ELOCTA, INN-Efmoroctocog Alfa

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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

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.

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.

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 / Factor VIII level Frequency of doses (hours)/ Duration of Type of surgical procedure required (%) (IU/dL) therapy (days) Haemorrhage Early haemarthrosis, muscle 20-40 Repeat injection every 12 to 24 hours for at bleeding or oral bleeding least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. 1

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

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

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

Major surgery 80-100 Repeat injection every 8 to 24 hours as (pre- and post-operative) 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 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.

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 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.

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 with ELOCTA 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 lactation 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 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).

6 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 Uncommon Dizziness Uncommon Dysgeusia Uncommon Cardiac disorders Bradycardia Uncommon Vascular disorders Hypertension Uncommon Hot flush Uncommon 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 Uncommon Myalgia Uncommon Back pain Uncommon Joint swelling Uncommon General disorders and administration site conditions Malaise Uncommon Chest pain Uncommon Feeling cold Uncommon 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 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 the national reporting system listed in Appendix V.

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

7 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 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 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 evaluated 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 evaluable 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 evaluable 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 evaluable 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).

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 ELOCTA 1 Pharmacokinetic parameters (95% CI)

N=28 2.24 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) 108 Cmax (IU/dL) (101-115) 1.95 CL (mL/h/kg) (1.71-2.22) 19.0 t½ (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 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 ELOCTA Pharmacokinetic parameters1 (95% CI)

N=27 2.49 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) 131 Cmax (IU/dL) (104-165) 2.11 CL (mL/h/kg) (1.85-2.41) 20.9 t½ (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 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 Study II Study I* Pharmacokinetic <6 years 6 to <12 years 12 to <18 years parameters1 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) inMRT (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 = 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 Study II Study I* Pharmacokinetic <6 years 6 to <12 years 12 to <18 years parameters1 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 = 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 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.

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 and special equipment for use, administration or implantation

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.

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.

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.

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 november 2015

10. DATE OF REVISION OF THE TEXT

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

ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

Biogen Inc 250 Binney Street Cambridge, MA 02142 United States

Name and address of the manufacturer responsible for batch release

Swedish Orphan Biovitrum AB (publ) Strandbergsgatan 49 SE-112 76 Stockholm Sweden

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

• Periodic safety update reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

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 efmoroctocog alfa recombinant coagulation factor VIII, Fc fusion protein

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Powder: 250 IU efmoroctocog alfa (approx. 83 IU/mL after reconstitution)

Powder: 500 IU efmoroctocog alfa (approx. 167 IU/mL after reconstitution)

Powder: 750 IU efmoroctocog alfa (approx. 250 IU/mL after reconstitution)

Powder: 1000 IU efmoroctocog alfa (approx. 333 IU/mL after reconstitution)

Powder: 1500 IU efmoroctocog alfa (approx. 500 IU/mL after reconstitution)

Powder: 2000 IU efmoroctocog alfa (approx. 667 IU/mL after reconstitution)

Powder: 3000 IU efmoroctocog alfa (approx. 1000 IU/mL after reconstitution)

3. LIST OF EXCIPIENTS

Powder: sucrose, sodium chloride, L-Histidine, calcium chloride dihydrate, polysorbate 20, sodium hydroxide, hydrochloric acid.

Solvent: water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for solution for injection

Content: 1 powder vial, 3 mL solvent in pre-filled syringe, 1 plunger rod, 1 vial adapter, 1 infusion set, 2 alcohol swabs, 2 plasters, 1 gauze.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use, after reconstitution. Read the package leaflet before use.

An instructional video on how to prepare and administer ELOCTA is available by scanning the QR code with a smartphone or via the website.

QR code to be included+ http://www.elocta-instructions.com

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

Use within 6 hours after reconstitution.

9. SPECIAL STORAGE CONDITIONS

Keep the vial in the outer carton in order to protect from light. Store in a refrigerator. Do not freeze. Can be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be returned to refrigerator after storage at room temperature. Date removed from refrigerator:

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Swedish Orphan Biovitrum AB (publ) SE-112 76 Stockholm Sweden

12. 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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

ELOCTA 250

ELOCTA 500

ELOCTA 750

ELOCTA 1000

ELOCTA 1500

ELOCTA 2000

ELOCTA 3000

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

ELOCTA 250 IU powder for solution for injection

ELOCTA 500 IU powder for solution for injection

ELOCTA 750 IU powder for solution for injection

ELOCTA 1000 IU powder for solution for injection

ELOCTA 1500 IU powder for solution for injection

ELOCTA 2000 IU powder for solution for injection

ELOCTA 3000 IU powder for solution for injection efmoroctocog alfa recombinant coagulation factor VIII IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

250 IU

500 IU

750 IU

1000 IU

1500 IU

2000 IU

3000 IU

6. OTHER

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Solvent for ELOCTA water for injections

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

3 mL

6. OTHER

B. PACKAGE LEAFLET

Package leaflet: information for the user

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

efmoroctocog alfa (recombinant coagulation factor VIII)

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What ELOCTA is and what it is used for 2. What you need to know before you use ELOCTA 3. How to use ELOCTA 4. Possible side effects 5. How to store ELOCTA 6. Contents of the pack and other information 7. Instructions for preparation and administration

1. What ELOCTA is and what it is used for

ELOCTA contains the active substance efmoroctocog alfa, a recombinant coagulation factor VIII, Fc fusion protein. Factor VIII is a protein produced naturally in the body and is necessary for the blood to form clots and stop bleeding. ELOCTA is a medicine used for the treatment and prevention of bleeding in all age groups of patients with haemophilia A (inherited bleeding disorder caused by factor VIII deficiency).

ELOCTA is prepared by recombinant technology without addition of any human- or animal-derived components in the manufacturing process.

How ELOCTA works In patients with haemophilia A, factor VIII is missing or not working properly. ELOCTA is used to replace the missing or deficient factor VIII. ELOCTA increases factor VIII level in the blood and temporarily corrects the bleeding tendency.

2. What you need to know before you use ELOCTA

Do not use ELOCTA: • if you are allergic to efmoroctocog alfa or any other ingredients of this medicine (listed in section 6).

Warnings and precautions Talk to your doctor, pharmacist or nurse before using ELOCTA.

• There is a small chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to ELOCTA. Signs of allergic reactions may include generalised itching, hives, tightness of the chest, difficulty breathing and low blood pressure. If any of these symptoms occur, stop the injection immediately and contact your doctor.

• The formation of inhibitors (antibodies) is a known complication that can occur during treatment with all factor VIII medicines. These inhibitors, especially at high levels, stop the treatment working properly and you or your child will be monitored carefully for the development of these inhibitors. If your or your child’s bleeding is not being controlled with ELOCTA, tell your doctor immediately.

Catheter-related complications If you require a central venous access device (CVAD), risk of CVAD-related complications including local infections, presence of bacteria in the blood and catheter site thrombosis should be considered.

Documentation It is strongly recommended that every time ELOCTA is given, the name and batch number of the product are recorded.

Other medicines and ELOCTA Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines No effects on ability to drive or use of machines have been observed.

ELOCTA contains sodium This medicinal product contains 14 mg sodium per vial after preparation. Talk to your doctor if you are on a controlled sodium diet.

3. How to use ELOCTA

Treatment with ELOCTA will be started by a doctor who is experienced in the care of patients with haemophilia. Always use this medicine exactly as your doctor has told you (see section 7). Check with your doctor, pharmacist or nurse if you are not sure.

ELOCTA is given as an injection into a vein. Your doctor will calculate your dose of ELOCTA (in International Units or “IU”) depending on your individual needs for factor VIII replacement therapy and on whether it is used for prevention or treatment of bleeding. Talk to your doctor if you think that your bleeding is not being controlled with the dose you receive.

How often you need an injection will depend on how well ELOCTA is working for you. Your doctor will perform appropriate laboratory tests to make sure that you have adequate factor VIII levels in your blood.

Treatment of bleeding The dose of ELOCTA is calculated depending on your body weight and the factor VIII levels to be achieved. The target factor VIII levels will depend on the severity and location of the bleeding.

Prevention of bleeding • The usual dose of ELOCTA is 50 IU per kg of body weight, given every 3 to 5 days. The dose may be adjusted by your doctor in the range of 25 to 65 IU per kg of body weight. In some cases, especially in younger patients, shorter dosing intervals or higher doses may be necessary.

Use in children and adolescents ELOCTA can be used in children and adolescents of all ages. In children below the age of 12, higher doses or more frequent injections may be needed.

If you use more ELOCTA than you should Tell your doctor as soon as possible. You should always use ELOCTA exactly as your doctor has told you, check with your doctor, pharmacist or nurse if you are not sure.

If you forget to use ELOCTA Do not take a double dose to make up for a forgotten dose. Take your dose as soon as you remember and then resume your normal dosing schedule. If you are not sure what to do, ask your doctor or pharmacist.

If you stop using ELOCTA Do not stop using ELOCTA without consulting your doctor. If you stop using ELOCTA you may no longer be protected against bleeding or a current bleed may not stop. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If severe, sudden allergic reactions (anaphylactic reaction) occur, the injection must be stopped immediately. You must contact your doctor immediately if you experience any of the following symptoms of allergic reactions: swelling of the face, rash, generalised itching, hives, tightness of the chest, difficulty breathing, burning and stinging at the injection site, chills, flushing, headache, low blood pressure, general feeling of being unwell, nausea, restlessness and fast heartbeat, feeling dizzy or loss of consciousness.

For patients who have received previous treatment with factor VIII (more than 150 days of treatment) inhibitor antibodies (see section 2) may form uncommonly (less than 1 in 100 patients). If this happens your medicine may stop working properly and you may experience persistent bleeding. If this happens, you should contact your doctor immediately.

The following side effects may occur with this medicine.

Uncommon side effects (may affect up to 1 in 100 people): headache, dizziness, taste alteration, slow heartbeat, high blood pressure, hot flushes, vascular pain after injection, cough, abdominal pain, rash, joint swelling, muscle pain, back pain, joint pain, general discomfort, chest pain, feeling cold, feeling hot and low blood pressure.

Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store ELOCTA

Keep this medicine out of the sight and reach of children.

Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light.

Alternatively, ELOCTA may be stored at room temperature (up to 30°C) for a single period not exceeding 6 months. Please record on the carton the date that ELOCTA is removed from the refrigerator and set at room temperature. After storage at room temperature, the product must not be put back in the refrigerator.

Do not use this medicine after the expiry date which is stated on the carton and the vial label after “EXP”. The expiry date refers to the last day of that month. Do not use this medicine if it has been stored at room temperature for longer than 6 months.

Once you have prepared ELOCTA it should be used right away. If you cannot use the prepared ELOCTA solution immediately, it should be used within 6 hours. Do not refrigerate the prepared solution. Protect the prepared solution from direct sunlight.

The prepared solution will be clear to slightly opalescent and colourless. Do not use this medicine if you notice that it is cloudy or contains visible particles.

Discard any unused solution appropriately. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What ELOCTA contains

Powder: • The active substance is efmoroctocog alfa (recombinant coagulation factor VIII, Fc fusion protein). Each vial of ELOCTA contains nominally 250, 500, 750, 1000, 1500, 2000 or 3000 IU efmoroctocog alfa. • The other ingredients are sucrose, sodium chloride, L-Histidine, calcium chloride dihydrate, polysorbate 20, sodium hydroxide and hydrochloric acid. If you are on a controlled sodium diet see section 2.

Solvent: 3 mL water for injections

What ELOCTA looks like and contents of the pack

ELOCTA is provided as a powder and solvent for solution for injection. The powder is a white to off-white powder or cake. The solvent provided for preparation of the solution to inject, is a clear, colourless solution. After preparation, the solution to inject is clear to slightly opalescent and colourless.

Each pack of ELOCTA contains 1 powder vial, 3 mL solvent in pre-filled syringe, 1 plunger rod, 1vial adapter, 1 infusion set, 2 alcohol swabs, 2 plasters and 1 gauze pad.

Marketing Authorisation Holder and Manufacturer Swedish Orphan Biovitrum AB (publ) SE-112 76 Stockholm, Sweden

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva Swedish Orphan Biovitrum BVBA Oy Swedish Orphan Biovitrum Ab c/o UAB CentralPharma Communications Tél/Tel: + 32 2880 6119 Tel: +370 5 2430444 e-mail: [email protected] e-mail: [email protected]

България Luxembourg/Luxemburg Cyидиш Орфан Биовитрум Swedish Orphan Biovitrum BVBA Клон България ООД Тел.: +420 257 222 034 Tél/Tel: + 32 2880 6119 e-mail: [email protected] e-mail: [email protected]

Česká republika Magyarország Swedish Orphan Biovitrum s.r.o. Swedish Orphan Biovitrum s.r.o. Magyarországi Fióktelepe Tel: +420 257 222 034 Tel: +420 257 222 034 e-mail: [email protected] e-mail: [email protected]

Danmark Malta Swedish Orphan Biovitrum A/S Swedish Orphan Biovitrum S.r.l. Tlf: + 45 32 96 68 69 Τel: +39 0521 19 111 e-mail: [email protected] e-mail: [email protected]

Deutschland Nederland Swedish Orphan Biovitrum GmbH Swedish Orphan Biovitrum BVBA Tel: +49 89 55066760 Tel: + 32 288 06119 e-mail: [email protected] e-mail: [email protected]

Eesti Norge Oy Swedish Orphan Biovitrum Ab Swedish Orphan Biovitrum AS c/o CentralPharma Communications OÜ Tel. +372 6 015 540 Tlf: +47 66 82 34 00 e-mail: [email protected] e-mail: [email protected]

Ελλάδα Österreich Swedish Orphan Biovitrum S.r.l. Swedish Orphan Biovitrum GmbH Τηλ: +39 0521 19 111 Tel: +49 89 55066760 e-mail: [email protected] e-mail: [email protected]

España Polska Swedish Orphan Biovitrum S.L Swedish Orphan Biovitrum Sp. z o.o. Oddział w Polsce Tel: + 34 913 91 35 80 Tel: +420 257 222 034 e-mail: [email protected] e-mail: [email protected]

France Portugal Swedish Orphan Biovitrum SARL Swedish Orphan Biovitrum S.L Tél: +33 1 85 78 03 40 Tel: + 34 913 91 35 80 e-mail: [email protected] e-mail: [email protected]

Hrvatska România SWEDISH ORPHAN BIOVITRUM, Glavna Swedish Orphan Biovitrum s.r.o. Praga - Sucursala Podružnica Zagreb Bucuresti Tel: +420 257 222 034 Tel: +420 257 222 034 e-mail: [email protected] e-mail: [email protected]

Ireland Slovenija Swedish Orphan Biovitrum Ltd Swedish Orphan Biovitrum s.r.o. - Podružnica v Sloveniji Tel: + 44 1223 891854 Tel: +420 257 222 034 e-mail: [email protected] e-mail : [email protected]

Ísland Slovenská republika Swedish Orphan Biovitrum A/S Swedish Orphan Biovitrum o.z. Tlf: + 45 32 96 68 69 Tel: +420 257 222 034 e-mail: [email protected] e-mail: [email protected]

Italia Suomi/Finland Swedish Orphan Biovitrum S.r.l. Oy Swedish Orphan Biovitrum Ab Tel: +39 0521 19 111 Puh/Tel: +358 201 558 840 e-mail: [email protected] e-mail: [email protected]

Κύπρος Sverige Swedish Orphan Biovitrum S.r.l. Swedish Orphan Biovitrum AB (publ) Τηλ: +39 0521 19 111 Tel: +46 8 697 20 00 e-mail: [email protected] e-mail: [email protected]

Latvija United Kingdom Oy Swedish Orphan Biovitrum Ab Swedish Orphan Biovitrum Ltd c/o CentralPharma Communications SIA Tel. +371 67 450 497 Tel: +44 1223 891854 e-mail: [email protected] e-mail: [email protected]

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.

Please turn the leaflet over for section 7. Instructions for preparation and administration

7. Instructions for preparation and administration

ELOCTA is administered by intravenous (IV) injection after dissolving the powder for injection with the solvent 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 31

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

Wash your hands before opening the pack

Preparation:

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 syringe with 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-top cap 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 of the 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 the adapter from its protective cap. Do not touch the inside of the vial adapter package.

6. Hold the vial adapter in its protective cap and place it squarely over the top of the vial. Press down 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 the tip of the plunger rod into the opening in the syringe plunger. Turn the plunger rod firmly clockwise until it is securely seated in the syringe plunger.

8. Break off the white, tamper-resistant, plastic cap from the solvent syringe by bending at the perforation cap until it snaps off. Set the cap aside by placing it with the top down on a flat surface. Do not touch 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 tip of the syringe into the adapter opening. Firmly push and turn the syringe 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 rod pressed 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 appear clear to slightly opalescent and colourless. Do not use the solution if cloudy or contains visible particles.

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 the solution through the vial adapter into the syringe.

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

Note: If you use more than one vial of ELOCTA per injection, each vial should be prepared separately as per the previous instructions (steps 1 to 13) and the solvent syringe should be removed, leaving the vial adapter in place. A single large luer lock syringe may be used to draw back the prepared contents of 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 the syringe 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 of the tubing. Attach the syringe with the prepared ELOCTA solution to the end of the infusion set tubing by turning clockwise.

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

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

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

5. After completing the injection and removing the needle, you should 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 vial in an appropriate medical waste container as these materials may hurt others if not disposed of properly. Do not reuse equipment.

ANNEX IV

SCIENTIFIC CONCLUSIONS

Scientific conclusions Treatment of congenital haemophilia is currently based on prophylactic or on-demand replacement therapy with coagulation factor VIII (FVIII). FVIII replacement therapy can be generally categorised into two broad classes of products; plasma derived (pdFVIII) and recombinant (rFVIII) FVIII. A wide range of individual pdFVIII and rFVIII products are authorised for use in the European Union. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralise FVIII activity, causing loss of bleeding control. Treatment of patients who have developed inhibitors requires careful individual management and can be resistant to therapy. Treatment with both pdFVIII and rFVIII can lead to development of inhibitors (tested with the Nijmegen method of the Bethesda assay and defined as ≥0.6 Bethesda units (BU) for “a low titre” inhibitor and >5 BU for a “high-titre” inhibitor). The occurrence of inhibitor development in haemophilia A patients receiving FVIII products mostly occurs in previously-untreated patients (PUPs) or minimally treated patients (MTPs) who are still within the first 50 days of exposure (EDs) to the treatment. Inhibitors are less likely to occur in previously-treated patients (PTPs). The known risk factors for inhibitor development can be grouped into patient and treatment-related factors: • Patient-related risk factors include type of F8 gene mutation, severity of haemophilia, ethnicity, family history of inhibitor development and possibly HLA-DR (Human Leukocyte Antigen - antigen D Related) constitution. • Treatment-related factors include intensity of exposure, number of exposure days (EDs), on demand treatment posing a greater risk than prophylaxis, particularly in the context of danger signals such as trauma or surgery, and young age at first treatment poses a higher risk. Whether there are significant differences in the risk of inhibitor development between different types of FVIII replacement product remains an area of uncertainty. Differences between products in each FVIII class and consequently differential risks between individual products, are biologically plausible. The pdFVIII class consists of products with or without Von Willebrand Factor (VWF), and those with VWF contain a range of VWF levels. Some experimental studies have suggested a role for VWF in protecting FVIII epitopes from recognition by the antigen-presenting cells, thereby reducing immunogenicity, although this remains theoretical. VWF is not present in rFVIII, but there is significant heterogeneity within the rFVIII class for instance due to the different manufacturing processes used, with a wide range of products from different manufacturers produced over the past 20 years. These different manufacturing processes (including the different cell lines used to engineer the rFVIII products) can in theory lead to differential immunogenicity. In May 2016, an open-label, randomised controlled trial aimed at addressing the incidence of inhibitors between the two classes (pdFVIII vs. rFVIII products) was published in the New England Journal of Medicine1. This trial, known as the SIPPET study (“Survey of Inhibitors in Plasma-Product Exposed Toddlers”) was conducted to evaluate the relative risk of inhibitors in patients treated with pdFVIII compared to rFVIII. It found that patients treated with rFVIII products had an 87% higher incidence of all inhibitors than those treated with pdFVIII (which contained VWF) (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). On 6 July 2016 Paul-Ehrlich-Institut Germany initiated a referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, and requested the PRAC to assess the potential impact of the results of the SIPPET study on the marketing authorisations of relevant FVIII products and to issue a recommendation on whether these should be maintained, varied, suspended or revoked and whether any risk

1 F. Peyvandi et al. “A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A” N Engl J Med. 2016 May 26;374(21):2054-64)

37 minimisation measures should be implemented. The referral focuses on the risk of inhibitor development in PUPs. Further to the recent publication on the SIPPET study, the MAHs were requested to assess the potential impact of the results of this study and other relevant safety data on inhibitor development in PUPs on the MA of their FVIII product including consideration on risk minimisation measures. The lead authors of the SIPPET study were also invited to respond to a list of questions regarding the study methods and findings and to present their conclusions at the February 2017 PRAC plenary meeting. Information submitted by the lead authors of the SIPPET study during the course of the referral was also taken into consideration by PRAC in reaching its conclusion.

Clinical discussion

Published observational studies The responses of MAHs referred to a range of published observational studies (the CANAL, RODIN, FranceCoag, UKHCDO, amongst others) which have sought to evaluate any differential risks of inhibitor development between the classes of pdFVIII and rFVIII, as well as any differential risk of inhibitor development between products within the rFVIII class. These studies have yielded different results and suffer from the limitations of observational studies, and in particular from possible selection bias. The risk of inhibitor development is multifactorial (aside from any putative product-specific risk), and such studies have not always been able to collect information on relevant covariates and to adjust the analyses accordingly; residual confounding is inevitably a significant uncertainty. Furthermore, over time there have been changes in manufacturing process of individual products and changes in treatment regimens between centres, hence “like for like” comparisons between products is not always possible. These factors make control of such studies and interpretation of the results challenging. The CANAL study2 found no evidence of a class difference, including pdFVIII products with considerable quantities of von Willebrand factor; for ‘clinically relevant’ inhibitors the adjusted hazard ratio was 0.7 (95% CI 0.4-1.1), and for high titre inhibitors (≥5 BU) was 0.8 (95% CI 0.4-1.3). The RODIN/Pednet study3 also found no evidence of a class difference in inhibitor risk between all pdFVIII vs all rFVIII; for ‘clinically relevant’ inhibitors the adjusted hazard ratio was 0.96 (95% CI 0.62-1.49), and for high titre inhibitors (≥5 BU/ml) was 0.95 (95% CI 0.56-1.61). However, the study found evidence of an increased risk of inhibitors (all and high titre) for 2nd generation rFVIII octocog alfa (Kogenate FS/Helixate NexGen) compared with 3rd generation rFVIII octocog alfa (which was driven solely by data for Advate). Similar to RODIN/Pednet, the UKHCDO study found a significant increased risk of inhibitors (all and high titre) for Kogenate FS/Helixate NexGen (2nd generation rFVIII) compared to Advate (3rd generation rFVIII). Although this became non-significant when UK patients (also included in the RODIN/Pednet study were excluded. There was also evidence for an increased risk with Refacto AF (another 3rd generation rFVIII) vs Advate, but only for all inhibitor development. Like the UKHCDO study, the FranceCoag study also found no statistically significant increased risk for any rFVIII products vs Advate when French patients (also in the RODIN/Pednet study) were excluded. Prior to the current referral, it was noted that PRAC had already considered the implications of the RODIN/Pednet, the UKHCDO and the FranceCoag studies for the EU marketing authorisations for FVIII products. In 2013, PRAC had concluded that the RODIN/Pednet findings were not sufficiently robust to support a conclusion that Kogenate FS/Helixate NexGen was associated with an increased risk of developing

2 http://www.bloodjournal.org/content/109/11/4648.full.pdf 3 Gouw SC et al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231-9. - http://www.bloodjournal.org/content/121/20/4046.full.pdf

38 factor VIII inhibitors compared with other products. In 2016, PRAC had considered the findings of meta- analysis of all three studies (RODIN/Pednet, UKHCDO and FranceCoag studies), and again concluded that the currently available evidence does not confirm that Kogenate Bayer/Helixate NexGen is associated with an increased risk of factor VIII inhibitors, compared with other recombinant factor VIII products in PUPs. MAH-sponsored studies The MAHs provided an analysis of low and high titre inhibitor development in PUPs with severe haemophilia A (FVIII < 1%) from all clinical trials and observational studies conducted with their products, along with critical discussion on the limitations of these studies. The data came from a very wide range of heterogenous studies across products and over time. Many of these studies were small and not specifically designed to evaluate the inhibitor risk in PUPs with severe haemophilia A. The studies were mostly single arm and do not provide data to perform comparative analysis (either between pdFVIII and rFVIII as a class comparison, or within the rFVIII class). However, the general estimates of inhibitor rates from these studies for individual products are broadly in line with the findings from large observational studies. Of the larger and more relevant studies for pdFVIII products, inhibitor rates observed (often not stated if high or low titre) ranged from 3.5 to 33%, with most around 10-25%. However, in many cases little information was provided on the methods, patient populations and nature of the inhibitors to assess the information in the context of more recent published data. For most rFVIII products, newer and more relevant information from clinical trials in PUPs is available. Inhibitor rates in these studies range from 15 to 38% for all inhibitors and 9 to 22.6% for high titre inhibitors; i.e. within the range of ‘very common’. The PRAC also considered interim results submitted by the MAHs from ongoing studies from CSL (CRD019_5001) and Bayer (Leopold KIDS, 13400, part B.). Furthermore, the PRAC examined clinical trials and the scientific literature for de novo inhibitors in PTPs. The analysis demonstrated that the frequency of inhibitor development is much lower in PTPs compared to PUPs. The available data showed that in many studies including the EUHASS registry (Iorio A, 20174; Fischer K, 20155) the frequency could be classified as “uncommon”. The SIPPET study The SIPPET study was an open-label, randomized, multi-centre, multi-national trial investigating the incidence of neutralising allo-antibodies in patients with severe congenital haemophilia A (plasma FVIII concentration<1%) with either the use of pdFVIII or rFVIII concentrates. Eligible patients (<6 years, male, severe haemophilia A, no previous treatment with any FVIII concentrate or only minimal treatment with blood components) were included from 42 sites. The primary and secondary outcomes assessed in the study were the incidence of all inhibitors (≥0.4 BU/ml) and the incidence of high-titre inhibitors (≥5 BU/ml), respectively. Inhibitors developed in 76 patients, 50 of whom had high-titre inhibitors (≥5 BU). Inhibitors developed in 29 of the 125 patients treated with pdFVIII (20 patients had high-titre inhibitors) and in 47 of the 126 patients treated with rFVIII (30 patients had high-titre inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with pdFVIII and 44.5% (95% CI, 34.7 to 54.3) with rFVIII; the cumulative incidence of high-titre inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, rFVIII

4 Iorio A, Barbara AM, Makris M, Fischer K, Castaman G, Catarino C, Gilman E, Kavakli K, Lambert T, Lassila R, Lissitchkov T, Mauser-Bunschoten E, Mingot-Castellano ME0, Ozdemir N1, Pabinger I, Parra R1, Pasi J, Peerlinck K, Rauch A6, Roussel- Robert V, Serban M, Tagliaferri A, Windyga J, Zanon E: Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series. Haemophilia. 2017 Mar;23(2):255-263. doi: 10.1111/hae.13167. Epub 2017 Feb 15. 5 Fischer K, Lassila R, Peyvandi F, Calizzani G, Gatt A, Lambert T, Windyga J, Iorio A, Gilman E, Makris M; EUHASS participants Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Thromb Haemost. 2015 May;113(5):968-75. doi: 10.1160/TH14-10-0826. Epub 2015 Jan 8.

39 was associated with an 87% higher incidence than pdFVIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association was consistently observed in multivariable analysis. For high-titre inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). Ad hoc expert group meeting The PRAC considered the views expressed by experts during an ad-hoc meeting. The expert group was of the view that the relevant available data sources have been considered. The expert group suggested that further data are needed to establish if there are clinically relevant differences in frequency of inhibitor development between different factor VIII products and that, in principle, such data should be collected separately for individual products, as degree of immunogenicity will be difficult to generalise across the classes of products (i.e. recombinant vs. plasma-derived). The experts also agreed that the degree of immunogenicity of different products was adequately described overall with the amendments to the SmPC proposed by the PRAC highlighting the clinical relevance of inhibitor development (in particular low compared to high titre inhibitors), as well as the frequency of ‘very common’ in PUPs and ‘uncommon’ in PTPs. The experts also suggested studies which could further characterise the immunogenic properties of the factor VIII medicinal products (e.g. mechanistic, observational studies).

Discussion The PRAC considered that as a prospective randomised trial, the SIPPET study avoided many of the design limitations of the observational and registry-based studies undertaken so far to evaluate the risk of inhibitor development in PUPs. However the PRAC is of the view that there are uncertainties with regards to the findings of the SIPPET study which preclude the conclusion that there is a higher risk of inhibitor development in PUPs treated with rFVIII products than pdFVIII products studied in this clinical trial, as detailed below: • The SIPPET analysis does not allow for product-specific conclusions to be made as it relates only to a small number of certain FVIII products. The study was not designed and powered to generate sufficient product-specific data and, therefore, to draw any conclusions on the risk of inhibitor development for individual products. In particular, only 13 patients (10% of the FVIII arm) received a third generation rFVIII product. However, despite the lack of robust evidence to support differential risks between rFVIII products, differential risks cannot be excluded, as this is a heterogeneous product class with differences in composition and formulations. Therefore, there is a high degree of uncertainty around extrapolating the SIPPET findings to the entire rFVIII class, particularly for more recently-authorised rFVIII products which were not included in the SIPPET trial. • The SIPPET study has methodological limitations, with particular uncertainty around whether the randomisation process (block size of 2) may have introduced a selection bias in the study. • There were also deviations from the final protocol and statistical analysis plan. The statistical concerns include the fact that no pre-specified primary analysis has been published and the fact that the study was stopped early following the publication of the RODIN study indicating that Kogenate FS might be associated with an increased risk of inhibitor formation. Although this could not have been prevented, an early termination of an open label trial raises the possibility of investigator bias and inflation of the probability of detecting an effect that is not present. • Treatment regimens in EU are different from those in the SIPPET study. The relevance for clinical practice in the EU (and therefore for the products subject to this procedure) is therefore questioned. It is uncertain whether the findings of SIPPET can be extrapolated to the risk of inhibitors in PUPs in current clinical practice in the EU as treatment modality and intensity have been suggested as risk

factors for inhibitor development in previous studies. Importantly, the EU SmPCs do not include modified prophylaxis (as defined in the SIPPET study) as an authorised posology, and the impact of the apparent imbalance in the unspecified other combinations of treatment modality on the SIPPET findings is unclear. Therefore, it remains uncertain whether the same differential risk of inhibitor development observed in the SIPPET study would be apparent in patient populations treated in routine care in other countries where the modality of treatment (i.e. primary prophylaxis) is different from that in the study. The additional points of clarification provided by the SIPPET authors do not fully resolve this uncertainty. Having considered the abovementioned results from SIPPET, the published literature and all the information submitted by the MAHs, as well as the views expressed by experts expressed at the ad-hoc expert meeting, the PRAC concluded that: • Inhibitor development is an identified risk with both pdFVIII and rFVIII products. Although the clinical studies for some individual products have identified limited numbers of cases of inhibitor development, these tend to be small studies with methodological limitations, or studies not adequately designed to evaluate this risk. • The FVIII products are heterogenous, and the plausibility of different rates of inhibitor development between individual products cannot be excluded. • Individual studies have identified a wide range of inhibitor development across products, but the direct comparability of study results is questionable based on diversity of study methods and patient populations over time. • The SIPPET study was not designed to evaluate the risk of inhibitor development for individual products, and included a limited number of FVIII products. Due to heterogeneity across products, there is considerable uncertainty in extrapolating the findings of studies that have evaluated only class effects to individual products; and particularly to products (including more recently authorised products) which are not included in such studies. • Finally, the PRAC noted that to date most studies evaluating a differential risk of inhibitor development between classes of FVIII products suffer from a variety of potential methodological limitations and based on the available data considered there is no clear and consistent evidence to suggest differences in relative risk between classes of FVIII products. Specifically, the findings from the SIPPET study, as well as those from the individual clinical trials and observational studies included in the MAH responses, are not sufficient to confirm any consistent statistically and clinically meaningful differences in inhibitor risk between the rFVIII and pdFVIII product classes. In view of the above, the PRAC recommended the following updates of sections 4.4, 4.8 and 5.1 of the SmPC as well as sections 2 and 4 of the Package Leaflet for the FVIII products indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency) as follows: • The section 4.4 of the SmPC should be amended to include a warning on the clinical importance of monitoring patients for FVIII inhibitor development (in particular warning on the clinical consequences of low compared to high titre inhibitors). • With regards to sections 4.8 and 5.1 of the SmPC, the PRAC noted that several FVIII products currently include reference to data from study results which do not allow for a definite conclusion on the inhibitor risk for individual products. As the evidence suggests that all human FVIII products carry a risk of inhibitor development such statements should be removed. The available data supports a frequency of FVIII inhibitor development within the frequency of ‘very common’ and ‘uncommon’, for PUPs and PTPs respectively, therefore the PRAC recommends that the SmPCs should be aligned with these frequencies unless justified by product specific data. For products for which section 4.2 contains the following statement for PUPs: “

established. No data are available. >), the above frequency for PUPs should not be implemented. In relation to section 5.1, any reference to inhibitor development studies in PUPs and PTPs should be deleted unless the studies were conducted in compliance with a Paediatric Investigation Plan or the studies provide robust evidence of a frequency of inhibitors in PUP which is less than ‘very common’ or for PTPs which is different from ‘uncommon’ (as laid down in the attachments of the PRAC AR). Further to the assessment of the totality of the responses submitted by the MAH for susoctocog alfa (Obizur), the PRAC is of the opinion that the outcome of this article 31 referral procedure does not apply to this product in view of the indication of Obizur (acquired haemophilia A due to inhibitory antibodies to endogenous FVIII) and the different target population.

Benefit –risk balance Based on the current evidence from the SIPPET study, as well as data from the individual clinical trials and observational studies included in the MAH responses, and the views expressed by the experts of the ad-hoc expert meeting, the PRAC agreed that the current evidence does not provide clear and consistent evidence of any statistically and clinically meaningful differences in inhibitor risk between rFVIII and pdFVIII products. No conclusions can be drawn on any role of VWF in protecting against inhibitor development. Given these are heterogenous products, this does not preclude individual products being associated with an increased risk of inhibitor development in ongoing or future PUP studies. Individual studies have identified a wide range of inhibitor frequency in PUPs across products, and the SIPPET study was not designed to differentiate between individual products in each class. Due to very different study methods and patient populations that have been studied over time, and inconsistent findings across studies, the PRAC found that the totality of evidence does not support a conclusion that recombinant factor VIII medicines, as a class, poses a greater risk of inhibitor development than the class derived from plasma. Besides, the PRAC noted that several FVIII products currently include in their product information reference to data from study results which do not allow a definite conclusion on the inhibitor risk for individual products. As the evidence suggests that all human FVIII products carry a risk of inhibitor development, within the frequency of ‘very common’ and ‘uncommon’ for PUPs and PTPs respectively, the PRAC recommends that the SmPCs should be aligned with these frequencies unless justified by product specific data. In view of the above, the PRAC concluded that the benefit-risk balance of Factor VIII products indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency), remains favourable subject to the changes to the product information agreed (section 4.4, 4.8 and 5.1 of the SmPC).

Re-examination procedure

Following the adoption of the PRAC recommendation during the May 2017 PRAC meeting, the MAH LFB Biomedicaments expressed their disagreement with the initial PRAC recommendation. Given the detailed grounds provided by the MAH, the PRAC carried out a new assessment of the available data in the context of the re-examination. PRAC discussion on grounds for re-examination The SIPPET study was not designed to evaluate the risk of inhibitor development for individual products, and included a limited number of FVIII products. Due to heterogeneity across products, there is considerable uncertainty in extrapolating the findings of studies that have evaluated only class effects to individual 42 products; and particularly to products (including more recently authorised products) which are not included in such studies. The findings from the SIPPET study, as well as those from the individual clinical trials and observational studies, are not sufficient to confirm any consistent statistically and clinically meaningful differences in inhibitor risk between the rFVIII and pdFVIII product classes. Overall, the PRAC maintains its conclusions that standardised information on the frequency for FVIII products in PUP and PTP should be reflected in section 4.8 of the SmPC, unless another frequency range for a specific medicinal product is demonstrated by robust clinical studies for which the results would be summarised in section 5.1. Expert consultation The PRAC consulted an ad-hoc expert meeting on some of the aspects that formed part of the detailed grounds submitted by LFB Biomedicaments. Overall, the expert group supported the PRAC initial conclusions and agreed that the proposed product information provides an adequate level of information to appropriately communicate to prescribers and patients about the risk of inhibitor development. No additional communication, on risk factors for inhibitor development beyond the product information or any additional risk minimisation measures was recommended. The group also agreed that specific data about frequency of inhibitors for each product should not be included in the SmPC as the available studies are not adequately powered to draw precise conclusions on the absolute frequency for each product or on the relative frequency of inhibitors between products. The experts emphasized that collaboration between academia, industry and regulators should be encouraged to collect harmonised data through registries. PRAC conclusions In conclusion, further to the initial assessment and the re-examination procedure, PRAC maintains its conclusion that the benefit-risk balance of the human plasma derived and recombinant coagulation Factor VIII containing medicinal products remains favourable subject to the agreed changes to the product information (section 4.4, 4.8 and 5.1 of the SmPC). The PRAC adopted a recommendation on 01 September 2017 which was then considered by the CHMP, in accordance with Article 107k of Directive 2001/83/EC.

Overall summary of the scientific evaluation by the PRAC Whereas, • The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, for human plasma derived and recombinant coagulation factor VIII containing medicinal products (see Annex I and Annex A). • The PRAC considered the totality of the data submitted with regards to the risk of inhibitor development for the classes of recombinant and plasma derived FVIII products, in previously untreated patients (PUPs). This included published literature (SIPPET study6), data generated in individual clinical trials and a range of observational studies submitted by the marketing authorisation holders, including the data generated in large multicentre cohort studies, data submitted by the national competent authorities of the EU Member States as well as responses provided by the Authors of the SIPPET study. PRAC also considered grounds submitted by LFB Biomedicaments as

6 Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. The New England journal of medicine 2016 May 26;374(21):2054-64

basis for their request for re-examination of the PRAC recommendation and the views of two experts meetings held on 22 February and 3 August 2017. • The PRAC noted that the SIPPET study was not designed to evaluate the risk of inhibitor development for individual products, and included a limited number of FVIII products in total. Due to the heterogeneity across products, there is considerable uncertainty in extrapolating the findings of studies evaluating only class effects to individual products; and particularly to the products that are not included in such studies. • The PRAC also considered that studies conducted to date suffer from a variety of methodological limitations and, on balance, there is no clear and consistent evidence to suggest differences in relative risks between FVIII product classes based on available data. Specifically, the findings from the SIPPET study, as well as those from the individual clinical trials and observational studies included in the MAH responses, are not sufficient to confirm any consistent statistically and clinically meaningful differences in inhibitor risk between rFVIII and pdFVIII product classes. Given these are heterogenous products, this does not preclude individual products being associated with an increased risk of inhibitor development in ongoing or future PUP studies. • The PRAC noted that the efficacy and safety of Factor VIII products as indicated in the treatment and prophylaxis of bleeding in patients with haemophilia A have been established.Based on the available data, the PRAC considered that SmPC updates for the FVIII products are warranted: section 4.4 should be amended to include a warning on the clinical importance of monitoring patients for FVIII inhibitor development. With regards to sections 4.8 and 5.1, the PRAC noted that several FVIII products currently include reference to data from study results which do not allow a definite conclusion on the inhibitor risk for individual products. Results of clinical studies not sufficiently robust (e.g. suffering from methodolical limitations) should not be reflected in the product information on FVIIII products. The PRAC recommended changes to the product information accordingly. Besides, as the evidence suggests that all human FVIII products carry a risk of inhibitor development, within the frequency of ‘very common’ and ‘uncommon’, for PUPs and PTPs respectively, the PRAC recommended that the product information of these products should be aligned with these frequencies unless justified by product specific data. Therefore, the PRAC concluded that the benefit-risk balance of the human plasma derived and recombinant coagulation Factor VIII containing medicinal products remains favourable and recommended the variations to the terms of the marketing authorisations.

CHMP opinion Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions and grounds for recommendation.