Consumer medicine information

Obizur

Susoctocog alfa

BRAND INFORMATION

Brand name

Obizur

Active ingredient

Susoctocog alfa

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Obizur.

SUMMARY CMI

OBIZUR®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using OBIZUR?

OBIZUR contains the active ingredient susoctocog alfa. OBIZUR is used to treat bleeding episodes in adults with acquired haemophilia A (a bleeding disorder caused by lack of Factor VIII activity due to antibody development against Factor VIII).

For more information, see Section 1. Why am I using OBIZUR? in the full CMI.

2. What should I know before I use OBIZUR?

Do not use if you have ever had an allergic reaction to OBIZUR, or you are allergic to hamster proteins or any of the ingredients listed at the end of the CMI. Do not use if you have congenital haemophilia A with inhibitors (CHAWI).

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use OBIZUR? in the full CMI.

3. What if I am taking other medicines?

There are no known interactions of OBIZUR with other medicines.

For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given OBIZUR?

  • OBIZUR injection will be prepared and administered by a qualified healthcare professional who is experienced in the care of patients with haemophilia.
  • Your doctor will calculate your dose of OBIZUR depending on your condition and body weight.
  • OBIZUR is given slowly by injection directly into your vein.
  • The frequency of infusions you receive, and the duration of treatment, will depend on how well OBIZUR is working for you.

More instructions can be found in Section 4. How do I use OBIZUR? in the full CMI.

5. What should I know while using OBIZUR?

Things you should do
  • Tell your doctor or healthcare professional straight away if you notice:
  • any sudden signs and symptoms of a severe allergic response, e.g. shortness of breath, wheezing, difficulty breathing; chest pain or discomfort; light headedness, dizziness or fainting; puffiness or swelling of your face, lips, or any other parts of the body; rash, itching or hives on the skin.
  • your bleeding is not controlled or worsens.
Driving or using machines
  • OBIZUR is not expected to have an influence on your ability to drive or use machines.
Looking after your medicine
  • OBIZUR is to be stored at 2°C to 8°C in the refrigerator. Do not freeze.
  • The staff at the hospital and/or Haemophilia Treatment Centre will be responsible for the correct storage of OBIZUR before and during its use.

For more information, see Section 5. What should I know while using OBIZUR? in the full CMI.

6. Are there any side effects?

Development of new antibodies and/or increases in pre-existing inhibitory antibodies against the medicine may occur, and this may result in lack of efficacy with continued bleeding.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

OBIZUR®

Active ingredient(s): susoctocog alfa

Consumer Medicine Information (CMI)

This leaflet provides important information about using OBIZUR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using OBIZUR.

Where to find information in this leaflet:

1. Why am I using OBIZUR?
2. What should I know before I use OBIZUR?
3. What if I am taking other medicines?
4. How do I use OBIZUR?
5. What should I know while using OBIZUR?
6. Are there any side effects?
7. Product details

1. Why am I using OBIZUR?

OBIZUR contains the active ingredient susoctocog alfa.

OBIZUR is a recombinant DNA derived, anti-haemophilic Factor VIII.

OBIZUR is used to treat bleeding episodes in adult patients with Acquired Haemophilia A (a bleeding disorder caused by lack of Factor VIII due to antibody development against Factor VIII).

Factor VIII is necessary for the blood to form clots and stop bleedings. In patients with acquired haemophilia A, Factor VIII is not working properly because the patient has developed antibodies to the human body's Factor VIII which neutralise this blood clotting Factor and prevent blood from clotting.

OBIZUR works by temporarily replacing the missing Factor VIII activity so that blood can form clots at the site of bleeding.

2. What should I know before I use OBIZUR?

Warnings

Do not use OBIZUR if:

  • you are allergic to susoctocog alfa, or any of the ingredients listed at the end of this leaflet.
  • you are allergic to hamster proteins or if you have a known allergy to medicines of hamster origin.
  • You have congenital haemophilia A with inhibitors (CHAWI).

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have or have had any other medical conditions especially heart problems.
  • have had a history of blood clots or are at risk of developing blood clots.
  • are on a controlled sodium diet.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. It is not known if OBIZUR may harm your unborn baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if OBIZUR passes into your milk and if it can harm your baby.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with each other and affect how they work.

There are no known interactions of OBIZUR with other medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect OBIZUR.

4. How will I be given OBIZUR?

OBIZUR will be given to you in a hospital or Haemophilia Treatment Centre and under the care of your doctor who is experienced in the care of patients with haemophilia.

How much you will be given

  • Your doctor will calculate your dose of OBIZUR depending on your condition and body weight.
  • The frequency of infusions you receive, and the duration of treatment will depend on how well OBIZUR is working for you.
  • The recommended first dose is 200 Units (U) per kilogram bodyweight. Your doctor will measure your Factor VIII activity regularly to see how well you are responding to OBIZUR and decide on how much OBIZUR to give you on your next dose. Your doctor will adjust the dose and duration of OBIZUR until your bleeding stopped.

How is OBIZUR given

  • OBIZUR is given slowly by injection and your doctor or a qualified healthcare professional will inject OBIZUR directly into your vein.
  • Before you receive your OBIZUR injection, your doctor or a qualified healthcare professional will mix the vial of OBIZUR powder with the water for injections, which is included in the pack, to form a clear solution.

If you forget to use OBIZUR

As OBIZUR is given to you by your doctor or a qualified healthcare professional, it is unlikely that you will have a missed dose.

If you use too much OBIZUR

As your dose is calculated by your doctor based on your condition and body weight, it is unlikely that you will be given too much OBIZUR.

However, if you think that you have used too much OBIZUR, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using OBIZUR?

Things you should do

You will have your blood tested before and after your first OBIZUR injection, and also regularly in between injections. This is so that your doctor and/or healthcare professional can monitor your blood level of Factor VIII to see how well OBIZUR is working for you. You will also have your bloods taken to check if you have developed any inhibitory antibodies to OBIZUR.

Tell your doctor and/or healthcare professional straight away if you notice:

  • any sudden signs and symptoms of a severe allergic response, e.g.
    - shortness of breath, wheezing, difficulty breathing,
    - chest pain or discomfort
    - light headedness, dizziness, fainting
    - puffiness or swelling of your face, lips, tongue, or any parts of your body
    - rashes, itchiness, or hives on your skin.
  • your bleeding is not controlled or worsens.

Things you should not do

  • Do not stop receiving OBIZUR because you are feeling better, unless advised by your doctor or healthcare professional.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how OBIZUR affects you.

OBIZUR is not expected to have an influence on your ability to drive and use machines.

Looking after your medicine

  • Store at 2°C to 8°C in a refrigerator. Do not freeze.

The staff at the hospital and/or Haemophilia Treatment Centre will be responsible for the correct storage of OBIZUR before and during its use. They will also take care of discarding any unused solution after you have received your injection.

Keep OBIZUR out of reach of children.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Development of antibodies against OBIZUR detected in blood test results.
Your doctor will discuss this with you and decide what to do.

Serious side effects

Serious side effectsWhat to do

Rapid increase in existing inhibitory antibodies to OBIZUR may develop, which may result in lack of efficacy with continued bleeding. Signs and symptoms include:

  • bruises
  • bleeding of the mouth and gums
  • blood in urine or stool
  • frequent and hard-to-stop nosebleeds
  • swelling and pain or tightness in the joints, e.g. knees, elbows and ankles.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

What OBIZUR contains

Active ingredient
(main ingredient)		susoctocog alfa
Other ingredients
(inactive ingredients)		polysorbate 80
sodium chloride
sucrose
sodium citrate dihydrate
calcium chloride dihydrate
trometamol
water for injections (diluent)
Potential allergensOBIZUR does not contain gluten, dyes or preservatives.

Do not take this medicine if you are allergic to any of these ingredients.

What OBIZUR looks like

OBIZUR is supplied in a glass vial as a white powder, which requires mixing with the prefilled syringe of water for injections that is included in the pack. After the powder is fully mixed with the water for injections, a clear and colourless solution is formed.

OBIZUR is packed in cartons of 1, 5 and 10 single-packs. Each single pack contains:

  • 1 vial of OBIZUR powder for injection
  • 1 prefilled syringe of water for injections
  • 1 vial adapter (a fluid transfer device)

Not all pack sizes may be marketed.

(AUST R 236475).

Who distributes OBIZUR

Takeda Pharmaceuticals Australia Pty Ltd
Level 39
225 George Street
Sydney NSW 2000
Australia
Telephone: 1800 012 612
www.takeda.com/en-au

This leaflet was prepared in March 2023.

OBIZUR® is a registered trademark of Baxalta Incorporated.

TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Obizur

Active ingredient

Susoctocog alfa

Schedule

Unscheduled

 

1 Name of Medicine

Susoctocog alfa (bhk).

2 Qualitative and Quantitative Composition

Each Obizur vial contains nominally 500 units (U) of susoctocog alfa, which is a B domain deleted recombinant derived antihaemophilic factor VIII (rpFVIII), porcine sequence.
After reconstitution, Obizur contains nominally 500 U/mL susoctocog alfa.
Each vial of Obizur is labelled with the actual rpFVIII activity expressed in units determined by a one stage clotting assay, using a reference rpFVIII material calibrated against the World Health Organization (WHO) 8th International Standard for human factor VIII concentrates. The specific activity of Obizur is in the range of 11,000-18,000 units per milligram of protein. The potency values of Obizur determined by the chromogenic assay vary and are approximately 20-50% lower than those of the one-stage clotting assay.
Susoctocog alfa is expressed in a genetically engineered baby hamster kidney (BHK) cell line and secreted into the cell culture medium, and the protein is purified using a series of chromatography and filtration steps. The production process includes two dedicated viral clearance steps - a solvent/detergent treatment step for viral inactivation and a nanofiltration step through a series of two 15 nanometre filters for removal of viruses. No additives of human or animal origin are used in the formulation of Obizur.

Excipient(s) with known effect.

Each vial of Obizur contains maximally 4.4 mg (198 mM) sodium per mL of reconstituted solution (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and diluent for solution for injection.
Obizur is formulated as a white, sterile, non-pyrogenic, lyophilised powder for intravenous injection after reconstitution with the diluent.
The diluent, water for injections, is a clear and colourless solution, practically free from visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Obizur, antihaemophilic factor (recombinant), porcine sequence, is a recombinant DNA derived, antihaemophilic factor indicated for the treatment of bleeding episodes in adults with acquired haemophilia A.
Safety and efficacy of Obizur have not been established in patients with baseline anti-porcine factor VIII inhibitor titre greater than 20 Bethesda Units (BU).
Obizur is not indicated for the treatment of congenital haemophilia A or von Willebrand disease.

4.2 Dose and Method of Administration

Treatment with Obizur under the supervision of a physician experienced in the treatment of bleeding disorders is recommended.
For prescribed doses of Obizur, "units" should be written in full.
The product is for single use in one patient only. Discard any residue.
Dosage, frequency, and duration of treatment with Obizur depends on the severity of bleeding episode, target factor VIII levels, and the patient's clinical condition.
Parenteral drug products should be inspected for particulate matter and discolouration prior to administration. Do not administer if particulate matter or discoloration is found; contact Takeda Customer Service.

Dose.

Dose, dosing frequency, and duration of treatment with Obizur depend on the location and severity of bleeding episode, target factor VIII levels, and the patient's clinical condition. Monitor replacement therapy in cases of major surgery or life-threatening bleeding episodes.
Each vial of Obizur has the recombinant porcine factor VIII potency in units stated on the vial.
Patients may vary in their pharmacokinetic (e.g. half-life, in vivo recovery) and clinical responses. Titrate dose and frequency based on factor VIII recovery levels and individual clinical response.
A guide for dosing Obizur for the treatment of bleeding episodes is provided in Table 1. Maintain the factor VIII activity within the target range. Plasma levels of factor VIII should not exceed 200% of normal or 200 units per dL.

Reconstitution.

Use aseptic technique during the reconstitution procedure.
If the patient needs more than one vial of Obizur per injection, reconstitute each vial according to the following instructions:
1. Bring the Obizur vial and the prefilled diluent syringe to room temperature.
2. Remove the plastic cap from the Obizur vial.
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. Do not touch the luer-lock (tip) in the center of the vial adapter. Do not remove the vial adapter from the plastic 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 prefilled syringe.
7. While firmly holding the vial adapter package, connect the prefilled syringe to the vial adapter by pushing the syringe tip down onto the luer lock in the center of the vial adapter, and turning it clockwise until the syringe is secured. Do not over tighten.
8. Remove the plastic package.
9. Place the Obizur vial on a clean, flat, hard surface. Place the vial adapter over the Obizur vial and firmly push the filter spike of the vial adapter through the center of the rubber circle until the clear plastic cap snaps onto the vial.
10. Push the plunger down to slowly inject all of the diluent from the syringe into the Obizur vial.
11. Gently swirl (in a circular motion) the Obizur vial without removing the syringe until all of the powder is fully dissolved. 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 prefilled syringe and in a counterclockwise motion unscrew the syringe from the vial adapter.
13. Use Obizur within 3 hours after reconstitution when stored at room temperature.

Administration.

For intravenous injection only.
Inspect the reconstituted Obizur solution for particulate matter and discoloration prior to administration. The solution should be clear and colourless in appearance. Do not administer if particulate matter or discolouration is observed.
Do not administer Obizur in the same tubing or container with other medicinal products for infusion.
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 center 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.
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.

4.3 Contraindications

Obizur is contraindicated in:
patients who have had life-threatening hypersensitivity reactions to Obizur or its components (including traces of hamster proteins);
congenital haemophilia A with inhibitors (CHAWI), see Section 4.8 Adverse Effects (Undesirable Effects), Immunogenicity.

4.4 Special Warnings and Precautions for Use

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

Hypersensitivity reactions.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticarial, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and may progress to severe anaphylaxis (including shock).
Immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur.

Inhibitory antibodies.

Inhibitory antibodies to Obizur have occurred in patients treated with Obizur. Lack of efficacy could be due to inhibitory antibodies to Obizur. Anamnestic reactions with rise in human factor VIII and/or recombinant factor VIII, porcine sequence inhibitors have also been reported in patients treated with Obizur. These anamnestic rises may result in lack of response to Obizur.
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.
Monitor patients for the development of antibodies to Obizur by appropriate assays (see Section 4.8 Adverse Effects (Undesirable Effects)). If the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled after Obizur administration, suspect the presence of an anti-porcine factor VIII antibody.
If such inhibitory antibodies to porcine factor VIII are suspected and there is a lack of clinical response, consider other therapeutic options.

Monitoring laboratory tests.

Perform one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and maintained (see Section 4.2 Dose and Method of Administration).
Monitor factor VIII activity 30 minutes and 3 hours after initial dose.
Monitor factor VIII activity 30 minutes after subsequent doses.
Monitor the development of inhibitory antibodies to Obizur. Perform a Nijmegen Bethesda inhibitor assay if expected plasma factor VIII activity levels are not attained or if bleeding is not controlled with the expected dose of Obizur. Use Bethesda Units (BU) to report inhibitor levels.

Others.

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.
Obizur contains maximally 4.4 mg (198 mM) sodium per 500 unit (nominal) vial. This should be taken into consideration by patients on a controlled sodium diet.

Use in the elderly.

Of the 29 subjects within the trial, the average age was 70 years of age. Nineteen subjects were 65 years of age or older. Clinical studies suggest that Obizur is safe and effective in the adult population (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). While no differences were observed between geriatric and adult responses to Obizur, these findings are inconclusive given the small number of subjects enrolled in either group.
Dose adjustments in the geriatric population have not been studied. Specific hazards associated with the concomitant use of Obizur with other drugs in the elderly population have not been studied in the clinical trial.

Paediatric use.

The safety and efficacy of Obizur have not been established in paediatric patients.
Use in children [from 0 (birth) to < 18 years] with congenital or in rare cases acquired haemophilia is currently not approved, also see Section 4.3 Contraindications.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions of Obizur with other medicinal products are known.
No interaction studies have been performed with Obizur. Further, no interactions of Obizur with other medicinal products have been reported.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Obizur on fertility have not been established.
(Category B2)
There are no adequate or well-controlled studies with Obizur, or other recombinant factor VIII products, in pregnant women. Studies in pregnant animals have not been conducted with susoctocog alfa. Therefore, Obizur should only be used in pregnant women if clearly needed.
 It is not known whether Obizur is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Obizur is administered to breastfeeding mothers.

4.7 Effects on Ability to Drive and Use Machines

There is no information of the effects of Obizur on the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical trials.

In the clinical trial of Obizur for acquired haemophilia A, 29 adult subjects were evaluable for safety. Of the 29 adult subjects, ten were between the ages of 42 and 65, and 19 were 65 years of age or older. Ten (34%) subjects were female.
In the clinical trial, serious adverse drug reactions (ADRs) occurred in 9 subjects. Two subjects (6.9%) developed anti-porcine factor VIII inhibitors (> 0.6 BU) that were considered an adverse reaction (AR) to Obizur by the investigator. Seven subjects (24.1%) developed anamnestic reactions with a rise ≥ 10 BU in human factor VIII and/or recombinant factor VIII, porcine sequence inhibitors. See Table 2.

Immunogenicity.

All subjects were monitored for development of inhibitory antibodies to Obizur using the Nijmegen modification of the Bethesda inhibitor assay. A subject was considered to have developed an Obizur inhibitor if the titre was ≥ 0.6 BU/mL.
Of the 29 subjects treated with Obizur, 19 subjects did not have a detectable anti-porcine factor VIII inhibitor titer at baseline (< 0.6 BU/mL). Of the 19 subjects, 12 subjects had no detectable anti-porcine factor VIII titer post-treatment, 5 subjects had an increase in titer (≥ 0.6 BU/mL), and 2 subjects had no post-treatment samples analysed. Seven subjects developed anamnestic reactions with a rise ≥ 10 BU/mL in human factor VIII and/or recombinant factor VIII, porcine sequence inhibitors. Of the 10 subjects with detectable anti-porcine factor VIII inhibitor titer at baseline, which can be considered to be cross reactive with anti-human factor VIII inhibitors, 8 subjects had no detectable anti-porcine factor VIII titer post-treatment (< 0.6 BU/mL based on the last reported result), 2 subjects experienced an increase in titre (≥ 0.6 BU/mL).
All subjects were also monitored for development of binding antibodies to baby hamster kidney (BHK) protein by a validated sequential ELISA (enzyme-linked immunosorbent assay). No patients developed de novo anti-BHK antibodies.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Obizur with the incidence of antibodies to other products may be misleading.
In the clinical study of Obizur in patients with congenital haemophilia A with factor VIII inhibitors (CHAWI) undergoing surgery, out of 8 adult patients evaluable for safety analysis a total of 5 subjects experienced anamnestic reactions.

Post-marketing adverse reactions.

No adverse reactions other than those reported during clinical trials have been observed in the post-marketing setting.

Reporting suspected adverse effects.

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

4.9 Overdose

No symptoms of overdose have been reported.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, porcine sequence.
ATC code: B02BD14.

Mechanism of action.

Patients with acquired haemophilia A have normal factor VIII genes but develop auto-antibodies against their own factor VIII (i.e. inhibitors). These auto-antibodies neutralise circulating human factor VIII and create a functional deficiency of this pro-coagulant protein. Acquired haemophilia A results in a prolonged clotting time as measured by the activated partial thromboplastin time (aPTT) assay, a conventional in vitro test for biological activity of factor VIII.
Treatment with Obizur should normalise the aPTT during treatment; however aPTT normalisation should not be used as a measure of efficacy. Once susoctocog alfa is activated, the resulting molecule has a comparable activity to the endogenous human activated factor VIII.

Clinical trials.

The efficacy of Obizur for the treatment of serious bleeding episodes in subjects with acquired haemophilia A was investigated in a prospective, open-label trial (N = 29). The trial was conducted in 18 Caucasian, 6 African-American, and 5 Asian subjects diagnosed with acquired haemophilia A, having auto-immune inhibitory antibodies to human factor VIII, and experiencing serious bleeding episodes that required hospitalisation. Subjects with a prior history of bleeding disorders other than acquired haemophilia A, anti-porcine factor VIII antibody titre > 20 BU, or in whom the bleeding episode was judged likely to resolve on its own were excluded. One subject was considered evaluable at study entry; however, it was later determined that this subject did not have acquired haemophilia A, leaving 28 subjects evaluable for efficacy.
An initial dose of 200 units per kg Obizur was administered to subjects for the treatment of life- or limb-threatening initial bleeding episodes. Patients were treated with Obizur until resolution of bleeding or dosing was continued at the physician's discretion according to the clinical assessment. These bleeding episodes included 19 intramuscular or joint bleeding episodes, 4 postsurgical bleeding episodes, 2 intracranial episodes, 2 surgeries, 1 retroperitoneal haemorrhage, and 1 periorbital bleed. Haemostatic response was assessed by the study site investigator at specified time points after initiation of Obizur treatment using a pre-specified rating scale that was based on subjective clinical assessments combined with objective factor VIII activity levels achieved. An assessment of effective or partially effective was considered as a positive response (see Table 3 for definitions).
Of the 28 subjects evaluable for efficacy, all subjects had a positive response to treatment for the initial bleeding episodes at 24 hours after dosing. 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 treatment of the initial bleeding episode. Of those subjects treated with Obizur as first-line therapy, defined as no immediate previous use of antihaemorrhagic agents prior to the first Obizur treatment, 16/17 (94%) had eventual treatment success reported. Eleven subjects were reported to have received antihaemorrhagics (e.g. rFVIIa, activated prothrombin-complex concentrate, tranexamic acid) prior to first treatment with Obizur. Of these 11 subjects, eight had eventual successful treatment (73%).
The median dose per infusion to successfully treat the primary bleeding episode was 133 units per kg and a median total dose of 1523 units per kg. In the initial 24 hour period, a median of 3 infusions (median dose 200 U/kg) were utilised in the clinical study. When treatment was required beyond 24 hours, a median of 10.5 infusions (median dose 100 U/kg) were given for a median of 6 days to control a bleeding episode.

5.2 Pharmacokinetic Properties

Pharmacokinetic (PK) data on Obizur are limited and were obtained from 5 subjects in a safety and efficacy study 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, open-label trial (N = 29). The trial was conducted in 18 Caucasian, African-American, and 5 Asian subject(s) experiencing serious bleeding requiring hospitalisation.
All blood draws were done while the subject was in a non-bleeding state. For each subject t1/2, Tmax, Amax, AUC from time 0 to last measurement (AUC0-t), AUC0-inf, CL, and the volume of distribution at steady state are presented. Mean values for each parameter are also presented.
For the final dose PK analysis, the % relative factor VIII activity data from the one-stage assays are presented as baseline-corrected values. The individual and summary PK parameters are presented in Table 4.
The summary parameters indicate a maximal activity of Obizur (Tmax) at about 26 minutes, with a mean terminal half time (t1/2) of 3.5 hours after dosing. The data are consistent with Obizur following first order elimination.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been conducted which is acceptable for a biotechnology-derived product such as Obizur.

Carcinogenicity.

Carcinogenicity studies have not been conducted which is acceptable for a biotechnology derived product such as Obizur.

6 Pharmaceutical Particulars

6.1 List of Excipients

Polysorbate 80, sodium chloride, calcium chloride dihydrate, sucrose, trometamol, sodium citrate dihydrate, water for injections (diluent).

6.2 Incompatibilities

Incompatibility studies have not been performed with Obizur. In the absence of compatibility studies with Obizur, this medicinal product should not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C-8°C). Do not freeze.
Do not use beyond the expiration date.

Storage after reconstitution.

The reconstituted product should be used immediately, but no longer than 3 hours after reconstitution.

6.5 Nature and Contents of Container

Each pack of Obizur contains 1, 5 or 10 each of the following:
powder vial(s) of 500 units susoctocog alfa;
diluent prefilled syringe(s) of 1 mL water for injections;
vial adapter(s) with filter.
Both the powder vial and the diluent prefilled syringe are supplied in type 1 glass with butyl rubber stopper.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Susoctocog alfa is a purified glycoprotein with an approximate molecular weight of 170 kDa, containing a 90 kDa heavy chain and a 80 kDa light chain. The B-domain normally present in naturally occurring porcine factor VIII has been replaced with a twenty-four amino acid linker.

CAS number.

1339940-90-7.

7 Medicine Schedule (Poisons Standard)

Unscheduled (Exempted).

Summary Table of Changes