This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

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 5000 IU powder and solvent for solution for injection

ELOCTA 6000 IU powder and solvent for solution for injection

2. Qualitative and quantitative composition

ELOCTA 250 IU powder and solvent for solution for injection

Each vial contains nominally 250 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 83 IU efmoroctocog alfa.

ELOCTA 500 IU powder and solvent for solution for injection

Each vial contains nominally 500 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 167 IU efmoroctocog alfa.

ELOCTA 750 IU powder and solvent for solution for injection

Each vial contains nominally 750 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 250 IU efmoroctocog alfa.

ELOCTA 1000 IU powder and solvent for solution for injection

Each vial contains nominally 1000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 333 IU efmoroctocog alfa.

ELOCTA 1500 IU powder and solvent for solution for injection

Each vial contains nominally 1500 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 500 IU efmoroctocog alfa.

ELOCTA 2000 IU powder and solvent for solution for injection

Each vial contains nominally 2000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 667 IU efmoroctocog alfa.

ELOCTA 3000 IU powder and solvent for solution for injection

Each vial contains nominally 3000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 1000 IU efmoroctocog alfa.

ELOCTA 4000 IU powder and solvent for solution for injection

Each vial contains nominally 4000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 1333 IU efmoroctocog alfa.

ELOCTA 5000 IU powder and solvent for solution for injection

Each vial contains nominally 5000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 1667 IU efmoroctocog alfa.

ELOCTA 6000 IU powder and solvent for solution for injection

Each vial contains nominally 6000 IU efmoroctocog alfa. After reconstitution, each mL of solution for injection contains approximately 2000 IU efmoroctocog alfa.

The potency (International Units) is determined using the European Pharmacopoeia chromogenic assay against an in-house standard that is referenced to the WHO factor VIII standard. The specific activity of ELOCTA is 4000-10200 IU/mg protein.

Efmoroctocog alfa (recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc)) has 1,890 amino acids. It is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line without the addition of any exogenous human- or animal-derived protein in the cell culture process, purification or final formulation.

Excipient with known effect

0.6 mmol (or 14 mg) sodium per vial.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

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

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

4. Clinical particulars
4.1 Therapeutic indications

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

ELOCTA can be used for all age groups.

4.2 Posology and method of administration

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

Previously untreated patients

The safety and efficacy of ELOCTA in previously untreated patients have not yet been established. No data are available.

Posology

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

The number of units of recombinant factor VIII Fc administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (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 of normal human plasma.

On-demand treatment

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

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

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case (see section 5.2). The time to peak activity is not expected to be delayed.

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

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

Degree of haemorrhage / Type of surgical procedure

Factor VIII level required (%) (IU/dL)

Frequency of doses (hours)/ Duration of therapy (days)

Haemorrhage

Early haemarthrosis, muscle bleeding or oral bleeding

20-40

Repeat injection every 12 to 24 hours for at least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. 1

More extensive haemarthrosis, muscle bleeding or haematoma

30-60

Repeat injection every 12 to 24 hours for 3-4 days or more until pain and acute disability are resolved. 1

Life threatening haemorrhages

60-100

Repeat injection every 8 to 24 hours until threat is resolved.

Surgery

Minor surgery including tooth extraction

30-60

Repeat injection every 24 hours, for at least 1 day, until healing is achieved.

Major surgery

80-100

(pre- and post-operative)

Repeat injection every 8 to 24 hours as necessary until adequate wound healing, then therapy at least for another 7 days to maintain a 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 for pharmacokinetic data.

Prophylaxis

For long term prophylaxis, the recommended dose is 50 IU/kg every 3 to 5 days. The dose may be adjusted based on patient response in the range of 25 to 65 IU/kg (see section 5.1 and 5.2). In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Treatment monitoring

During the course of treatment, appropriate determination of factor VIII levels (by one-stage clotting or chromogenic 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 and recoveries. Dose based on bodyweight may require adjustment in underweight and overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients' blood samples, plasma factor VIII activity results can be significantly affected by both the type of the aPTT reagent and the reference standard used in the assay. This is of importance particularly when changing the laboratory and/or reagent used in the assay.

Elderly

There is limited experience in patients ≥65 years.

Paediatric population

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

Method of administration

ELOCTA is for intravenous use.

ELOCTA should be injected intravenously over several minutes. The rate of administration should be determined 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.

4.3 Contraindications

Hypersensitivity to the active substance (recombinant human coagulation factor VIII, and/or Fc domain) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Hypersensitivity

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 their physician. Patients should be informed of the signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.

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

Inhibitors

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.

The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre inhibitors which are transiently present or remain consistently low titre posing less 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 the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor 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 of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.

Cardiovascular events

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

Catheter-related complications

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

Recording of batch number

It is strongly recommended that every time that ELOCTA is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.

Paediatric population

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'.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Pregnancy and breast-feeding

Animal reproduction studies have not been conducted with ELOCTA. A placental transfer study in mice was conducted (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.

Fertility

There are no fertility data available. No fertility studies have been conducted in animals with ELOCTA.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

Hypersensitivity or allergic reactions (which may include swelling of the face, rash, hives, tightness of the chest and difficulty breathing, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hypotension, lethargy, nausea, restlessness, tachycardia) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).

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

Tabulated list of adverse reactions

The frequencies in Table 2 below were observed in a total of 276 patients with severe haemophilia A in phase III clinical studies and an extension study with a duration of up to four years. Adverse reactions were monitored for a total of 893.72 subject-years. The total number of exposure days was 80,848 with a median of 294 (range 1-735) exposure days per subject.

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

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).

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

Table 2: Adverse reactions reported for ELOCTA in clinical trials

MedDRA System Organ Class

Adverse reactions

Frequency category

Blood and lymphatic system disorders

FVIII inhibition

Uncommon (PTPs)1

Nervous system disorders

Headache

Dizziness

Dysgeusia

Uncommon

Cardiac disorders

Bradycardia

Uncommon

Vascular disorders

Hypertension

Hot flush

Angiopathy2

Uncommon

Respiratory, thoracic, and mediastinal disorders

Cough

Uncommon

Gastrointestinal disorders

Abdominal pain, lower

Uncommon

Skin and subcutaneous tissue disorders

Rash

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia

Back pain

Joint swelling

Uncommon

General disorders and administration site conditions

Malaise

Chest pain

Feeling cold

Feeling hot

Uncommon

Injury, poisoning, and procedural complications

Procedural hypotension

Uncommon

1 Frequency is based on studies with all FVIII products which included patients with severe haemophilia A.

PTPs= previously treated patients.

2 Investigator term: vascular pain after injection of ELOCTA

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

4.9 Overdose

No symptoms of overdose have been reported.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

The factor VIII/von Willebrand factor complex consists of 2 molecules (factor VIII and von Willebrand factor) with different physiological functions. Upon activation of the clotting cascade, factor VIII is converted to activated factor VIII and released from von Willebrand factor. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X on phospholipid surfaces. Activated factor X converts prothrombin 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 functional factor VIII and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result 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.

ELOCTA (efmoroctocog alfa) is a fully recombinant fusion protein with extended half-life. ELOCTA is comprised 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 that protects 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 this same naturally occurring pathway to delay lysosomal degradation and allow for longer plasma half-life than endogenous factor VIII.

Clinical efficacy and safety

The safety, efficacy, and pharmacokinetics of ELOCTA were evaluated in 2 multinational, open-label, pivotal studies; a phase 3 study, referred to as Study I and a phase 3 paediatric study, referred to as Study II (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 prophylaxis arm. Subjects on on-demand therapy prior to entry either entered the individualised prophylaxis arm or were randomised 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 total time on Study I+III was 4.2 years and median no 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 I and 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) for 23 patients randomised to the on-demand treatment arm in Study I and 671 IU/kg (min 286, max 913) for 6 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 ABR of 1.67.

Of note, ABR is not comparable between different factor concentrates and between different clinical studies.

Treatment of bleeding: 2490 bleeding events were treated during Study I and III with a median dose of 43.8 IU/kg (min 13.0, max 172.8) to control each bleed. 79.2 % of first injections were rated as excellent or good by the patients.

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

Paediatric population

Study II enrolled a total of 71 previously treated male paediatric patients <12 years of age with severe haemophilia A. Of the 71 enrolled subjects, 69 received at least 1 dose of ELOCTA and were evaluable for efficacy (35 were <6 years of age and 34 were 6 to <12 years of age). The starting prophylactic regimen consisted of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. Dosing of up to 80 IU/kg and a dosing interval as short as 2 days was allowed and used in a limited number of patients. Out of 67 subjects having completed Study II, 61 enrolled onto Study III (extension study). Median total time on study II+III was 3.4 years and median no of exposure days was 332.

Prophylaxis, age <6 years: Median dose interval was 3.50 days in Study II and Study III. Median annual factor 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 and 4990 IU/kg (min 3856, max 9527) in Study III. Respective median ABR was 2.01 (min 0, max 27.2) and 1.59 (min 0, max 8.0).

12 adolescent subjects age 12 up to 18 years were included in the adult study population on prophylactic treatment. Median annual factor consumption was 5572 IU/kg (min 3849, max 7035) in Study I and 4456 IU/kg (min 3563, max 8011) in Study III. Respective median ABR was 1.92 (min 0, max 7.1) and 1.25 (min 0, max 9.5).

Treatment of bleeding: 447 bleeding events were treated during Study II and III with a median dose of 63 IU/kg (min 28, max 186) to control each bleed. 90.2 % of first injections were rated as excellent or good by the patients and their caregivers.

Immunogenicity

The immunogenicity of ELOCTA was evaluated in the clinical trial programme in 276 previously treated patients with severe haemophilia A (207 adolescents and adult and 69 paediatric patients). None of these patients developed inhibitors.

The European Medicines Agency has deferred the obligation to submit the results of studies with ELOCTA in one or more subsets of the paediatric population in the treatment of hereditary Factor VIII deficiency (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

All pharmacokinetic studies with ELOCTA were conducted in previously treated patients with severe haemophilia 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 the one-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 to 120 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

Pharmacokinetic parameters1

ELOCTA

(95% CI)

N=28

Incremental Recovery (IU/dL per IU/kg)

2.24

(2.11-2.38)

AUC/Dose

(IU*h/dL per IU/kg)

51.2

(45.0-58.4)

Cmax (IU/dL)

108

(101-115)

CL (mL/h/kg)

1.95

(1.71-2.22)

t½ (h)

19.0

(17.0-21.1)

MRT (h)

25.2

(22.7-27.9)

Vss (mL/kg)

49.1

(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 time curve; t½= terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = mean residence time.

Table 4: Pharmacokinetic parameters of ELOCTA using the chromogenic assay

Pharmacokinetic parameters1

ELOCTA

(95% CI)

N=27

Incremental Recovery (IU/dL per IU/kg)

2.49

(2.28-2.73)

AUC/Dose

(IU*h/dL per IU/kg)

47.5

(41.6-54.2)

Cmax (IU/dL)

131

(104-165)

CL (mL/h/kg)

2.11

(1.85-2.41)

t½ (h)

20.9

(18.2-23.9)

MRT (h)

25.0

(22.4-27.8)

Vss (mL/kg)

52.6

(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 time curve; t½= terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = mean residence time.

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

Paediatric population

Pharmacokinetic parameters of ELOCTA were determined for adolescents in study I (pharmacokinetic sampling 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 by assessment at multiple time points up to 72 hours (3 days) post-dose). Tables 5 and 6 present the pharmacokinetic 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

Pharmacokinetic parameters1

Study II

Study I*

<6 years

6 to <12 years

12 to <18 years

N = 23

N = 31

N = 11

Incremental Recovery (IU/dL per IU/kg)

1.90

(1.79-2.02)

2.30

(2.04-2.59)

1.81

(1.56-2.09)

AUC/Dose (IU*h/dL per IU/kg)

28.9

(25.6-32.7)

38.4

(33.2-44.4)

38.2

(34.0-42.9)

t½ (h)

12.3

(11.0-13.7)

13.5

(11.4-15.8)

16.0

(13.9-18.5)

MRT (h)

16.8

(15.1-18.6)

19.0

(16.2-22.3)

22.7

(19.7-26.1)

CL (mL/h/kg)

3.46

(3.06-3.91)

2.61

(2.26-3.01)

2.62

(2.33-2.95)

Vss (mL/kg)

57.9

(54.1-62.0)

49.5

(44.1-55.6)

59.4

(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 = terminal half-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 different sampling schemes

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

Pharmacokinetic parameters1

Study II

Study I*

<6 years

6 to <12 years

12 to <18 years

N = 24

N = 27

N = 11

Incremental Recovery (IU/dL per IU/kg)

1.88

(1.73-2.05)

2.08

(1.91-2.25)

1.91

(1.61-2.27)

AUC/Dose (IU*h/dL per IU/kg)

25.9

(23.4-28.7)

32.8

(28.2-38.2)

40.8

(29.3-56.7)

t½ (h)

14.3

(12.6-16.2)

15.9

(13.8-18.2)

17.5

(12.7-24.0)

MRT (h)

17.2

(15.4-19.3)

20.7

(18.0-23.8)

23.5

(17.0-32.4)

CL (mL/h/kg)

3.86

(3.48-4.28)

3.05

(2.62-3.55)

2.45

(1.76-3.41)

Vss (mL/kg)

66.5

(59.8-73.9)

63.1

(56.3-70.9)

57.6

(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 = terminal half-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 different sampling schemes

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

5.3 Preclinical safety data

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 a placental transfer study, ELOCTA has been shown to cross the placenta in small amounts in mice.

6. Pharmaceutical particulars
6.1 List of excipients

Powder

Sucrose

Sodium chloride

L-Histidine

Calcium chloride dihydrate

Polysorbate 20

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Solvent

Water for injections

6.2 Incompatibilities

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

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

6.3 Shelf life

Unopened vial

4 years

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

After reconstitution

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

6.4 Special precautions for storage

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

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

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

The vial of lyophilised product powder for injection must be reconstituted with the supplied solvent (water for 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.

See package leaflet for additional information on reconstitution and administration.

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

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

7. Marketing authorisation holder

Swedish Orphan Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

8. Marketing authorisation number(s)

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

EU/1/15/1046/009

EU/1/15/1046/010

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19 November 2015

10. Date of revision of the text

13/12/2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.