent is clear and colourless.
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Treatment of bleeding episodes in patients with acquired haemophilia caused by antibodies to Factor VIII.
OBIZUR is indicated in adults.
4.2Posology and method of administration
Treatment with OBIZUR should be under the supervision of a physician experienced in the treatment of haemophilia.
The product is for
Posology
The dose, frequency, and duration of the therapy with OBIZUR depend on the location, extent and severity of the bleeding episode, target Factor VIII activity, and on the patient´s clinical condition.
The number of units of Factor VIII administered is expressed in Units (U) that are derived from an
The recommended initial dose is 200 U per kilogram bodyweight, given by intravenous injection (see section 6.6).
The required initial dose of OBIZUR for a patient is calculated using the following formula:
Initial dose (U/kg) Product strength (U/vial) × Body weight (kg) = Number of vials
e.g. for a 70 kg subject the number of vials for an initial dose will be calculated as follows: 200 U/kg 500 U/vial × 70 kg = 28 vials
Monitor Factor VIII activity and clinical condition 30 minutes after the first injection and 3 hours after administering OBIZUR.
Monitor Factor VIII activity immediately prior to and 30 minutes after subsequent doses and refer to the table below for recommended target Factor VIII trough levels.
The
The dose and frequency of administration should be based on results of Factor VIII activity (to be maintained within recommended limits) and on the clinical response achieved.
Efficacy and safety data in patients with acquired haemophilia are limited (see section 5.1).
Initial Phase
Type of Bleeding | Target Factor VIII | Initial | Subsequent | Frequency and |
| Trough Activity | Dose | Dose | Duration of |
| (Units per dL or % of | (Units per |
| Subsequent |
| normal) | kg) |
| Dosing |
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Mild and moderate |
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superficial muscle / |
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no neurovascular | > 50% |
| Titrate | Dose |
compromise and |
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| subsequent | |
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| every 4 to 12 hours, | ||
joint bleeding |
|
| doses based on | |
|
| frequency may be | ||
Major moderate to |
|
| clinical response | |
|
| adjusted based on | ||
severe |
| |||
| and to maintain | clinical response | ||
intramuscular, |
|
| target Factor | |
|
| and measured | ||
retroperitoneal, |
|
| VIII trough | |
> 80% |
| Factor VIII activity | ||
gastrointestinal, |
| activity | ||
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intracranial bleeding |
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Healing phase
Once bleeding has responded, usually within the first 24 hours, continue OBIZUR with a dose that maintains the trough FVIII activity at
The length of treatment depends on clinical judgement.
Paediatric population
Use in children and adolescents below 18 years with congenital or in rare cases of acquired haemophilia is currently not approved.
Method of administration
Intravenous use.
The total volume of reconstituted OBIZUR should be administered at a rate of 1 to 2 mL per minute.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3Contraindications
Known anaphylactic reactions to the active substance, hamster protein, or to any of the excipients listed in section 6.1.
4.4Special warnings and precautions for use
Hypersensitivity
Allergic type hypersensitivity reactions are possible with OBIZUR. The product contains trace amounts of hamster proteins.
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, standard medical treatment for shock should be implemented.
Development of inhibitory antibodies
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. Inhibitor titres of up to 29 Bethesda units were recorded at baseline yet subjects 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.
There is a lack of clinical information on the development of inhibitory antibodies to OBIZUR following repeated administration. Therefore, OBIZUR must only be administered when considered clinically necessary. Extensive cutaneous purpura do not necessarily require treatment.
OBIZUR is produced by recombinant DNA technology in baby hamster kidney cells. Antibodies to baby hamster kidney cell protein were not detected in subjects after exposure to OBIZUR.
High and sustained Factor VIII activity in blood may predispose to thromboembolic events. Those with
If venous catheterisation is required, the risk of
Factor VIII activity determined by the chromogenic assay is generally lower than Factor VIII activity determined by the
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
- Onivyde - Baxalta Innovations GmbH
- Rixubis - Baxalta Innovations GmbH
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- Hyqvia - Baxalta Innovations GmbH
Prescription drugs listed. Manufacturer: "Baxalta Innovations GmbH"
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.
4.5Interaction with other medicinal products and other forms of interaction
No interactions of OBIZUR with other medicinal products have been reported.
4.6Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with OBIZUR. Experience regarding the use of OBIZUR during pregnancy and
4.7Effects on ability to drive and use machines
OBIZUR has no or negligible influence on the ability to drive and use machines.
4.8Undesirable effects
Summary of the safety profile:
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and may progress to severe anaphylaxis (including shock) (see section 4.4).
Patients with acquired haemophilia may develop inhibitory antibodies to porcine Factor VIII.
Tabulated list of adverse reactions:
The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). In the clinical trial of OBIZUR for acquired haemophilia, 29 adult subjects were evaluable for safety.
Frequencies have been evaluated according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
System Organ Class | Preferred MedDRA term | Frequency |
Investigations | Positive test for inhibitory | Common |
| antibodies against porcine Factor |
|
| VIII (see section 4.4) |
|

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 the national reporting system listed in Appendix V.
4.9Overdose
The effects of higher than recommended doses of OBIZUR have not been characterised.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation Factor VIII, porcine sequence. ATC code: B02BD14
Mechanism of action
Obizur is a recombinant,
Immediately after release in the patient’s circulation, Factor VIII binds to von Willebrand factor (vWF). The Factor VIII/von Willebrand factor complex consists of two molecules (Factor VIII and von Willebrand factor) with different physiological functions. Activated Factor VIII acts as a
Acquired haemophilia is a rare bleeding disorder in which patients with normal Factor VIII genes develop inhibitory autoantibodies directed against Factor VIII. These autoantibodies neutralize circulating human Factor VIII thus creating a deficiency of available Factor VIII. Circulating antibodies (inhibitors) targeted against human Factor VIII have minimal or no cross reactivity against OBIZUR.
OBIZUR temporarily replaces the inhibited endogenous Factor VIII that is needed for effective haemostasis.
Clinical efficacy and safety
The safety and efficacy of OBIZUR for the treatment of serious bleeding episodes in subjects with acquired haemophilia with autoimmune inhibitory antibodies to human Factor VIII was investigated in a prospective,
All initial bleeding episodes had a positive response to treatment at 24 hours after initial dosing as assessed by the primary investigator. A positive response was one where bleeding had stopped or was reduced, with clinical improvement or with Factor VIII activity above a
A positive response was observed in 95% (19/20) of subjects evaluated at 8 hours and 100% (18/18) at 16 hours. In addition to response to treatment, the overall treatment success was determined by the investigator based on his/her ability to discontinue or reduce the dose and/or dosing frequency of OBIZUR. A total of 24/28 (86%) had successful control (resolution) of the initial bleeding episode. Of those subjects treated with OBIZUR as

rFVIIa, activated
The median dose per injection to successfully treat the primary bleed was 133 U/kg and the median total dose was 1523 U/kg for a median of 6 days. The median number of daily infusions per subject was 1.76 (range: 0.2 to 5.6). In the initial 24 hour period, the median total dose of 493 U/kg were utilized in the clinical study with a median of 3 infusions. When treatment was required
beyond 24 hours, a median total dose of 1050 U/kg were utilized with a median of 10.5 infusions (median dose 100 U/kg) to control a bleeding episode.
Other information
The European Medicines Agency has waived the obligation to submit the results of studies with OBIZUR in all subsets of the paediatric population in treatment of acquired haemophilia (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
5.2Pharmacokinetic properties
Pharmacokinetic data from 5 subjects with acquired haemophilia whilst in a
Table 1: Individual pharmacokinetic data for factor VIII activity after administration of the final dose of OBIZUR to 5 subjects with acquired haemophilia. Subjects were in a
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| Dose | Baseline |
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Subject | Dose (U) | (U/kg) | hFVIII | t½ (h) | Tmax | Amax | (%·t) | |
| activity | (h) | (%) | (%·t) |
| |||
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| (%) |
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76.7 | 0.42 | |||||||
30.0 | 4.6 | 0.42 | ||||||
144.2 | 5.3 | 0.45 | ||||||
206.8 | 1.8 | 0.50 | ||||||
133.3 | N/A | 4.2 | 0.75 |
Amax = maximum observed % activity;
The mean recovery rate after the initial dose of 200 U/kg was 1.06 ± 0.75 U/ml per U/kg (range
Although factor VIII activity determined by the chromogenic assay is generally lower than the Factor VIII activity determined by the
Inhibitory antibodies against OBIZUR were measured using a modification of the Nijmegen variation of the Bethesda assay method. Three subjects included in pharmacokinetic analysis had a detectable
The mean
5.3Preclinical safety data
of 75, 225 and 750 U/kg/day tended to increase over time.
Animal reproduction studies have not been conducted with OBIZUR.
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Powder
Polysorbate 80
Sodium chloride
Calcium chloride dihydrate
Sucrose
Tris Base
Tris HCl
Solvent
Sterilised water for injections
- Flixabi - L04AB02
- Foclivia - J07BB02
- Neofordex - H02AB02
- Remsima - L04AB02
- Cerezyme - A16AB02
- Novoseven - B02BD08
Prescription drugs listed. ATC Code: "B02"
6.2Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3Shelf life
30 months.
The reconstituted solution should be used immediately, but no longer than 3 hours after reconstitution.
6.4Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5Nature 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) and a
fluid transfer device with an integral plastic spike
6.6Special precautions for disposal and other handling
After reconstitution, the solution is clear, colourless, free from particles and has a pH of 6.8 to 7.2. The osmolality of the formulation buffer ranges between 59 and 65 10% mOsm/kg H2O.
Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. Solutions with particles or discolouration must not be administered.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Preparation
Before starting reconstitution you will need the following:
Calculated number of powder vials
Same number of 1 mL solvent syringes and sterile vial adapters
Alcohol swabs
Large sterile syringe to contain the final volume of reconstituted product
The procedures below are provided as general guidelines for the preparation and reconstitution of OBIZUR. Repeat following reconstitution instructions for each powder vial to be reconstituted.
Reconstitution
Use aseptic technique during the reconstitution procedure.
1.Bring the OBIZUR powdervial and the
2.Remove the plastic cap from the OBIZUR powder vial (Figure A).
3.Wipe the rubber stopper with an alcohol swab (not supplied) and allow it to dry prior to use.
4.Peel back the cover of the vial adapter package (Figure B). Do not to touch the luer lock (tip) in the centre of the vial adapter. Do not remove the vial adapter from the package.
5.Place the vial adapter package on a clean surface with the luer lock pointing up.
6.Snap off the tamper resistant cap of the
7.While firmly holding the vial adapter package connect the
8.Remove the plastic package (Figure E).
9.Place the OBIZUR powder vial on a clean, flat, hard surface. Place the vial adapter over the OBIZUR powder vial and firmly push the filter spike of the vial adapter through the centre of the OBIZUR powder vial’s rubber circle until the clear plastic cap snaps onto the vial (Figure F).
10.Push the plunger down to slowly inject all of the diluent from the syringe into the OBIZUR powder vial.
11.Gently swirl (in a circular motion) the OBIZUR powder vial without removing the syringe until all of the powder is fully dissolved /reconstituted (Figure G). The reconstituted solution should be inspected visually for particulate matter before administration. Do not use if particulate matter or discoloration is observed.
12.With one hand hold the vial and vial adapter, and with the other hand firmly grasp the barrel of the
13.Use OBIZUR immediately and within 3 hours after reconstitution when stored at room temperature.

Figure A | Figure B | Figure C | Figure D |
Figure E | Figure F | Figure G | Figure H |
Administration
For intravenous injection only!
Inspect the reconstituted OBIZUR solution for particulate matter and discoloration prior to administration. The solution should be clear and colorless in appearance. Do not administer if particulate matter or discoloration is observed.
Do not administer OBIZUR in the same tubing or container with other medicinal products for injection.
Using aseptic technique, administer using the following procedure:
1.Once all vials have been reconstituted, connect a large syringe to the vial adapter by gently pushing the syringe tip down onto the luer lock in the centre of the vial adapter, and turning clockwise until the syringe is secured.
2.Invert the vial; push the air in the syringe into the vial and withdraw the reconstituted OBIZUR into the syringe (Figure I).
Figure I
3.Unscrew the large syringe counterclockwise from the vial adapter, and repeat this process for all reconstituted vials of OBIZUR until the total volume to be administered is reached.
4.Administer the reconstituted OBIZUR intravenously at a rate of 1 to 2 mL per minute.
7.MARKETING AUTHORISATION HOLDER
Baxalta Innovations GmbH
Industriestrasse 67
Austria
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/15/1035/001
EU/1/15/1035/002
EU/1/15/1035/003
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 11 November 2015
10.DATE OF REVISION OF THE TEXT
- Iblias
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Prescription drugs listed:
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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