OBIZUR 500U 500U / ml powder + solvent for injection medication leaflet

OBIZUR 500 U powder and solvent for solution for injection

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

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

The potency (U) is determined using the one-stage coagulation assay (OSCA). The specific activity of

OBIZUR is approximately 10,000 U/mg protein.

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

It is produced by recombinant DNA technology in baby hamster kidney (BHK) cells. The BHK cellsare cultured in media that contains foetal bovine serum. The manufacturing process is free of humanserum and human protein products and does not contain any additional animal derived materials.

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

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white.

The solvent is clear and colourless.

Treatment of bleeding episodes in patients with acquired haemophilia caused by antibodies tofactor VIII.

OBIZUR is indicated in adults.

Treatment with OBIZUR should be under the supervision of a physician experienced in the treatmentof haemophilia (see section 4.4).

The product is for in-patient administration only. It requires clinical supervision of the bleeding statusof the patient.

During the course of treatment, appropriate determination of factor VIII levels is advised to guide thedose to be administered and the frequency of repeated infusions (see section 4.4). Individual patientsmay vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dosebased on bodyweight may require adjustment in underweight or overweight patients.

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

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

The dose, frequency, and duration of the therapy with OBIZUR depend on the location, extent andseverity 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 anin-house standard that has been calibrated with the current World Health Organisation (WHO)standard for factor VIII products. One Unit (U) of factor VIII activity is equivalent to that quantity offactor VIII in one ml of normal human plasma.

The recommended initial dose is 200 U per kilogram bodyweight, given by intravenous injection (seesection 6.6).

The required initial dose of OBIZUR for a patient is calculated using the following formula:

Initial dose (U/kg)  Medicinal product strength (U/vial) × Body weight (kg) = Number of vialse.g. for a 70 kg patient 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 afteradministering OBIZUR.

Monitor factor VIII activity immediately prior to and 30 minutes after subsequent doses and refer tothe table below for recommended target factor VIII trough levels.

The one-stage clotting assay for factor VIII is recommended as it has been used in determination ofthe potency of OBIZUR and the mean recovery rate (see section 4.4 and 5.2).

The dose and frequency of administration should be based on results of factor VIII activity (to bemaintained within recommended limits) and on the clinical response achieved.

If testing of anti-rpFVIII antibodies is negative at baseline, a dose lower than the recommended200 U/kg may be used as the initial treatment dose. Clinical response should be closely monitored asdosing below 200 U/kg has been associated with a lack of efficacy (see section 4.4).

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 andtrough activity (units dose dose duration ofper dL or % of (units per subsequent dosingnormal) kg)

Mild and moderatesuperficial muscle /no neurovascular > 50% Titratecompromise and Dosesubsequentjoint bleeding every 4 to 12 hours,doses based on

Major moderate to frequency may beclinicalsevere adjusted based on200 response and tointramuscular, clinical responsemaintain targetretroperitoneal, and measuredfactor VIIIgastrointestinal, > 80% factor VIII activitytrough activityintracranialbleeding

Healing phase

Once bleeding has responded, usually within the first 24 hours, continue OBIZUR with a dose thatmaintains the trough factor VIII activity at 30-40% until bleeding is controlled. The maximum bloodfactor VIII activity must not exceed 200%.

The length of treatment depends on clinical judgement.

The safety and efficacy of OBIZUR in children and adolescents aged below 18 years with acquiredhaemophilia have not yet been established. No data are available.

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.

* Hypersensitivity to the active substance, hamster protein, or to any of the excipients listed insection 6.1.

* Congenital Haemophilia A with Inhibitors (CHAWI) (see section 5.1).

Dosing

Initial dosing below the recommended 200 U/kg has been associated with lack of efficacy (see section4.2).

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

Allergic type hypersensitivity reactions are possible with OBIZUR. The medicinal product containstrace amounts of hamster proteins.

If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinalproduct immediately and contact their physician. Patients should be informed of the early signs ofhypersensitivity 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.

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. Treatmentdecisions can be further supported by monitoring factor VIII levels. Inhibitory antibodies againstporcine 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 inhibitoryantibodies to OBIZUR. Inhibitor titres of up to 29 Bethesda units were recorded at baseline yetpatients responded positively to OBIZUR. It is recommended that treatment should be based onclinical 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 alsobeen reported in patients treated with OBIZUR. These anamnestic rises may result in lack of efficacy.

If such inhibitory antibodies to OBIZUR are suspected and there is a lack of efficacy, consider othertherapeutic options.

There is a lack of clinical information on the development of inhibitory antibodies to OBIZURfollowing repeated administration. Therefore, OBIZUR must only be administered when consideredclinically necessary. Extensive cutaneous purpura do not necessarily require treatment.

OBIZUR is produced by recombinant DNA technology in baby hamster kidney cells. Antibodies tobaby hamster kidney cell protein were not detected in patients after exposure to OBIZUR.

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

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

Factor VIII activity determined by the chromogenic assay is generally lower than factor VIII activitydetermined by the one-stage clotting assay. Measurement of factor VIII activity must always becarried out using the same assay methodology on any one patient. The one-stage assay isrecommended because it has been used in determination of the potency and the mean recovery rate of

OBIZUR (see sections 4.2 and 5.2).

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 betaken per dose.

E.g., a 70 kg patient using the recommended 200 U/kg dose would require 28 vials which results in asodium intake of 128.8 mg per treatment. This is equivalent to 6.44% of the WHO recommendedmaximum daily intake of 2 g of sodium for an adult.

No interactions of OBIZUR with other medicinal products have been reported.

Animal reproduction studies have not been conducted with OBIZUR. Experience regarding the use of

OBIZUR during pregnancy and breast-feeding is not available. Therefore, OBIZUR should be usedduring pregnancy and lactation only if clearly indicated.

OBIZUR has no or negligible influence on the ability to drive and use machines.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at theinjection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea,restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) are possible and mayprogress to severe anaphylaxis (including shock) (see section 4.4).

Patients with acquired haemophilia may develop inhibitory antibodies to porcine factor VIII.

Inhibitory antibodies, including anamnestic responses, may result in a lack of efficacy.

The table presented below is according to the MedDRA system organ classification (SOC andpreferred term level). In the clinical study of OBIZUR for acquired haemophilia, 29 adult patientswere evaluable for safety. Nineteen subjects did not have a detectable anti-porcine factor VIII inhibitortiter at baseline (< 0.6 BU/mL). Of the 19 subjects, twelve had no detectable anti-porcine factor VIIItiter 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 inhuman factor VIII and/or recombinant factor VIII porcine sequence inhibitors.

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 Adverse reaction Frequency

Investigations Positive test for inhibitory Commonantibodies against porcinefactor VIII (see section 4.4)

Immune system disorders Anamnestic reaction Very common

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions the national reporting system listedin Appendix V.

The effects of higher than recommended doses of OBIZUR have not been characterised.

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factors, ATC code: B02BD14

OBIZUR is a recombinant, B-domain deleted, porcine sequence factor VIII (susoctocog alfa). It is aglycoprotein.

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 cofactor foractivated factor IX, accelerating the conversion of factor X to activated factor X, which ultimatelyconverts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can beformed.

Acquired haemophilia is a rare bleeding disorder in which patients with normal factor VIII genesdevelop inhibitory autoantibodies directed against factor VIII. These autoantibodies neutralisecirculating 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 effectivehaemostasis.

The safety and efficacy of OBIZUR for the treatment of serious bleeding episodes in patients withacquired haemophilia with autoimmune inhibitory antibodies to human factor VIII was investigated ina prospective, non-randomised, open-label study of 28 patients (18 caucasian, 6 black, and 4 asian).

The study included patients presenting with life and/or limb threatening bleeding requiringhospitalisation.

All initial bleeding episodes had a positive response to treatment at 24 hours after initial dosing asassessed by the primary investigator. A positive response was one where bleeding had stopped or wasreduced, with clinical improvement or with factor VIII activity above a pre-specified target.

A positive response was observed in 95% (19/20) of patients evaluated at 8 hours and 100% (18/18)at 16 hours. In addition to response to treatment, the overall treatment success was determined by theinvestigator 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. Ofthose patients treated with OBIZUR as first-line therapy, defined as no immediate previous use ofanti-haemorrhagic agents prior to the first OBIZUR treatment, 16/17 (94%) had eventual treatmentsuccess reported. Eleven patients were reported to have received anti-haemorrhagic agents (e.g.

rFVIIa, activated prothrombin-complex concentrate, tranexamic acid) prior to first treatment with

OBIZUR. Of these 11 patients, eight had eventual successful treatment (73%).

The median dose per injection to successfully treat the primary bleed was 133 U/kg and the mediantotal dose was 1523 U/kg for a median of 6 days. The median number of daily infusions per patientwas 1.76 (range: 0.2 to 5.6). In the initial 24 hours period, the median total dose of 493 U/kg wereutilised in the clinical study with a median of 3 infusions. When treatment was requiredbeyond 24 hours, a median total dose of 1050 U/kg were utilised with a median of 10.5 infusions(median dose 100 U/kg) to control a bleeding episode.

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 samplesanalysed and seven subjects developed anamnestic reactions with a rise ≥ 10 BU in human factor VIIIand/or recombinant factor VIII porcine sequence inhibitors.

In the clinical study of OBIZUR in patients with congenital haemophilia A with FVIII inhibitors(CHAWI) undergoing surgery, out of 8 adult patients evaluable for safety analysis a total of 5 subjectsexperienced anamnestic reactions.

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 (seesection 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

Pharmacokinetic data from 5 patients with acquired haemophilia whilst in a non-bleeding state arepresented in table 1.

Table 1: Individual pharmacokinetic data for factor VIII activity after administration of thefinal dose of OBIZUR to 5 patients with acquired haemophilia. Patients were in anon-bleeding state. Factor VIII activity was measured by the one-stage clotting assay.

Dose Baseline AUC0-∞(U/kg) hFVIII Amax AUC0-t (%·t)

Patient Dose (U) t½ (h) Tmax (h)activity (%) (%·t)(%)1 5000 76.7 89 17 0.42 213 3124 49882 2934 30.0 18 4.6 0.42 100 694 7123 7540 144.2 3 5.3 0.45 74 473 4924 9720 206.8 0 1.8 0.50 53 122 1355 10000 133.3 N/A 4.2 0.75 178 1583 1686

Amax = maximum observed % activity; AUC0-t = area under the concentration-time curve fromtime 0 to the last measurable concentration; AUC0-∞ = area under the concentration-time curve fromtime 0 extrapolated to infinity; t½ = terminal half-life; Tmax = time of maximum observed % activity,

N/A = not available.

The mean recovery rate after the initial dose of 200 U/kg was 1.06 ± 0.75 U/ml per U/kg(range 0.10-2.61) measured with the one stage coagulation assay.

Although factor VIII activity determined by the chromogenic assay is generally lower than thefactor VIII activity determined by the one-stage clotting assay, post-infusion factor VIII activities inpatients with acquired haemophilia in clinical study OBI-1-301 tended to be higher when determinedwith the chromogenic assay than with the one-stage clotting assay (see section 4.4).

Inhibitory antibodies against OBIZUR were measured using a modification of the Nijmegen variationof the Bethesda assay method. Three patients included in pharmacokinetic analysis had a detectableanti-porcine factor VIII inhibitor titre at baseline (≥ 0.6 Bethesda Units (BU)/mL). Three of thefive patients had no detectable anti-porcine factor VIII titres post-treatment (< 0.6 BU/mL based onthe last reported result); two patients had a detectable anti-porcine factor VIII titre (≥ 0.6 BU/mL).

The mean half-life of OBIZUR in nine evaluable patients in the bleeding state was (about) 10 hours(range 2.6 to 28.6 hours).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology or repeated dose toxicity. However, in repeated dose toxicity studies, the incidence andseverity of glomerulopathy observed in monkeys intravenously administered OBIZUR at dosesof 75, 225, and 750 U/kg/day tended to increase over time.

Animal reproduction studies have not been conducted with OBIZUR.

Polysorbate 80

Sodium chloride

Calcium chloride dihydrate

Sucrose

Trometamol

Trometamol hydrochloride

Sodium citrate

Water for injections

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

3 years.

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

Store in a refrigerator (2°C-8°C). Do not freeze.

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

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-offseal;

* pre-filled (type I glass) syringes with a stopper (bromobutyl rubber coated with FluroTec® foilon the contact side), a bromobutyl rubber tip cap and a Luer lock adapter;

* fluid transfer device with an integral plastic spike.

Not all pack sizes may be marketed.

After reconstitution, the solution is clear, colourless, free from particles and has a pH of 6.8 to 7.2. Theosmolality of the formulation buffer ranges between 59 and 65 10% mOsm/kg H2O.

Reconstituted medicinal product should be inspected visually for particulate matter and discolourationprior 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 localrequirements.

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.

Use aseptic technique during the reconstitution procedure.

1. Bring the OBIZUR powder vial and the pre-filled solvent syringe to room temperature.

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) inthe 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 pre-filled solvent syringe (figure C).

7. While firmly holding the vial adapter package connect the pre-filled solvent syringe to the vialadapter by pushing the syringe tip down onto the Luer lock in the centre of the vial adapter, andturning it clockwise until the syringe is secured. Do not over tighten (figure D).

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 ofthe 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 OBIZURpowder vial.

11. Gently swirl (in a circular motion) the OBIZUR powder vial without removing the syringe untilall of the powder is fully dissolved /reconstituted (figure G). The reconstituted solution shouldbe inspected visually for particulate matter before administration. Do not use if particulatematter or discolouration is observed.

12. With one hand hold the vial and vial adapter, and with the other hand firmly grasp the barrel ofthe pre-filled solvent syringe and in a counterclockwise motion unscrew the syringe from thevial adapter (figure H).

13. Use OBIZUR immediately and within 3 hours after reconstitution when stored at roomtemperature.

Figure A Figure B Figure C Figure D

Figure E Figure F Figure G Figure H

For intravenous injection only.

* Inspect the reconstituted OBIZUR solution for particulate matter and discolouration prior toadministration. The solution should be clear and colourless in appearance. Do not administer ifparticulate matter or discolouration is observed.

* Do not administer OBIZUR in the same tubing or container with other medicinal products forinjection.

Using aseptic technique, administer using the following procedure:

1. Once all vials have been reconstituted, connect a large syringe to the vial adapter by gentlypushing the syringe tip down onto the Luer lock in the centre of the vial adapter, and turningclockwise until the syringe is secured.

2. Invert the vial; push the air in the syringe into the vial and withdraw the reconstituted OBIZURinto the syringe (figure I)3. Unscrew the large syringe counterclockwise from the vial adapter and repeat this process for allreconstituted 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.

Figure I

Baxalta Innovations GmbH

Industriestrasse 671221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/15/1035/001

EU/1/15/1035/002

EU/1/15/1035/003

Date of first authorisation: 11 November 2015

Date of latest renewal: 16 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.