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 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.

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 1890 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.

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 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

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 population

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

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.

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.

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 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.

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 and children.

Excipient related considerations

This medicinal product contains 0.6 mmol (or 14 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

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

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 lactation only if clearly indicated.

Fertility

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

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

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).

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. 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 233 patients with severe haemophilia A in phase III clinical studies and an extension study. The total number of exposure days was 34,746 with a median of 129 (range 1-326) 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 eva luated 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

¹ Investigator term: vascular pain after injection of ELOCTA

² One adult subject had a positive anti-Factor VIII antibody test result coincident with a single measurement of a neutralising antibody titre of 0.73 Bethesda Units/mL at Week 14. The neutralising antibody was not confirmed upon repeat testing 18 days later and was negative at subsequent visits. There was an increase in clearance (CL) at Week 14 that resolved with continued rFVIIIFc treatment.

Post Marketing Experience

In post-marketing experience, FVIII inhibitor development has been observed.

Paediatric population

No age-specific differences in adverse reactions were observed between paediatric and adults 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: medsafety@hpra.ie

No symptoms of overdose have been reported.

Pharmacotherapeutic group: 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 a 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 was eva luated 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 compared the efficacy of each of 2 prophylactic treatment regimens (individualised and weekly) to on demand treatment. The study enrolled a total of 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. In the individualised prophylaxis arm, subjects started with a twice weekly regimen consisting of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The individualised prophylaxis dose and interval were adjusted between the range of 25 to 65 IU/kg every 3 to 5 days. The weekly prophylaxis dose was 65 IU/kg. In addition, study I eva luated haemostatic efficacy in the treatment of bleeding episodes; and determined haemostatic efficacy during perioperative management in subjects undergoing major surgical procedures.

Individualised prophylaxis: In 117 eva luable subjects enrolled in the individualised prophylaxis arm of study I, the median dose interval was 3.51 (interquartile range 3.17-4.43) days and the median total weekly dose was 77.90 (interquartile range 72.35-91.20) IU/kg.

Median annualised bleeding rates in subjects eva luable for efficacy were 1.60 (interquartile range 0.0-4.69) for subjects in the individualised prophylaxis arm, 3.59 (1.86-8.36) for subjects in the weekly prophylaxis arm and 33.57 (21.14-48.69) for subjects in the on demand treatment arm. No bleeding episodes were experienced in 45.3% of subjects while on individualised prophylaxis and in 17.4% of subjects while on weekly prophylaxis.

Treatment of bleeding: Of the 757 bleeding events observed during study I, 87.3% were controlled with 1 injection and overall 97.8% with 2 or less injections. The median dose per injection to treat a bleeding episode was 27.35 (interquartile range 22.73-32.71) IU/kg. The median overall dose to treat a bleeding episode was 31.32 IU/kg (23.53, 52.53) in the individualised prophylaxis arm and in the weekly prophylaxis arm and 27.35 IU/kg (22.59, 32.71) in the on demand treatment arm.

Perioperative management (surgical prophylaxis): A total of 23 major surgical procedures were performed and assessed in 22 subjects in study I and an extension study. Most subjects (95.7%) received a single pre-operative dose to maintain haemostasis during surgery. The median dose per injection to maintain haemostasis during surgery was 58.3 (range 45-102) IU/kg. On the day of surgery, most subjects received a second injection. The total dose on the day of surgery ranged from 50.8 to 126.6 IU/kg.

Paediatric population<12 years of age

Study II enrolled a total of 71 previously treated male paediatric patients with severe haemophilia A. Of the 71 enrolled subjects, 69 received at least 1 dose of ELOCTA and were eva luable for efficacy. Subjects were less than 12 years of age (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 in the study.

Individualised prophylaxis: In paediatric subjects on individualised prophylaxis regimen, the median dose interval was 3.49 (interquartile range 3.46-3.51) days and the median total weekly dose was 91.63 (interquartile range 84.72-104.56) IU/kg for subjects <6 years of age and 86.88 (interquartile range 79.12-103.08) IU/kg for subjects 6 to <12 years of age. A majority of patients (78.3%) remained on a treatment regimen with alternating doses (median of 31.73 IU/kg lower dose and 55.87 IU/kg higher dose). The median overall annualised bleeding rate was 1.96 (interquartile range 0.00-3.96). No bleeding episodes were experienced in 46.4% of paediatric subjects.

Treatment of bleeding: Of the 86 bleeding events observed during study II, 81.4% were controlled with 1 injection, and overall 93.0% of bleedings episodes were controlled with 2 or fewer injections. The median dose per injection to treat a bleeding episode was 49.69 (interquartile range 29.41-56.82) IU/kg. The median overall dose to treat a bleeding episode was 54.90 IU/Kg (29.41, 71.09).

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).

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 eva luated 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

¹ Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; C_max= maximum activity; AUC = area under the FVIII activity time curve; t_½= terminal half-life; CL = clearance; V_ss = volume of distribution at steady-state; MRT = mean residence time.

Table 4: Pharmacokinetic parameters of ELOCTA using the chromogenic assay

¹ Pharmacokinetic parameters are presented in Geometric Mean (95% CI)

Abbreviations: CI = confidence interval; C_max= maximum activity; AUC = area under the FVIII activity time curve; t_½= terminal half-life; CL = clearance; V_ss = 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

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

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.

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.

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

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.

Unopened vial

3 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.

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.

Each pack contains:

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

- 3 mL solvent in a type 1 glass pre-filled syringe with a latex-free 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 (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.

Please 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.

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

Date of first authorisation: 19 November 2015

26^th March 2016

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