ELOCTA 1500UI powder + solvent for injection medication leaflet

ELOCTA 250 IU powder and solvent for solution for injection

ELOCTA 500 IU powder and solvent for solution for injection

ELOCTA 750 IU powder and solvent for solution for injection

ELOCTA 1000 IU powder and solvent for solution for injection

ELOCTA 1500 IU powder and solvent for solution for injection

ELOCTA 2000 IU powder and solvent for solution for injection

ELOCTA 3000 IU powder and solvent for solution for injection

ELOCTA 4000 IU powder and solvent for solution for injection

ELOCTA 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU efmoroctocog alfa.

ELOCTA contains approximately 83 IU/mL of recombinant human coagulation factor VIII, efmoroctocogalfa after reconstitution.

ELOCTA 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU efmoroctocog alfa. ELOCTA contains approximately 167 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 750 IU powder and solvent for solution for injection

Each vial contains nominally 750 IU efmoroctocog alfa. ELOCTA contains approximately 250 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU efmoroctocog alfa. ELOCTA contains approximately 333 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 1500 IU powder and solvent for solution for injection

Each vial contains nominally 1500 IU efmoroctocog alfa. ELOCTA contains approximately 500 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU efmoroctocog alfa. ELOCTA contains approximately 667 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 3000 IU powder and solvent for solution for injection

Each vial contains nominally 3000 IU efmoroctocog alfa. ELOCTA contains approximately 1000 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

ELOCTA 4000 IU powder and solvent for solution for injection

Each vial contains nominally 4000 IU efmoroctocog alfa. ELOCTA contains approximately 1333 IU/mL ofrecombinant efmoroctocog alfa after reconstitution.

The potency (International Units (IU)) is determined using the European Pharmacopoeia chromogenic assay.

The specific activity of ELOCTA is 4000-10200 IU/mg protein.

Efmoroctocog alfa (recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc)) has1,890 amino acids. It is produced by recombinant DNA technology in a human embryonic kidney (HEK) cellline without the addition of any exogenous human- or animal-derived protein in the cell culture process,purification or final formulation.

Excipient with known effect0.6 mmol (or 14 mg) sodium per vial.

0.4 mg of polysorbate 20 per vial.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Powder: lyophilised, white to off-white powder or cake.

Solvent: water for injections, a clear, colourless solution.

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

ELOCTA can be used for all age groups.

Treatment should be initiated under the supervision of a physician experienced in the treatment ofhaemophilia.

During the course of treatment, appropriate determination of factor VIII levels (by one-stage clotting orchromogenic assays) is advised to guide the dose to be administered and the frequency of repeated injections.

Individual patients may vary in their response to factor VIII, demonstrating different half-lives andrecoveries. Dose based on bodyweight may require adjustment in underweight and overweight patients. Inthe case of major surgical interventions in particular, precise monitoring of the substitution therapy by meansof 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 the aPTT reagent and the reference standard used in the assay. Also there can besignificant discrepancies between assay results obtained by aPTT-based one stage clotting assay and thechromogenic assay according to Ph. Eur. This is of importance particularly when changing the laboratoryand/or reagent used in the assay.

The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on thelocation and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in IU, which are related to the current WHOstandard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relativeto normal human plasma) or in IU (relative to an International Standard for factor VIII in plasma).

One IU of recombinant factor VIII Fc activity is equivalent to that quantity of factor VIII in one mL ofnormal human plasma.

On-demand treatment

The calculation of the required dose of recombinant factor VIII Fc is based on the empirical finding that 1 IUfactor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dL. The required dose isdetermined using the following formula:

Required units = body weight (kg) × desired factor VIII rise (%) (IU/dL) × 0.5 (IU/kg per IU/dL)

The amount to be administered and the frequency of administration should always be oriented to the clinicaleffectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the givenplasma activity level (in % of normal or IU/dL) in the corresponding period. Table 1 can be used to guidedosing in bleeding episodes and surgery:

Table 1: Guide to ELOCTA dosing for treatment of bleeding episodes and surgery

Degree of haemorrhage/Factor VIII level Frequency of doses (hours)/ Duration of

Type of surgical procedure required (%) (IU/dL) therapy (days)

Early haemarthrosis, muscle 20-40 Repeat injection every 12 to 24 hours for atbleeding or oral bleeding least 1 day, until the bleeding episode asindicated by pain is resolved or healing isachieved. 1

More extensive 30-60 Repeat injection every 12 to 24 hours for 3-4haemarthrosis, muscle days or more until pain and acute disabilitybleeding or haematoma are resolved. 1

Life threatening 60-100 Repeat injection every 8 to 24 hours untilhaemorrhages threat is resolved.

Minor surgery including 30-60 Repeat injection every 24 hours, for at least 1tooth extraction day, until healing is achieved.

Major surgery 80-100 Repeat injection every 8 to 24 hours as(pre- and post- necessary until adequate wound healing, thenoperative) therapy at least for another 7 days to maintaina factor VIII activity of 30% to 60% (IU/dL).

1 In some patients and circumstances the dosing interval can be prolonged up to 36 hours. See section 5.2 forpharmacokinetic data.

For long term prophylaxis, the recommended dose is 50 IU of factor VIII per kg body weight at intervals of 3to 5 days. The dose may be adjusted based on patient response in the range of 25 to 65 IU/kg (see section 5.1and 5.2).

In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

There is limited experience in patients ≥65 years.

For children below the age of 12, more frequent or higher doses may be required (see section 5.1). Foradolescents of 12 years of age and above, the dose recommendations are the same as for adults.

ELOCTA is for intravenous use.

ELOCTA should be injected intravenously over several minutes. The rate of administration should bedetermined by the patient’s comfort level and should not exceed 10 mL/min.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Allergic type hypersensitivity reactions are possible with ELOCTA. If symptoms of hypersensitivity occur,patients should be advised to discontinue use of the medicinal product immediately and contact theirphysician. Patients should be informed of the signs of hypersensitivity reactions including hives, generalisedurticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.

In case of shock, standard medical treatment for shock should be implemented.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in themanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directedagainst the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasmausing the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as wellas the exposure to factor VIII, this risk being highest within the first 50 exposure days but continuesthroughout life although the risk is uncommon.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posingless of a risk of insufficient clinical response than high titre inhibitors.

In general, all patients treated with coagulation factor VIII products should be carefully monitored for thedevelopment of inhibitors by appropriate clinical observations and laboratory tests. If the expectedfactor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose,testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor,factor VIII therapy may not be effective and other therapeutic options should be considered. Management ofsuch patients should be directed by physicians with experience in the care of haemophilia and factor VIIIinhibitors.

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

If a central venous access device (CVAD) is required, risk of CVAD-related complications including localinfections, bacteraemia and catheter site thrombosis should be considered.

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

The listed warnings and precautions apply both to adults, children and adolescents.

Excipient related considerations

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially‘sodium-free’.

However, depending on the body weight and posology, the patient could receive more than one vial (seesection 2 for information on content per vial). This should be taken into consideration by patients on acontrolled sodium diet.

Polysorbate

This medicine contains 0.4 mg of polysorbate 20 in each vial. Polysorbates may cause allergic reactions.

No interactions of human coagulation factor VIII (rDNA) with other medicinal products have been reported.

No interaction studies have been performed.

Animal reproduction studies have not been conducted with factor VIII. A placental transfer study in micewas conducted with ELOCTA (see section 5.3). Based on the rare occurrence of haemophilia A in women,experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore,factor VIII should be used during pregnancy and breast-feeding only if clearly indicated.

ELOCTA has no influence on the ability to drive and use machines.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusionsite, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness,tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in somecases progress to severe anaphylaxis (including shock).

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated withfactor VIII, including with ELOCTA. If such inhibitors occur, the condition will manifest itself as aninsufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre becontacted.

The Table 2 presented below is according to the MedDRA system organ classification (SOC and Preferred

Term Level). Frequencies of adverse reactions are based on clinical studies with a total of 379 patients withsevere haemophilia A, of which 276 were previously treated patients (PTPs) and 103 were previouslyuntreated patients (PUPs). See section 5.1 for additional details on the clinical studies.

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), notknown (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions reported for ELOCTA in clinical trials1

MedDRA System Organ Class Adverse reactions Frequency category1

Blood and lymphatic system disorders FVIII inhibition Uncommon (PTPs)2

Very common (PUPs)2

Nervous system disorders Headache Uncommon

Dizziness Uncommon

Dysgeusia Uncommon

Cardiac disorders Bradycardia Uncommon

Vascular disorders Hypertension Uncommon

Hot flush Uncommon

Angiopathy4 Uncommon

Respiratory, thoracic, and mediastinal Cough Uncommondisorders

Gastrointestinal disorders Abdominal pain, lower Uncommon

Skin and subcutaneous tissue disorders Papular rash Common (PUPs)3

Rash Uncommon

Musculoskeletal and connective tissue Arthralgia Uncommondisorders Myalgia Uncommon

Back pain Uncommon

Joint swelling Uncommon

General disorders and administration site Device related thrombosis Common (PUPs)3conditions Malaise Uncommon

Chest pain Uncommon

Feeling cold Uncommon

Feeling hot Uncommon

Injury, poisoning, and procedural Procedural hypotension Uncommoncomplications

PTPs = previously treated patients, PUPs = previously untreated patients.1 ADRs and frequency are based on occurrence in PTPs only, unless otherwise noted.2 Frequency is based on studies with all FVIII products which included patients with severe haemophilia A.3 ADRs and frequency are based on occurrence in PUPs only.4 Investigator term: vascular pain after injection of ELOCTA.

No age-specific differences in adverse reactions were observed between paediatric and adult subjects.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

No symptoms of overdose have been reported.

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrandfactor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds tovon Willebrand factor in the patient’s circulation. Activated factor VIII acts as a cofactor for activatedfactor IX, accelerating the conversion of factor X to activated factor X. Activated factor X convertsprothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of functionalfactor VIII:C and results in bleeding into joints, muscles or internal organs, either spontaneously or as aresult of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased,thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates andbetween different clinical studies.

ELOCTA (efmoroctocog alfa) is a fully recombinant fusion protein with extended half-life. ELOCTA iscomprised of recombinant B-domain deleted human coagulation factor VIII covalently linked to the

Fc domain of human immunoglobulin G1. The Fc region of human immunoglobulin G1 binds to the neonatal

Fc receptor. This receptor is expressed throughout life and is part of a naturally occurring pathway thatprotects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation,resulting in their long plasma half-life. Efmoroctocog alfa binds to neonatal Fc receptor thereby utilising thissame naturally occurring pathway to delay lysosomal degradation and allow for longer plasma half-life thanendogenous factor VIII.

The safety, efficacy, and pharmacokinetics of ELOCTA in previously treated patients (PTPs) were evaluatedin 2 multinational, open-label, pivotal phase 3 studies, Study I and Study II (see Paediatric population), andan extension study (Study III) with a duration of up to four years. In total 276 PTPs were followed for a totalof 80,848 exposure days with a median of 294 (range 1-735) exposure days per patient. In addition, a phase 3study (Study IV) was performed to evaluate the safety and efficacy of ELOCTA in previously untreatedpatients (PUPs) (see Paediatric population).

Study I enrolled 165 previously treated male patients (12 to 65 years of age) with severe haemophilia A.

Subjects on prophylaxis regimens prior to entering the study were assigned to the individualised prophylaxisarm. Subjects on on-demand therapy prior to entry either entered the individualised prophylaxis arm or wererandomised to the weekly prophylaxis or on-demand arms.

Prophylaxis regimens:

Individualised prophylaxis: 25 to 65 IU/kg every 3 to 5 days.

Weekly prophylaxis: 65 IU/kg

Out of 153 subjects who completed Study I, 150 were enrolled onto Study III (extension study). Median totaltime on Study I+III was 4.2 years and median number of exposure days was 309.

Individualised prophylaxis: Median annual factor consumption was 4212 IU/kg (min. 2877, max. 7943) in

Study I and 4223 IU/kg (min. 2668, max 8317) in Study III. Respective median Annualized Bleed Rate(ABR) was 1.60 (min. 0, max. 18.2) and 0.74 (min. 0, max. 15.6).

Weekly prophylaxis: Median annual factor consumption was 3805 IU/kg (min. 3353, max. 6196) in Study Iand 3510 IU/kg (min. 2758, max. 3984) in Study III. Respective median ABR was 3.59 (min. 0, max. 58.0)and 2.24 (min. 0, max. 17.2).

On-demand treatment: Median annual factor consumption was 1039 IU/kg (min. 280, max. 3571) for23 patients randomised to the on-demand treatment arm in Study I and 671 IU/kg (min. 286, max. 913) for6 patients remaining on on-demand treatment for at least one year in Study III.

Subjects that switched from on-demand treatment to weekly prophylaxis during Study III had a median ABRof 1.67.

Treatment of bleeding: 2490 bleeding events were treated during Study I and III with a median dose of43.8 IU/kg (min. 13.0, max. 172.8) to control each bleed. 79.2 % of first injections were rated as excellent orgood by the patients.

Perioperative management (surgical prophylaxis): A total of 48 major surgical procedures were performedand assessed in 34 subjects in Study I and Study III. The haemostatic response was rated by the physicians asexcellent in 41 and as good in 3 of 44 major surgeries. Median dose to maintain haemostasis during surgerywas 60.6 IU/kg (min. 38, max. 158).

Study II enrolled a total of 71 previously treated male paediatric patients <12 years of age with severehaemophilia A. Of the 71 enrolled subjects, 69 received at least 1 dose of ELOCTA and were evaluable forefficacy (35 were <6 years of age and 34 were 6 to <12 years of age). The starting prophylactic regimenconsisted of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. Dosing of up to 80 IU/kg anda dosing interval as short as 2 days was allowed and used in a limited number of patients. Out of 67 subjectshaving completed Study II, 61 enrolled onto Study III (extension study). Median total time on study II+IIIwas 3.4 years and median number of exposure days was 332.

Prophylaxis, age <6 years: Median dose interval was 3.50 days in Study II and Study III. Median annualfactor consumption was 5146 IU/kg (min. 3695, max. 8474) in Study II and 5418 IU/kg (min. 3435, max.

9564) in Study III. Respective median Annualized Bleed Rate (ABR) was 0.00 (min. 0, max. 10.5) and 1.18(min. 0, max. 9.2).

Prophylaxis, age 6 up to 12 years: Median dose interval was 3.49 days in Study II and 3.50 days in Study III.

Median annual factor consumption was 4700 IU/kg (min. 3819, max. 8230 IU/kg) in Study II and4990 IU/kg (min. 3856, max. 9527) in Study III. Respective median ABR was 2.01 (min. 0, max. 27.2) and1.59 (min. 0, max. 8.0).

12 adolescent subjects age 12 up to 18 years were included in the adult study population on prophylactictreatment. Median annual factor consumption was 5572 IU/kg (min. 3849, max. 7035) in Study I and4456 IU/kg (min. 3563, max. 8011) in Study III. Respective median ABR was 1.92 (min. 0, max. 7.1) and1.25 (min. 0, max. 9.5).

Treatment of bleeding: During Studies II and III, 447 bleeding events were treated with a median dose of63 IU/kg (min. 28, max. 186) to control each bleed. 90.2 % of first injections were rated as excellent or goodby the patients and their caregivers.

Study IV evaluated 103 male previously untreated patients (PUPs) <6 years of age with severehaemophilia A. Patients were followed for a total of 11,255 exposure days with a median of 100 (range0-649) exposure days per patient. Most subjects started on episodic treatment (N=81) with subsequenttransition to prophylaxis (N=69). At any time during the study, 89 PUPs received prophylaxis. Therecommended initial dose on prophylaxis was 25-80 IU/kg at 3-5-day intervals. For subjects onprophylaxis, the median average weekly dose was 101.4 IU/kg (range: 28.5-776.3 IU/kg) and themedian dosing interval was 3.87 days (range 1.1 to 7 days). Median annual factor consumption was3971.4 IU/kg. Annualized Bleeding Rate was 1.49 (min. 0.0, max. 18.7).

All pharmacokinetic studies with ELOCTA were conducted in previously treated patients with severehaemophilia A. Data presented in this section were obtained by chromogenic and one-stage clotting assays.

The pharmacokinetic parameters from the chromogenic assay data were similar to those derived for theone-stage assay.

Pharmacokinetic properties were evaluated in 28 subjects (≥15 years) receiving ELOCTA (rFVIIIFc).

Following a washout period of at least 96 hours (4 days), the subjects received a single dose of 50 IU/kg of

ELOCTA. Pharmacokinetic samples were collected pre-dose and then subsequently at 7 time points up to120 hours (5 days) post-dose. Pharmacokinetic parameters after 50 IU/kg dose of ELOCTA are presented in

Tables 3 and 4.

Table 3: Pharmacokinetic parameters of ELOCTA using the one-stage clotting assay

ELOCTA

Pharmacokinetic parameters1 (95% CI)

N=282.24

Incremental Recovery (IU/dL per IU/kg)(2.11-2.38)

AUC/Dose 51.2(IU*h/dL per IU/kg) (45.0-58.4)

Cmax (IU/dL)(101-115)1.95

CL (mL/h/kg)(1.71-2.22)19.0t½ (h)(17.0-21.1)25.2

MRT (h)(22.7-27.9)49.1

Vss (mL/kg)(46.6-51.7)1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; Cmax = maximum activity; AUC = area under the FVIII activity timecurve; t½ = terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = meanresidence time.

Table 4: Pharmacokinetic parameters of ELOCTA using the chromogenic assay

ELOCTA

Pharmacokinetic parameters1(95% CI)

N=272.49

Incremental Recovery (IU/dL per IU/kg)(2.28-2.73)

AUC/Dose 47.5(IU*h/dL per IU/kg) (41.6-54.2)

Cmax (IU/dL)(104-165)2.11

CL (mL/h/kg)(1.85-2.41)20.9t½ (h)(18.2-23.9)25.0

MRT (h)(22.4-27.8)52.6

Vss (mL/kg)(47.4-58.3)1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; Cmax = maximum activity; AUC = area under the FVIII activity timecurve; t½ = terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = meanresidence time.

The PK data demonstrate that ELOCTA has a prolonged circulating half-life.

Pharmacokinetic parameters of ELOCTA were determined for adolescents in study I (pharmacokineticsampling was conducted pre-dose followed by assessment at multiple time points up to 120 hours (5 days)post-dose) and for children in study II (pharmacokinetic sampling was conducted pre-dose followed byassessment at multiple time points up to 72 hours (3 days) post-dose). Tables 5 and 6 present thepharmacokinetic parameters calculated from the paediatric data of subjects less than 18 years of age.

Table 5: Pharmacokinetic parameters of ELOCTA for paediatrics using the one-stage clotting assay

Study II Study I*

Pharmacokinetic<6 years 6 to <12 years 12 to <18 yearsparameters1

N = 23 N = 31 N = 11

Incremental Recovery 1.90 2.30 1.81(IU/dL per IU/kg) (1.79-2.02) (2.04-2.59) (1.56-2.09)

AUC/Dose 28.9 38.4 38.2(IU*h/dL per IU/kg) (25.6-32.7) (33.2-44.4) (34.0-42.9)t½ (h) 12.3 13.5 16.0(11.0-13.7) (11.4-15.8) (13.9-18.5)

MRT (h) 16.8 19.0 22.7(15.1-18.6) (16.2-22.3) (19.7-26.1)

CL (mL/h/kg) 3.46 2.61 2.62(3.06-3.91) (2.26-3.01) (2.33-2.95)

Vss (mL/kg) 57.9 49.5 59.4(54.1-62.0) (44.1-55.6) (52.7-67.0)1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; AUC = area under the FVIII activity time curve; t½ = terminalhalf-life;

CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state

*Pharmacokinetic parameters in 12 to <18 years included subjects from all the arms in Study I with differentsampling schemes

Table 6: Pharmacokinetic parameters of ELOCTA for paediatrics using the chromogenic assay

Study II Study I*

Pharmacokinetic<6 years 6 to <12 years 12 to <18 yearsparameters1

N = 24 N = 27 N = 11

Incremental Recovery 1.88 2.08 1.91(IU/dL per IU/kg) (1.73-2.05) (1.91-2.25) (1.61-2.27)

AUC/Dose 25.9 32.8 40.8(IU*h/dL per IU/kg) (23.4-28.7) (28.2-38.2) (29.3-56.7)t½ (h) 14.3 15.9 17.5(12.6-16.2) (13.8-18.2) (12.7-24.0)

MRT (h) 17.2 20.7 23.5(15.4-19.3) (18.0-23.8) (17.0-32.4)

CL (mL/h/kg) 3.86 3.05 2.45(3.48-4.28) (2.62-3.55) (1.76-3.41)

Vss (mL/kg) 66.5 63.1 57.6(59.8-73.9) (56.3-70.9) (50.2-65.9)1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; AUC = area under the FVIII activity time curve; t½ = terminalhalf-life;

CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state

* Pharmacokinetic parameters in 12 to <18 years included subjects from all the arms in Study I with differentsampling schemes

In comparison with adolescents and adults, children less than 12 years of age may have a higher clearanceand a shorter half-life which is consistent with observations of other coagulation factors. These differencesshould be taken into account when dosing.

Non-clinical data reveal no special hazard for humans based on acute and repeated dose toxicity studies(which included assessments of local toxicity and safety pharmacology). Studies to investigate genotoxicity,carcinogenicity, toxicity to reproduction or embryo-foetal development have not been conducted. In aplacental transfer study, ELOCTA has been shown to cross the placenta in small amounts in mice.

Sucrose

Sodium chloride

Histidine

Calcium chloride dihydrate

Polysorbate 20

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

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

Only the provided infusion set should be used because treatment failure can occur as a consequence ofcoagulation factor VIII adsorption to the internal surfaces of some injection equipment.

Unopened vial5 years

During the shelf-life, the product may be stored at room temperature (up to 30°C) for a single period notexceeding 6 months. The date that the product is removed from refrigeration should be recorded on thecarton. After storage at room temperature, the product may not be returned to the refrigerator. Do not usebeyond the expiry date printed on the vial or six months after removing the carton from refrigeration,whichever is earlier.

After reconstitution, chemical and physical stability has been demonstrated for 6 hours when stored at roomtemperature (up to 30°C). Protect product from direct sunlight. After reconstitution, if the product is not usedwithin 6 hours, it must be discarded. From a microbiological point of view, the product should be usedimmediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use arethe responsibility of the user.

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect fromlight.

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

Each pack contains:

- powder in a type 1 glass vial with a chlorobutyl rubber stopper

- 3 mL solvent in a type 1 glass pre-filled syringe with a bromobutyl rubber plunger stopper

- a plunger rod

- a sterile vial adapter for reconstitution

- a sterile infusion set

- two alcohol swabs

- two plasters

- one gauze pad.

Pack size of 1.

The vial of lyophilised product powder for injection must be reconstituted with the supplied solvent (waterfor injections) from the pre-filled syringe using the sterile vial adapter for reconstitution.

The vial should be gently swirled until all of the powder is dissolved.

Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior toadministration. The solution should be clear to slightly opalescent and colourless. Do not use solutions thatare cloudy or have deposits.

Additional information on reconstitution and administration:

ELOCTA is administered by intravenous (IV) injection after dissolving the powder for injection with thesolvent supplied in the pre-filled syringe. ELOCTA pack contains:

A) 1 Powder vial

B) 3 mL solvent in pre-filled syringe

C) 1 Plunger rod

D) 1 Vial adapter

E) 1 Infusion set

F) 2 Alcohol swabs

G) 2 Plasters

H) 1 Gauze pad

ELOCTA should not be mixed with other solutions for injection or infusion.

Wash your hands before opening the pack.

1. Check the name and strength of the package, to make sure it contains the correct medicine.

Check the expiry date on the ELOCTA carton. Do not use if the medicine has expired.

2. If ELOCTA has been stored in a refrigerator, allow the vial of ELOCTA (A) and the syringewith solvent (B) to reach room temperature before use. Do not use external heat.

3. Place the vial on a clean flat surface. Remove the plastic flip-topcap from the ELOCTA vial.

4. Wipe the top of the vial with one of the alcohol swabs (F)provided in the pack, and allow to air dry. Do not touch the top ofthe vial or allow it to touch anything else once wiped.

5. Peel back the protective paper lid from the clear plastic vial adapter (D). Do not remove theadapter from its protective cap. Do not touch the inside of the vial adapter package.

6. Place the vial on a flat surface. Hold the vial adapter in itsprotective cap and place it squarely over the top of the vial. Pressdown firmly until the adapter snaps into place on top of the vial,with the adapter spike penetrating the vial stopper.

7. Attach the plunger rod (C) to the solvent syringe by inserting thetip of the plunger rod into the opening in the syringe plunger. Turnthe plunger rod firmly clockwise until it is securely seated in thesyringe plunger.

8. Break off the white, tamper-resistant, plastic cap from the solventsyringe by bending at the perforation cap until it snaps off. Set thecap aside by placing it with the top down on a flat surface. Do nottouch the inside of the cap or the syringe tip.

9. Lift the protective cap away from the adapter and discard.

10. Connect the solvent syringe to the vial adapter by inserting the tipof the syringe into the adapter opening. Firmly push and turn thesyringe clockwise until it is securely connected.

11. Slowly depress the plunger rod to inject all the solvent into the

ELOCTA vial.

12. With the syringe still connected to the adapter and the plunger rodpressed down, gently swirl the vial until the powder is dissolved.

Do not shake.

13. The final solution must be inspected visually before administration. The solution should appearclear to slightly opalescent and colourless. Do not use the solution if cloudy or contains visibleparticles.

14. Ensuring that the syringe plunger rod is still fully pressed down,invert the vial. Slowly pull on the plunger rod to draw back all thesolution through the vial adapter into the syringe.

15. Detach the syringe from the vial adapter by gently pulling andturning the syringe counterclockwise.

Note: If you use more than one vial of ELOCTA per injection, each vial should be prepared separatelyas per the previous instructions (steps 1 to 13) and the solvent syringe should be removed, leaving thevial adapter in place. A single large luer lock syringe may be used to draw back the prepared contentsof each of the individual vials.

16. Discard the vial and the adapter.

Note: If the solution is not to be used immediately, the syringe cap should be carefully put back on thesyringe tip. Do not touch the syringe tip or the inside of the cap.

After preparation, ELOCTA can be stored at room temperature for up to 6 hours before administration.

After this time, the prepared ELOCTA should be discarded. Protect from direct sunlight.

Administration (Intravenous injection):

ELOCTA should be administered using the infusion set (E) provided in this pack.

1. Open the infusion set package and remove the cap at the end ofthe tubing. Attach the syringe with the prepared ELOCTAsolution to the end of the infusion set tubing by turningclockwise.

2. If needed apply a tourniquet and prepare the injection site by wiping the skin well with theother alcohol swab provided in the pack.

3. Remove any air in the infusion set tubing by slowly depressing on the plunger rod until liquidhas reached the infusion set needle. Do not push the solution through the needle. Remove theclear plastic protective cover from the needle.

4. Insert the infusion set needle into a vein as instructed by your doctor or nurse and remove thetourniquet. If preferred, you may use one of the plasters (G) provided in the pack to hold theplastic wings of the needle in place at the injection site. The prepared product should beinjected intravenously over several minutes. Your doctor may change your recommendedinjection rate to make it more comfortable for you.

5. After completing the injection and removing the needle, youshould fold over the needle protector and snap it over the needle.

6. Please safely dispose of the used needle, any unused solution, the syringe and the empty vialin an appropriate medical waste container as these materials may hurt others if not disposed ofproperly. Do not reuse equipment.

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

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

EU/1/15/1046/001

EU/1/15/1046/002

EU/1/15/1046/003

EU/1/15/1046/004

EU/1/15/1046/005

EU/1/15/1046/006

EU/1/15/1046/007

EU/1/15/1046/008

Date of first authorisation: 19 November 2015

Date of latest renewal: 19 August 2020

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

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